Conditions: HIV Infection
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 792
Healthy volunteers: no

Brief summary:
A new anti-HIV medicine (Dolutegravir) combined with 2 currently used anti-HIV medicines is non-inferior to the standard combination of medicines used in terms of efficacy and better in terms of toxicity.

Detailed description:
The ODYSSEY study was an international randomised trial evaluating dolutegravir based antiretroviral therapy (ART) versus standard of care in HIV-infected children aged less than 18 years who were starting first line treatment (ODYSSEY A) or switching to second line treatment (ODYSSEY B). Participants had visits 4 weeks and 12 weeks after randomisation and every 12 weeks subsequent of that. They were followed up for a minimum of 96 weeks. The primary objective of the study was to assess the difference in virological or clinical failure by 96 weeks between children receiving a DTG-based regimen and those on standard of care.

At the end of study visit for the randomised phase, children and carers were invited to consent to extended follow-up. Children's visit schedules and care were as per local clinic guidelines. Participants were followed up until July 2023 in this phase of the trial. The objectives of the extended follow-up were two-fold: 1. to provide safety data for ViiV Healthcare for participants who, in the opinion of the treating physician, continue to derive benefit from dolutegravir and receive dolutegravir from ViiV Healthcare where it was not available through their country's national HIV treatment programme; 2. to monitor long-term safety and effectiveness of dolutegravir versus standard of care.

Arms:
arm 1: Standard of Care (SOC) for ODYSSEY A is defined as a PI or non nucleoside transcriptase inhibitors + 2 or 3 nucleoside transcriptase inhibitor SOC for ODYSSEY B is defined as a PI or non nucleoside transcriptase inhibitor+ 2 nucleoside transcriptase inhibitors arm 2: DTG + 2 nucleoside transcriptase inhibitors

Interventions: intervention 1: Dolutegravir intervention 2: Standard of Care
Intervention descriptions: intervention 1: None intervention 2: PI or non nucleoside transcriptase inhibitors

Protocol document:
Prot_SAP_ICF_000.pdf: 
 
ODYSSEY (PENTA 20): 
A randomised trial of dolutegravir 
(DTG)-based antiretroviral therapy vs. 
standard of care (SOC) in children with 
HIV infection starting first-line or 
switching to second-line ART. 
Version: 6.0 
Date: 8th November 2019 
ISRCTN #: ISRCTN91737921 
EUDRACT #: 2014-002632-14 
NCT #: NCT02259127      
Authorised by: 
Name: Professor Ian Weller 
Role: Chair ODYSSEY Trial Steering Committee 
Signature: 
Date: 8th November 2019 
Name: Professor Carlo Giaquinto 
Role: Chair, PENTA Foundation 
Signature: 
Date:  11th November 2019


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Page ii 
GENERAL INFORMATION 
The trial will be co-ordinated and monitored by the UK Medical Research Council (MRC) Clinical Trials 
Unit at University College London (UCL), (hereafter referred to as MRC CTU) in collaboration with 
INSERM-ANRS SC10-US019, France (INSERM-ANRS) and the Program for HIV Prevention and 
Treatment, Thailand (PHPT).  Liaison between these Clinical Trials Units (CTUs) and clinical centres in 
each country will be similar to that organised for other trials conducted by the Paediatric European 
Network for the treatment of AIDS (PENTA), with a combination of direct liaison with a CTU (see 
Section 2.3) and liaison via a local co-ordinating centre.  Clinical centres in South Africa, Uganda and 
Zimbabwe will be coordinated by MRC CTU; clinical centres in US, Uganda and South Africa joining the 
trial from the International Maternal Pediatric Adolescent AIDS Clinical Trials Network (IMPAACT, US) 
will also be coordinated through MRC CTU. The trial will be supervised by the ODYSSEY Trial 
Management Group (TMG) who will report to the ODYSSEY Trial Steering Committee (TSC) (see 
Appendix XVII for the committee structure within PENTA).  The TSC may decide to terminate the trial 
for any reason including the recommendation of the Independent Data Monitoring Committee 
(IDMC). 
 
This document was constructed using the MRC CTU Protocol Template Version 7.0. The CTU 
endorses the Standard Protocol Items: Recommendations For Interventional Trials (SPIRIT) initiative. 
It describes the  
ODYSSEY (PENTA 20): trial, coordinated by the MRC CTU, INSERM-ANRS and PHPT, 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 children or young people with HIV infection.  
Every care was taken in drafting this protocol, but corrections or amendments may be necessary.  
These will be circulated to the registered investigators in the trial, but centres entering participants 
for the first time are advised to contact one of the co-ordinating CTUs to confirm they have the most 
up-to-date version.  Clinical problems relating to this trial should be addressed with the relevant CTU.   
 
COMPLIANCE 
The trial will be conducted in compliance with the approved protocol, the Declaration of Helsinki 
2013, the principles of Good Clinical Practice (GCP) as laid down by the ICH topic E6 (R2), 
Commission Clinical Trials Directive 2005/28/EC* with the implementation in national legislation in 
the UK by Statutory Instrument 2004/1031 and subsequent amendments, General Data Protection 
Regulation and the UK Data Protection Act 2018 (DPA number: Z6364106), and the UK Policy 
Framework for Health and Social Care Research.  
 
*Until the Clinical Trials Regulation EU No 536/2014 becomes applicable, the trial will be conducted 
in accordance with the Clinical Trials Directive as implemented in the UK statutory instrument. When 
the directive is repealed on the day of entry into application of the Clinical Trial Regulation the trial 
will work towards implementation of the Regulation (536/2014) following any transition period. 
 
SPONSOR 
Paediatric European Network for Treatment of AIDS (PENTA) Foundation is the trial Sponsor and has 
delegated responsibility for the overall management of the  
ODYSSEY (PENTA 20): trial to the MRC CTU at UCL, INSERM-ANRS and PHPT. Queries relating to 
Penta sponsorship of this trial should be addressed to Carlo Giaquinto, Chair of Penta 
Foundation, Torre di Ricerca Pediatrica, Corso Stati Uniti 4, Padova, 35127, Italy. 
 
 
 
CHIEF INVESTIGATORS 
Dr Pablo Rojo, Hospital 12 de Octubre, Madrid, Spain 
 
 
 


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ODYSSEY (PENTA 20) 
Page iii 
Professor Diana M Gibb, MRC CTU at UCL, London, UK 
 
FUNDING 
This study is funded by ViiV Healthcare.  MRC CTU at UCL and INSERM SC10 are supported by the MRC 
(UK) and INSERM-ANRS (France) respectively.  INSERM-ANRS supports the trial in France.  PENTA 
Foundation and EuroCoord provide support to sites in Europe. 
 
AUTHORISATIONS AND APPROVALS 
This trial will be submitted for approval by Research Ethics Committees/Institutional Review Boards 
and by all required regulatory authorities in each of the participating countries. 
 
TRIAL REGISTRATION 
This trial has been registered with EudraCT, ISRCTN and Clinicaltrials.gov.   
 
 
 
SAE REPORTING 
Within 24 hours of becoming aware of an SAE, please fax or email a 
completed Event form to the relevant CTU. Please ensure that an acknowledgment of 
receipt by the CTU is received.   
 
MRC CTU: fax: +44 (0) 20 7670 4814 or email: mrcctu.trial-odyssey@ucl.ac.uk 
 
Inserm-ANRS: fax: + 33 1 46 58 72 93 or email: penta.sc10@inserm.fr 
 
PHPT: fax: +66 53 240 913 or email: suwalai.chalermpantmetagul@phpt.org 
RANDOMISATIONS  
 
For those sites randomising directly, training will be provided for DIRECT 
RANDOMISATION ONLINE as part of the site initiation and database training. Individual 
passwords will be provided. 
 
Alternatively, sites can fax or send by password protected email the Randomisation CRF to 
the relevant CTU: 
MRC CTU, Monday to Friday 09:00 to 17:00 
Tel: +44 (0) 20 7670 4786 
Fax: +44 (0) 20 7670 4814 
Email: mrcctu.trial-odyssey@ucl.ac.uk 
 
Inserm-ANRS, Monday to Friday 09:00 to 17:00 
Tel: + 33 1 45 59 50 83 / 52 55 
Fax: + 33 1 46 58 72 93 
Email: penta.sc10@inserm.fr 
 
PHPT, Monday to Friday 09:00 to 18:00 
Tel: +66 (0) 53 814 633 240 910-12 ext. 710316 
Fax: +66 53 240 913814 269 
Email: suwalai.chalermpantmetagul@phpt.org 


ODYSSEY Protocol  
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ODYSSEY (PENTA 20) 
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SPONSOR 
 
PENTA FOUNDATION, ITALY: 
PENTA Foundation 
 
 
 
 
Torre della Ricerca Pediatrica Corso Stati Uniti 4 
 
 
 
 
Padova, 35127, Italy 
 
 
 
 
Tel: +39 049 821 5447 
 
 
STAFF:  
Chair: 
Carlo Giaquinto 
Project 
Managers: 
Tiziana Grossele 
Giulio Vecchia 
 


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ODYSSEY (PENTA 20) 
Page v 
TRIAL ADMINISTRATION AND MAIN CONTACTS  
Please direct all queries to the relevant CTU (see contacts below) in the first instance; clinical queries 
will be passed to the Medical Experts via the MRC CTU Trial Manager. 
 
MRC CTU, UK:  MRC CTU at UCL 
 
 
 
 
Institute of Clinical Trials & Methodology 
 
90 High Holborn, 2nd Floor 
 
 
London, WC1V 6LJ, UK  
 
Tel: +44 (0) 207 670 4700 
 
Email: mrcctu.trial-odyssey@ucl.ac.uk 
STAFF:  
Programme Lead: 
Diana M Gibb, MD, MSc 
Clinical Project Manager: 
Clare Shakeshaft, BA, MSc 
Trial Managers: 
Tatiana Sarfati, BSc, MSc 
Shabinah Ali, BSc, MSc 
Data Managers: 
Anne Marie Borges Da Silva, BSc 
Rachel Oguntimehin, BSc 
Trial Statistician: 
Debbie Ford, PhD 
Statisticians: 
Ben Wynne, BSc, Msc 
Ellen White, BSc, MSc 
Trial Physician: 
Anna Turkova, MRCPCH  
 
SITES: 
 Participating PENTA Centres in:  
Germany, UK, (as listed on www.penta-id.org) 
Collaborating Centres 
 Thanyawee Puthanakit, MD 
 
The HIV Netherlands Australia Thailand Research 
Collaboration (HIV-NAT), 104 Ratchadamri Road, 
Pathumwan, Bangkok 10330, Thailand 
 James Gita Hakim, FRCP  
 Kusum Nathoo, MBChB, MRCP, MSc  
 Hilda Angela Mujuru, MBChB, MMed, 
MSc 
 Mutsa Bwakura-Dangarembizi, MBChB, 
MMed, MSc  
University of Zimbabwe Clinical Research Centre 
(UZCRC),  
Box A1578 Avondale, Harare, Zimbabwe 
 
 
 Cissy Kityo Mutuluuza, MSc, MBChB  
 Victor Musiime, MBChB, MMED, PhD 
 Elizabeth Kaudha, MBChB, MMED 
Joint Clinical Research Centre (JCRC),Plot 101 
Lubowa Estates, off Entebbe road, Kampala, 
Uganda 
 Abbas Lugemwa MBChB 
Joint Clinical Research Centre (JCRC), Mbarara, P.O 
Box 40, Mbarara Regional referral Hospital, 
Mbarara, Uganda 
 Adeodata Kekitiinwa MBChB MMED 
Baylor College of Medicine Bristol Myers Squibb 
Children’s Clinical Centre of Excellence, Block 5, 
Mulago Hospital, P.O. Box 72052, Kampala, Uganda 
 Mark F. Cotton, FCPaed (SA), M.Med 
(Paed), PhD, DCH (SA), DTM&H 
Family Clinical Research Unit (FAM-CRU),  
University of Stellenbosch, Tygerberg Children’s 
Hospital, Ward J8, Francie van Zijl Avenue, Parow, 
7505, Cape Town, South Africa 
 Avy Violari, MD, FCPaed (SA) 
 
Chris Hani Baragwanath Hospital: Perinatal HIV 
Research Unit, Chris Hani Baragwanath Hospital, 


ODYSSEY Protocol  
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ODYSSEY (PENTA 20) 
Page vi 
 
 
 
P.O. Box 114, Diepkloof, 1864, Soweto, South 
Africa 
 
Perinatal HIV Research Unit, Klerksdorp/Tsepong 
Hospital Complex 
Matlosana, South Africa 
 Moherndran Archary MBChB. DCH(SA). 
FCPaeds(SA). Paeds ID (SA)  
 
 
 
 
 
 
 Nigel Klein, BSc, MBBS, MRCP, PhD, 
FRCPCH 
Durban International Clinical Research Site, 
Parkhome, Gate 1-King Edward VIII Hospital, 
Umbilo Road, Congella, Durban, KwaZulu-Natal, 
4013, South Africa 
 
Ward D1, Wentworth Hospital, Sidmouth Avenue 
Wentworth, Durban, 4052, South Africa 
 
Africa Health Research Institute (AHRI), 
Hlabisa Hospital, 60 Saunders Street,  
Hlabisa 3937, South Africa 
 
INSERM-ANRS, FRANCE:  
16 Avenue Paul Vaillant Couturier  
            
 
Villejuif Cedex, 94807, France 
 
Tel: +33 1 4559 5290 
 
 
Email: penta.sc10@inserm.fr 
 
 
STAFF: 
Project leader: 
Alexandra Compagnucci, MD  
Trial Managers: 
Yoann Riault, MSc 
Alexandra Coelho, PhD 
Christelle Koukam 
Senior Trial 
Manager: 
Yacine Saidi, PhD 
 
SITES:  
Participating PENTA Centres in:  
Portugal, and Spain (as listed on www.penta-id.org) 
 
 
PHPT, THAILAND:  
PHPT/IRD  
 
 
  
195 (3rd-4th Floor), Kaew Nawarat Rd., 
Muang, 50000 Chiang Mai, Thailand  
 
Tel: + 66 (0) 5324 0910-12 
 
Email: tim.cressey@phpt.org 
 
STAFF: 
Project leader: 
Tim Cressey, PhD 
Trial Manager: 
Suwalai Chalermpantmetagul, RN, MPH 
Trial Physician 
Specialist: 
Gonzague Jourdain, MD, PhD 
Thai Site Leader: Chaiwat Ngampiyasakul, MD 
Trial virologist   
Woottichai Khamduang, PhD 
Trial pharmacist  Asst. Prof. Dujrudee Chinwong, M.Pharm, PhD  
 


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SITES: 
 Participating PHPT Centres in:  
Thailand:  
Chaiwat Ngampiyaskul, MD 
Prapokklao Hospital, Chantaburi; 
Pornchai Techakunakorn, MD 
Phayao Hospital, Phayao 
Pradthana Ounchanum, MD 
Chiangrai Prachanukroh Hospital, Chiang Rai 
Suparat Kanjanavanit, MD 
Nakornping Hospital, Chiang Mai 
Ussanee Srirompotong, MD 
Khon Kaen Hospital, Khon Kaen; 
Sathaporn Na-Rajsima, MD 
Mahasarakam Hospital, Mahasarakam 
Woottichai Khamduang, PhD 
Faculty of Associated Medical Sciences, Chiang 
Mai University 
 
IMPAACT, US: IMPAACT Operations Center 
 
FHI 360 
 
359 Blackwell Street, Ste 200 
 
Durham, NC27701, US 
 
Email: IMPAACT.OperationsCenter@fstrf.org 
 
STAFF: 
Co-ordinator: 
Elaine Abrams, MD 
Clinical Trials 
Specialist: 
Katie McCarthy, MPH 
 
 
SITES: 
Collaborating Centres in: 
Uganda 
Linda N. Barlow-Mosha, MD, MPH, FAAP 
Philippa Musoke, MD 
Makerere University – John Hopkins University 
Research Collaboration, Upper Mulago Hill Road, 
MU-JHU Research House, Old Mulago Hill, P.O. Box 
23491, Kampala, Uganda 
 
Protocol expert: Pharmacology 
864 Department of Clinical Pharmacy and Nijmegen Institute for Infection, Inflammation and 
Immunity (N4i),  
Radboud Univ, Nijmegen Med. Ctr. Nijmegen Geert Grooteplein 10, 6525 GA Nijmegen,  
The Netherlands. 
David Burger, PhD 
Email: david.burger@radboudumc.nl 
 
Immunology/Virology Committee  
Nigel Klein, BSc, MBBS, 
MRCP, PhD, FRCPCH 
UCL Institute of Child Health, 
London, UK  
Email: n.klein@ucl.ac.uk 
Anita De Rossi, PhD 
University of Padova, Italy 
Email: anita.derossi@unipd.it 
Eleni Nastouli, FRCPCH, 
FRCPath  
UCL Division of Infection & Immunity 
Email: e.nastouli@ucl.ac.uk 
Maria Angeles Munoz 
Fernandez, PhD 
Hospital General Gregorio Marañón, 
Madrid, Spain 
 
Email: 
mmunoz.hgugm@gmail.com 
Other members to be confirmed 
 


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SUMMARY OF TRIAL 
SUMMARY INFORMATION TYPE 
SUMMARY DETAILS 
ACRONYM  
ODYSSEY (Once daily dolutegravir based ART in young people vs. 
standard therapy) 
Long Title of Trial 
A randomised trial of dolutegravir (DTG)-based antiretroviral therapy 
vs. standard of care (SOC) in children with HIV infection starting first-
line or switching to second-line ART (PENTA 20) 
Version 
5.0 
Date 
1st March 2019 
ISRCTN # 
ISRCTN91737921 
EudraCT # 
2014-002632-14 
NCT # 
NCT02259127 
Study Design 
An open-label, multi-centre, randomised (1:1), non-inferiority, Phase 
II/III, 96-week, 2-arm clinical trial to compare the efficacy and toxicity 
of DTG plus 2 NRTI vs. standard of care (SOC) in HIV-infected children 
aged less than 18 years who are starting first-line ART (ODYSSEY A) or 
switching to second-line ART (ODYSSEY B). 
Type of Participants to 
be Studied 
HIV-1 infected children younger than 18 years planning to start first-
line or second-line antiretroviral therapy 
Setting 
International 
Interventions to be 
Compared 
DTG + 2 NRTI (DTG arm) vs. SOC (SOC arm) in first-line and second-line 
antiretroviral regimens 
Study Hypothesis 
DTG + 2 NRTIs is non-inferior to SOC (NNRTI or bPI or INSTI + 2 or 3 
NRTIs) in terms of efficacy and superior in terms of toxicity profile 
Primary Outcome 
Measure(s) for the 
Randomised Phase 
Difference in proportion with failure (clinical or virological) by 96 
weeks, estimated using time to the first occurrence of any of the 
following components: 
 Insufficient virological response defined as <1 log10 drop at week 
24 and switch to second/third line ART for treatment failure 
 Viral load (VL)≥400 c/ml at or after 36 weeks confirmed by next 
visit 
 Death due to any cause 
 Any new or recurrent AIDS defining event (WHO 4) or severe WHO 
3 event, adjudicated by the Endpoint Review Committee 
Secondary Outcome 
Measure(s) for the 
Randomised Phase 
Secondary efficacy outcomes:  
 Difference in proportion with clinical or virological failure (as 
defined above) by 48 weeks 
 Time to any new or recurrent AIDS defining event (WHO 4) or 
severe WHO 3 event, confirmed by the Endpoint Review 
Committee  
 Proportion of children with VL <50 c/ml at 48 and 96 weeks  
 Proportion of children with VL <400 c/ml at 48 and 96 weeks  
 Rate of clinical events over 96 weeks: WHO 4, severe WHO 3 
events and death 
 Change in CD4 count, CD4 percentage and CD4 / CD8 ratio from 
baseline to weeks 48 and 96 
 Proportion developing new resistance mutations  
Secondary safety outcomes: 


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 Change in total cholesterol, triglycerides and lipid fractions (LDL, 
HDL) from baseline to weeks 48 and 96. Change in total 
cholesterol from baseline to week 96 will be used to formally 
assess superiority of DTG arm  vs SOC arm 
 Incidence of serious adverse events 
 Incidence of new clinical and laboratory grade 3 and 4 adverse 
events 
 Incidence of adverse events (of any grade) leading to treatment 
modification 
Other secondary outcomes: 
 Quality of life 
 Adherence and acceptability 
Randomisation 
Children starting first- and second-line ART will be randomised 
separately (both in 1:1 ratio) : 
ODYSSEY A (first-line ART):  
 
DTG + 2 NRTIs 
 
SOC (defined as NNRTI or bPI or INSTI + 2 or 3 NRTIs) 
ODYSSEY B (second-line ART): 
 
DTG + 2 NRTI 
 
SOC (defined as NNRTI or bPI or INSTI+ 2 NRTIs) 
Number of Participants 
to be Studied 
700 HIV-1 infected children, including 310 children starting first-line 
(ODYSSEY A) and 390 starting second-line ART (ODYSSEY B). At least 
60 additional children weighing 3-<14kg will be enrolled in separate 
strata.  
Duration 
Participants will be enrolled in the main trial over 96-120 weeks; with 
up to 78 weeks (July 2018 to end of 2019) to recruit participants 
weighing 3-<14kg.  Participants recruited in the main trial (≥14kg) will 
be followed until the last recruited participant reaches week 96; 
participants recruited weighing 3-<14kg will each be followed for a 
minimum of 96 weeks.  
Ancillary 
Studies/Substudies 
The following sub-studies will be performed in selected sites (see 
Section 10 for participating countries): 
TB-PK substudy will evaluate the pharmacokinetics of dolutegravir co-
administered with rifampicin in HIV/TB co-infected children.  
Weight band PK substudies WB-PK1 and WB-PK2 will be undertaken 
in children 3 to < 40 kg with the aims of simplifying doses and 
formulations of DTG using WHO weight bands. 
Immunology/virology substudy will explore mechanisms of CD4 
reconstitution, immune activation, HIV reservoir and replication in 
DTG and SOC arms. 
Qualitative substudy will investigate how best to support children and 
young people to maintain optimal adherence to second-line 
treatment.  
The Youth Trial Board will develop a model of meaningful engagement 
and participation of adolescent patient representatives in paediatric 
clinical trials. 
Folate substudy will look at possible differences in folate and vitamin 
B12 levels between the DTG and SOC arms 
Sponsor 
PENTA Foundation 
Funder 
Funded by ViiV Healthcare and the PENTA Foundation.  MRC CTU at 
UCL and INSERM SC10 are supported by the MRC (UK) and INSERM-


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Page x 
ANRS (France) respectively; INSERM-ANRS supports the trial in France; 
Eurocoord provide support for the sites in Europe 
Partners 
MRC CTU at UCL, INSERM-ANRS, PHPT, IMPAACT, Eurocoord, PENTA  
Chief Investigator 
Pablo Rojo and Diana M Gibb 


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TRIAL SCHEMA 
 
Note: 
At least 60 additional children weighing 3-<14kg will be enrolled and followed up for 96 weeks 


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 TRIAL ASSESSMENT SCHEDULE FOR RANDOMISED PHASE OF THE TRIAL 
 
 
 
WEEK 
 
Screening 
 
 
Randomisation 
0a 
(2) 
4 
12 
24 
36 
48 
60 
72 
84 
96 
 
Further follow-up  
 
Study visit at 
end of  
randomised 
phase* 
Patient information sheet and 
consent for screening 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent for trial 
enrolment 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
History and clinical assessment b  
X 
X 
(X)t 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Every 12 weeks 
X 
Tanner scale c 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
Every 24 weeks 
X 
Lipodystrophy assessment p 
 
X 
 
 
 
 
 
X 
 
 
 
X 
Every 48 weeks 
X 
Drug supply to next visit 
 
X 
(X) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Every 12 weeks 
 
HIV-1 RNA viral load d 
Xd 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
As per local practice 
Xd 
T cell lymphocyte subsets e 
X 
X 
 
X 
X 
X 
(X) 
X 
(X) 
X 
(X) 
X 
As per local practice 
X 
Biochemistry f 
X 
(X) 
(X)t 
X 
(X) 
X 
(X) 
X 
(X) 
X 
(X) 
X 
As per local practice 
X 
Haematology g 
X 
X 
(X)t 
X 
(X) 
X 
(X) 
X 
(X) 
X 
(X) 
X 
As per local practice 
X 
Lipids/glucose h 
 
Xo 
 
 
 
(X) 
 
X 
 
 
 
X 
Every 48 weeks 
X 
Bone profile i 
 
(X) 
 
 
 
 
 
(X) 
 
 
 
(X) 
(Every 48 weeks) 
(X) 
Urine dipstick j 
 
X 
 
 
 
 
 
X 
 
 
 
X 
Every 48 weeks 
X 
Quality of Life questionnaire c 
 
X 
 
 
X 
X 
 
X 
 
 
 
X 
Every 48 weeks 
X 
Pregnancy test k 
X 
Xk 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Every 12 weeks 
X 
Plasma storage l, q 
X 
X 
(X) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Every 12 weeks 
X 
Red blood cell folate (RBC)/RBC 
storage and B12/serum storage u 
 
 
 
 
 
 
 
 
 
 
 
X 
(At next clinic visit if 
the 96 week sample 
is not collected) 
 
PBMC (Cell) storage m 
 
Xm 
 
 
Xm 
 
 
Xm 
 
 
 
Xm 
 
 
Adherence questionnaire, q, r 
Xn 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Every 12 weeks 
X 
Acceptability, sleep & mood 
questionnaire q, r, v 
 
Xs 
 
X 
X 
X 
 
X 
 
X 
 
X 
Every 24 weeks 
X 


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Notes:  
(  )      Optional, not mandatory. 
* For participants recruited weighing  ≥14kg this will be after the last participant reaches 96 weeks follow-up; for participants recruited weighing <14kg this 
will be their 96 week visit which should be at or after 96 weeks. Participants receiving DTG 5mg in sites in sub-Saharan Africa (South Africa, Uganda and 
Zimbabwe) and DTG 50mg or Triumeq in Thailand (at PHPT sites and HIV-NAT) at their study visit at the end of the randomised phase will be asked to 
consent to extended follow-up in order to collect safety data so that DTG can continue to be provided to these participants. Other participants will also be 
asked to consent to extended follow-up. Please see Appendix XX for more details. 
Darker shaded boxes indicate visits where overnight fasting is required for blood lipids/glucose. 
Up to 12 mls of blood may be collected at each visit for routine assays and tests plus an additional  8-18 mls blood may be collected for storage (plasma and 
when requested, PBMCs). Total amounts drawn will depend upon the size of the child and their health, please refer to Appendix XI for the maximum 
allowable blood-draw volumes for children. 
a. 
Randomisation visit should take place within 4 weeks after the screening visit, ideally within 2 weeks 
b. 
Clinical assessment: including height, weight (and adjustment of drug doses accordingly) and mid upper arm circumference (MUAC), change in HIV 
disease stage, clinical events and presence of adverse events  
c. 
In children aged 8 or over 
d. 
Real-time viral loads will be measured on all children in ODYSSEY B at the screening visit, unless a viral load result of ≥500 c/ml dated within four weeks 
of the screening visit is available.  If such a result is not available it is mandatory that this test is done in ODYSSEY B participants. Please always ensure 
that there is enough blood taken for this assay as it is a priority test at screening for ODYSSEY B.  For children recruited in ODYSSEY A, this is not 
mandatory.  Thereafter in both ODYSSEY A and B, viral loads should be measured locally at sites according to the routine frequency, where viral loads 
are not measured in real time, they will be run retrospectively in batches on stored plasma 
e. 
CD4 and CD8 percentage and absolute, total lymphocyte count. In addition, immunophenotyping (IPT) on the same blood draw will be done at the sites 
participating in the immunology/virology substudy, and where IPT tests are available. At the other sites IPT will be done on the cell storage samples. 
f. 
Biochemistry: mandatory: creatinine, bilirubin, ALT; optional (if results are available or routinely done): AST 
g. 
Haematology: Hb, MCV, WBC, lymphocytes, neutrophils, platelets  
h. 
Lipids/Glucose: triglycerides, cholesterol (total, HDL, LDL), glucose (overnight fasting required at randomisation and weeks 24 and 48, and then every 
48 weeks, and at the study visit at the end of the randomised phase) 
i. 
Bone profile (optional): calcium, phosphate, alkaline phosphatase 
j. 
Urine dipstick: for protein and glucose, performed at randomisation and then every 48 weeks and at end of study visit 
k. 
Pregnancy test: urine sample; the test should be performed for all females of childbearing potential at screening, randomisation and all trial follow-up 
visits and at other time-points if required.   


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l. 
Plasma storage: for retrospective HIV-1 RNA viral load, resistance testing where not routinely available locally, sparse PK sampling, folate substudy and 
immunology/virology substudy. See Appendix XII, Appendix XIII, Manual of Operations (MOP) and Lab MOP for more details.  Samples may be assayed 
locally, or moved to another country. 
m. Peripheral blood mononuclear cells (PBMCs) will be stored at selected sites only, for use in the immunology/virology substudy. Please see Appendix XII, 
MOP and Lab MOP for more details. 
n. 
Baseline adherence questionnaire for patients screened for ODYSSEY B and currently taking their first-line treatment 
o. 
The glucose test at the randomisation visit may be omitted if there is a medical justification (e.g. anaemia) to limit the total volume of blood drawn.  
p. 
At selected sites bioelectrical impedance analysis (BIA) measurements will be done. 
q. 
In case of attendance at an unscheduled visit at the point of treatment failure, plasma storage and adherence and acceptability questionnaires should 
be done. (The acceptability questionnaire should also be done if treatment failure occurs at a scheduled visit where it is not normally done, e.g. week 
36). 
r. 
Adherence and acceptability questionnaires should also be completed if ART regimen is changed. 
s. 
The mood and sleep section of the acceptability questionnaire should be completed at the enrolment visit. 
t. 
Clinical assessment, haematology and biochemistry tests at week 2 are required for all children 3-<14kg and optional for children ≥14kg. 
u. 
RBC storage for RBC folate levels and serum / serum storage for B12 levels for Folate/B12 substudy at selected sites only (see section 10.5). The bloods 
will be taken from the same blood draw as used for plasma isolation and storage. 
v. 
The sleep and mood section of the acceptability questionnaire should only be completed for participants aged 6 years and over. 


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CONTENTS 
GENERAL INFORMATION .............................................................................................................. II 
SUMMARY OF TRIAL ................................................................................................................. VIII 
TRIAL SCHEMA ........................................................................................................................... 11 
TRIAL ASSESSMENT SCHEDULE FOR RANDOMISED PHASE OF THE TRIAL ...................................... 12 
CONTENTS ................................................................................................................................. 15 
ABBREVIATIONS ......................................................................................................................... 20 
1 
BACKGROUND ............................................................................................................... 23 
1.1 
DTG ADULT TRIALS ............................................................................................................ 23 
1.2 
DTG IN CHILDREN .............................................................................................................. 24 
1.3 
FIRST- AND SECOND-LINE ART OPTIONS FOR CHILDREN: THE PLACE OF DTG .................................... 25 
1.4 
DTG WITH ANTI-TUBERCULOSIS (TB) THERAPY ......................................................................... 26 
1.5 
DTG AND PREGNANCY ......................................................................................................... 26 
1.6 
DTG FORMULATIONS AND MARKETING AUTHORISATION ............................................................. 26 
1.7 
RATIONALE AND OBJECTIVES ................................................................................................ 27 
2 
SELECTION OF SITES/CLINICIANS ..................................................................................... 28 
2.1 
SITE/INVESTIGATOR INCLUSION CRITERIA ................................................................................. 28 
2.2 
APPROVAL AND ACTIVATION ................................................................................................. 28 
2.3 
SITE MANAGEMENT ............................................................................................................ 29 
3 
SELECTION OF PATIENTS ................................................................................................. 30 
3.1 
PATIENT INCLUSION CRITERIA ................................................................................................ 30 
3.1.1 
All patients: .............................................................................................................................. 30 
3.1.2 
Additional criteria for ODYSSEY A: ........................................................................................... 30 
3.1.3 
Additional criteria for ODYSSEY B: ........................................................................................... 30 
3.2 
PATIENT EXCLUSION CRITERIA ............................................................................................... 31 
3.3 
CONSIDERATIONS FOR USE OF DIFFERENT NRTI ......................................................................... 31 
3.3.1 
ABC-containing products.......................................................................................................... 31 
3.4 
NUMBER OF PATIENTS ......................................................................................................... 32 
3.5 
CO-ENROLMENT GUIDELINES ................................................................................................. 32 
3.6 
SCREENING PROCEDURES & PRE-RANDOMISATION INVESTIGATIONS .............................................. 33 
3.6.1 
Screening visit .......................................................................................................................... 33 
4 
REGISTRATION & RANDOMISATION ............................................................................... 34 
4.1 
RANDOMISATION PRACTICALITIES .......................................................................................... 34 
4.2 
CO-ENROLMENT GUIDELINES ................................................................................................. 35 
5 
TREATMENT OF PATIENTS .............................................................................................. 36 
5.1 
GENERAL INFORMATION ...................................................................................................... 36 
5.1.1 
NRTI BACKBONE CHANGE DURING FOLLOW UP ...................................................................... 37 
5.2 
SOC ARM ........................................................................................................................ 37 
5.2.1 
SOC ODYSSEY A ........................................................................................................................ 37 
5.2.2 
SOC ODYSSEY B ........................................................................................................................ 38 
5.3 
DTG ARM ........................................................................................................................ 39 


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5.3.1 
DTG ........................................................................................................................................... 40 
5.3.2 
Fixed dose combination of DTG, ABC and 3TC ......................................................................... 42 
5.4 
DISPENSING ...................................................................................................................... 42 
5.5 
ART MODIFICATIONS, INTERRUPTIONS & DISCONTINUATIONS ...................................................... 42 
5.5.1 
General considerations on changes of arvs during the trial .................................................... 42 
5.5.2 
Adverse reactions & Discontinuations of DTG ......................................................................... 43 
5.6 
ACCOUNTABILITY & UNUSED DRUGS/DEVICES .......................................................................... 45 
5.7 
ADHERENCE & ACCEPTABILITY ............................................................................................... 45 
5.8 
OVERDOSE OF TRIAL MEDICATION .......................................................................................... 45 
5.9 
PROTOCOL TREATMENT DISCONTINUATION .............................................................................. 45 
5.10 
NON-TRIAL TREATMENT AND SIGNIFICANT DRUG INTERACTIONS ........................................... 46 
6 
ASSESSMENTS & FOLLOW-UP ......................................................................................... 47 
6.1 
TRIAL ASSESSMENT SCHEDULE ............................................................................................... 47 
6.1.1 
Randomised Phase ................................................................................................................... 47 
6.1.2 
Extended Follow-up of ODYSSEY Participants.......................................................................... 48 
6.2 
PROCEDURES FOR ASSESSING EFFICACY ................................................................................... 48 
6.2.1 
Clinical: ..................................................................................................................................... 48 
6.2.2 
Immunology: ............................................................................................................................ 49 
6.2.3 
Viral load testing: ..................................................................................................................... 49 
6.2.4 
Resistance testing .................................................................................................................... 49 
6.3 
PROCEDURES FOR ASSESSING SAFETY ...................................................................................... 50 
6.4 
PROCEDURES FOR ASSESSING QUALITY OF LIFE .......................................................................... 50 
6.5 
ADHERENCE ASSESSMENTS ................................................................................................... 50 
6.6 
MANAGEMENT OF PARTICIPANTS WITH TREATMENT FAILURE ...................................................... 50 
6.7 
MANAGEMENT OF CHILDREN DIAGNOSED WITH TUBERCULOSIS (TB) ............................................... 51 
6.7.1 
Management of children with tuberculosis infection in the DTG arm .................................... 51 
6.7.2 
Management of children with tuberculosis in the SOC arm .................................................... 51 
6.8 
MANAGEMENT OF PREGNANCY .............................................................................................. 51 
6.9 
EARLY STOPPING OF FOLLOW-UP ............................................................................................ 53 
6.10 
PARTICIPANT TRANSFERS ..................................................................................................... 53 
6.11 
END OF TRIAL .................................................................................................................... 54 
7 
SAFETY REPORTING ........................................................................................................ 56 
7.1 
DEFINITIONS ..................................................................................................................... 56 
7.1.1 
Medicinal Products .................................................................................................................. 57 
7.1.2 
Adverse Events ......................................................................................................................... 57 
7.1.3 
Disease-related Events ............................................................................................................. 57 
7.1.4 
Other Notable Events ............................................................................................................... 57 
7.2 
INVESTIGATOR RESPONSIBILITIES ............................................................................................ 58 
7.2.1 
Investigator Assessment .......................................................................................................... 59 
7.2.2 
Notification Procedure ............................................................................................................. 60 
7.3 
CTU RESPONSIBILITIES ........................................................................................................ 62 
8 
QUALITY ASSURANCE & CONTROL .................................................................................. 63 
8.1 
RISK ASSESSMENT .............................................................................................................. 63 
8.2 
CENTRAL MONITORING AT CTU ............................................................................................. 63 
8.3 
ON-SITE MONITORING ........................................................................................................ 63 
8.3.1 
Direct Access to Participant Records ....................................................................................... 64 
8.3.2 
Confidentiality .......................................................................................................................... 64 
9 
STATISTICAL CONSIDERATIONS ....................................................................................... 65 
9.1 
METHOD OF RANDOMISATION .............................................................................................. 65 


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9.2 
OUTCOME MEASURES ......................................................................................................... 65 
9.2.1 
Primary efficacy outcome (over 96 weeks) .............................................................................. 65 
9.2.2 
Secondary efficacy outcomes .................................................................................................. 65 
9.2.3 
Secondary safety outcomes ..................................................................................................... 66 
9.2.4 
Other secondary outcomes ...................................................................................................... 66 
9.3 
SAMPLE SIZE ..................................................................................................................... 66 
9.4 
INTERIM MONITORING & ANALYSES ....................................................................................... 66 
9.5 
ANALYSIS PLAN (BRIEF) ....................................................................................................... 66 
10 
ANCILLARY STUDIES ....................................................................................................... 68 
10.1 
PHARMACOKINETIC SUBSTUDIES ............................................................................................ 68 
10.1.1 WB-PK1..................................................................................................................................... 68 
10.1.2 WB-PK2..................................................................................................................................... 68 
10.1.3 TB-PK SUBSTUDY ...................................................................................................................... 68 
10.2 
IMMUNOLOGY/VIROLOGY SUBSTUDY ...................................................................................... 69 
10.3 
QUALITATIVE SUBSTUDY: OPTIMISING ADHERENCE TO SECOND-LINE TREATMENT. .............................. 69 
10.4 
YOUTH TRIAL BOARD PROJECT .............................................................................................. 69 
10.5 
FOLATE AND VITAMIN B12 SUBSTUDY ..................................................................................... 70 
11 
REGULATORY & ETHICAL ISSUES ..................................................................................... 71 
11.1 
COMPLIANCE ..................................................................................................................... 71 
11.1.1 Regulatory Compliance ............................................................................................................ 71 
11.1.2 Site Compliance ........................................................................................................................ 71 
11.1.3 Data Collection & Retention .................................................................................................... 71 
11.2 
ETHICAL CONDUCT OF THE STUDY ........................................................................................... 72 
11.2.1 Ethical Considerations .............................................................................................................. 72 
11.2.2 Ethical Approvals ...................................................................................................................... 73 
11.3 
COMPETENT AUTHORITY APPROVALS ...................................................................................... 73 
11.4 
OTHER APPROVALS ............................................................................................................. 74 
12 
INDEMNITY .................................................................................................................... 75 
13 
FINANCE ........................................................................................................................ 76 
14 
OVERSIGHT & TRIAL COMMITTEES .................................................................................. 77 
14.1 
TRIAL MANAGEMENT GROUP (TMG) ..................................................................................... 77 
14.2 
TRIAL STEERING COMMITTEE (TSC) ........................................................................................ 77 
14.3 
INDEPENDENT DATA MONITORING COMMITTEE (IDMC] ............................................................. 77 
14.4 
ENDPOINT REVIEW COMMITTEE ............................................................................................. 77 
14.5 
ROLE OF STUDY SPONSOR .................................................................................................... 77 
15 
PUBLICATION ................................................................................................................. 78 
15.1 
PUBLICATION .................................................................................................................... 78 
15.2 
FEEDBACK TO PARTICIPANTS .................................................................................................. 78 
16 
DATA AND/OR SAMPLE SHARING ................................................................................... 79 
17 
PROTOCOL AMENDMENTS ............................................................................................. 80 
18 
REFERENCES ................................................................................................................... 92 
19 
APPENDIX I  TEMPLATE PATIENT INFORMATION SHEETS ................................................. 96 
PARENT/CARER INFORMATION SHEET - MAIN STUDY ONLY ......................................................... 96 


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PARTICIPANT INFORMATION SHEET - MAIN STUDY ONLY .......................................................... 103 
CHILDREN’S INFORMATION SHEET - MAIN STUDY ONLY ............................................................. 109 
PARENT/CARER INFORMATION SHEET – EXTENDED FOLLOW-UP ............................................... 110 
PARTICIPANT INFORMATION SHEET – EXTENDED FOLLOW-UP ................................................... 114 
CHILDREN’S INFORMATION SHEET – EXTENDED FOLLOW-UP ........................................................ 118 
PARENT/CARER INFORMATION SHEET – MAIN STUDY & WEIGHT BAND PK 1 (3 TO <14KG).......... 119 
CHILDREN’S INFORMATION SHEET – MAIN STUDY & WEIGHT BAND PK 1 (3 TO <14KG) ............... 126 
PARENT/CARER INFORMATION SHEET –WEIGHT BAND PK 1 (3KG TO <25KG) ............................. 127 
CHILDREN’S INFORMATION SHEET – WEIGHT BAND PK 1 (3 TO <25KG) ....................................... 130 
PARENT/CARER INFORMATION SHEET – WEIGHT BAND PK 2 (25KG TO <40KG) ........................... 131 
PARTICIPANT INFORMATION SHEET –WEIGHT BAND PK 2 (25KG TO <40KG) ............................... 134 
PARENT/CARER INFORMATION SHEET FOR TB PHARMACOKINETIC (PK) SUBSTUDY .................... 136 
PARTICIPANT INFORMATION SHEET FOR TB PHARMACOKINETIC (PK) SUBSTUDY ....................... 139 
PARTICIPANT INFORMATION SHEET FOR IN-DEPTH INTERVIEWS 15-18 YEAR OLDS ..................... 143 
PARTICIPANT INFORMATION SHEET FOR IN-DEPTH INTERVIEWS 10-14 YEAR OLDS ..................... 146 
PARENT/CARER INFORMATION SHEET FOR IN-DEPTH INTERVIEWS ............................................ 149 
PARTICIPANT INFORMATION SHEET FOR IN-DEPTH INTERVIEWS - CAREGIVERS ............................. 152 
PARTICIPANT INFORMATION SHEET FOR IN-DEPTH INTERVIEW 15-19 YEAR OLDS (DTG ALERT) ..... 155 
PARTICIPANT INFORMATION SHEET FOR IN-DEPTH INTERVIEW 10-14 YEAR OLDS (DTG ALERT) ..... 158 
PARENT/CARER INFORMATION SHEET FOR IN-DEPTH INTERVIEW (DTG ALERT) ............................ 161 
PARTICIPANT INFORMATION SHEET FOR FOCUS GROUPS 15-19 YEAR OLDS................................ 164 
PARTICIPANT INFORMATION SHEET FOR FOCUS GROUPS 10-14 YEAR OLDS................................ 167 
PARENT/CARER INFORMATION SHEET FOR FOCUS GROUPS ....................................................... 170 
PARTICIPANT INFORMATION SHEET FOR YOUNG PEOPLE .......................................................... 174 
PARENT/CARER INFORMATION SHEET ...................................................................................... 177 
YTB FACILITATOR INFORMATION SHEET .................................................................................... 180 
20 
APPENDIX II TEMPLATE CONSENT AND ASSENT FORMS ................................................. 182 
PARENT/CARER – MAIN STUDY CONSENT TO SCREENING .......................................................... 182 
PARENT/CARER – MAIN STUDY CONSENT TO RANDOMISATION ................................................ 183 
PARTICIPANT –MAIN STUDY ASSENT TO SCREENING.................................................................. 185 
PARTICIPANT- MAIN STUDY ASSENT TO RANDOMISATION ........................................................ 186 
PARTICIPANT – MAIN STUDY CONSENT TO CONTINUED PARTICIPATION FOR YOUNG PEOPLE WHO REACH THE 
AGE OF CONSENT WHILST IN THE TRIAL .......................................................................... 188 
PARENT/CARER – CONSENT TO EXTENDED FOLLOW-UP ............................................................. 196 
PARTICIPANT – CONSENT TO EXTENDED FOLLOW-UP ................................................................ 198 
PARTICIPANT – ASSENT TO EXTENDED FOLLOW-UP ................................................................... 200 
PARTICIPANT - CONSENT TO STORAGE OF BLOOD SAMPLES FOR FUTURE TESTING ..................... 203 
PARTICIPANT – ASSENT TO STORAGE OF BLOOD SAMPLES FOR FUTURE TESTING ........................ 204 
PARENT/CARER – MAIN STUDY & WB PK 1 CONSENT TO SCREENING (3 TO <14KG) ...................... 205 
PARENT/CARER – MAIN STUDY & WB PK 1 CONSENT TO RANDOMISATION (3 TO <14KG) ............ 206 
PARTICIPANT – MAIN STUDY & WB PK 1  ASSENT TO SCREENING (3 TO <14KG) ........................... 208 
PARTICIPANT- MAIN STUDY & WB PK 1 ASSENT TO RANDOMISATION (3 TO <14KG) ................... 209 
PARENT/CARER - CONSENT TO PHARMACOKINETIC (WB PK 1) STUDY (3 TO <25KG) .................... 211 
PARTICIPANT - ASSENT TO PHARMACOKINETIC (WB PK 1) SUBSTUDY (3 TO <25KG) .................... 213 
PARENT/CARER - CONSENT TO PHARMACOKINETIC (WB PK 2) STUDY (≥25KG) ........................... 215 
PARTICIPANT - ASSENT TO PHARMACOKINETIC (WB PK 2) STUDY (≥25KG) .................................. 216 
PARENT/CARER - CONSENT TO PHARMACOKINETIC (TB PK) STUDY ............................................ 218 
PARTICIPANT - ASSENT TO PHARMACOKINETIC (TB PK) STUDY ................................................... 219 
ASSENT FORM FOR IN-DEPTH INTERVIEWS 10-17 YEAR OLDS ..................................................... 222 
CONSENT FORM FOR IN-DEPTH INTERVIEWS YOUNG PEOPLE (18 YEARS OLD) ............................ 223 
CONSENT FORM FOR IN-DEPTH INTERVIEWS PARENT/CARERS................................................... 225 


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CONSENT FORM FOR IN-DEPTH INTERVIEWS WITH CAREGIVERS ..................................................... 227 
ASSENT FORM FOR IN-DEPTH INTERVIEWS 10-17 YEAR OLDS (DTG) ............................................ 229 
CONSENT FORM FOR IN-DEPTH INTERVIEWS YOUNG PEOPLE (18-19 YEARS OLD) (DTG) .............. 230 
CONSENT FORM FOR IN-DEPTH INTERVIEWS PARENT/CARERS (DTG) ......................................... 232 
ASSENT FORM FOR FOCUS GROUP DISCUSSIONS (10-17 YEAR OLDS) .......................................... 234 
CONSENT FORM FOR FOCUS GROUP DISCUSSIONS (YOUNG PEOPLE OVER 18-19 YEARS .............. 236 
CONSENT FORM FOR FOCUS GROUP DISCUSSIONS (PARENT/CARERS) ....................................... 238 
ASSENT FORM FOR YOUTH TRIAL BOARD PROJECT FOR YOUNG PEOPLE ..................................... 241 
CONSENT FORM FOR YOUTH TRIAL BOARD PROJECT FOR YOUNG ADULT PARTICIPANTS ................ 243 
CONSENT FORM FOR YOUTH TRIAL BOARD PROJECT FOR PARENTS/ GUARDIANS ....................... 245 
21 
APPENDIX III  TEMPLATE GP LETTER .............................................................................. 249 
22 
APPENDIX IV  TEMPLATE ADHERENCE QUESTIONNAIRES ............................................... 250 
23 
APPENDIX V  TEMPLATE ACCEPTABILITY QUESTIONNAIRES ........................................... 252 
24 
APPENDIX VI  ADAPTED WHO CLINICAL STAGING OF HIV/AIDS FOR PATIENTS WITH 
CONFIRMED HIV INFECTION ..................................................................................................... 257 
25 
APPENDIX VII  ADAPTED DIAGNOSTIC CRITERIA FOR WHO CLINICAL STAGING EVENTS IN 
CHILDREN YOUNGER THAN 15 YEARS ....................................................................................... 260 
26 
APPENDIX VIII  CRITERIA FOR WHO CLINICAL STAGING EVENTS FOR YOUNG PEOPLE 15 
YEARS AND OLDER ................................................................................................................... 266 
27 
APPENDIX IX  ADAPTED DAIDS TOXICITY GRADINGS ...................................................... 272 
28 
APPENDIX X  TANNER SCALES ....................................................................................... 288 
29 
APPENDIX XI  SAFE LIMITS OF BLOOD SAMPLE VOLUMES IN CHILDREN.......................... 290 
30 
APPENDIX XII IMMUNOLOGY/VIROLOGY SUBSTUDY ..................................................... 291 
31 
APPENDIX XIII  WEIGHT BAND PHARMACOKINETIC SUBSTUDIES (WB-PK) 1 & 2 ............. 297 
32 
APPENDIX XIV  PHARMACOKINETIC SUBSTUDY IN PARTICIPANTS RECEIVING RIFAMPICIN 
AS PART OF ANTI-TB TREATMENT OR TB PREVENTION THERAPY WHILE ON DTG: ...................... 305 
33 
APPENDIX XV  QUALITATIVE SUBSTUDY ........................................................................ 308 
34 
APPENDIX XVI  YOUTH TRIAL BOARD  PROJECT ............................................................. 313 
35 
APPENDIX XVII  ODYSSEY STRUCTURE ........................................................................... 316 
36 
APPENDIX XVIII  FOLATE AND VITAMIN B12 SUBSTUDY ................................................. 317 
37 
APPENDIX XIX DOLUTEGRAVIR DOSING IN THE ODYSSEY TRIAL ACROSS DIFFERENT 
PROTOCOL VERSIONS ............................................................................................................... 321 
38 
APPENDIX XX ARRANGEMENTS FOR THE EXTENDED FOLLOW-UP OF ODYSSEY 
PARTICIPANTS ......................................................................................................................... 322 


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ABBREVIATIONS 
Abbreviation 
Expansion 
ABC 
Abacavir 
AE 
Adverse Event 
ANRS 
National Agency for Research (France) 
AR 
Adverse Reaction 
ART 
Antiretroviral Therapy 
ARV 
Antiretrovirals 
ATV 
Atazanavir 
AUC 
Area Under Curve 
BIA 
Bioelectrial impedance analysis 
BID 
Twice Daily 
bPI 
Boosted Protease Inhibitor 
c/ml 
Copies per ml 
CDC 
 
COBI or c 
Centres for Disease Control 
 
Cobicistat 
CI 
Confidence Interval 
CI 
Chief Investigator 
CRF 
Case Report Form 
CTA 
 
Clinical Trials Authorisation (Europe) 
CTU 
Clinical Trials Unit (MRC, INSERM-ANRS, PHPT - as appropriate for the country) 
d4T 
Stavudine 
ddI 
 
DRV/r 
Didanosine 
 
Darunavir/ritonavir 
DSMS 
Drug Supply Management System 
DSUR 
Development Safety Update Report 
DT 
Dispersible tablet 
DTG 
Dolutegravir 
EFV 
Efavirenz 
EMA 
European Medicines Agency 
ERC 
Endpoint Review Committee 
EU 
European Union 
EUDRACT 
European Union Drug Regulatory Agency Clinical Trial 
EVG 
Elvitegravir 


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Abbreviation 
Expansion 
EVI  
Eviplera 
FCT 
Film-coated tablet 
FDA 
Food and Drug Administration 
FDC 
Fixed Dose Combination 
FTC 
Emtricitabine 
HAART  
Highly Active Antiretroviral Therapy 
HBV 
Hepatitis B Virus 
HDL 
High-Density Lipoproteins 
HIV 
Human Immunodeficiency Virus 
HIV NAT 
HIV Netherlands Australia Thailand Research Collaboration 
HSR 
Hypersensitive Reaction 
IB 
Investigator’s Brochure 
ICH GCP 
International Conference on Harmonisation (of Technical Requirements for 
Registration of Pharmaceuticals for Human Use) Good Clinical Practice 
IDMC 
Independent Data Monitoring Committee 
IMP 
Investigational Medical Product 
IMPAACT 
International Maternal Paediatric Adolescents AIDS Clinical Trials 
INSTI 
Integrase Strand Transfer Inhibitor 
INSERM-ANRS 
Institut National de la Santé et de la Recherche Médicale 
INSERM-ANRS 
SC10-US019 
Institut National de la Santé et de la Recherche Médicale Service Commun 10 – 
Unité de Services 019 
ISF 
Investigator Site File 
ISRCTN  
International Standard Randomised Controlled Trial Number  
LDL 
Low-Density Lipoproteins 
LPV/r 
Lopinavir/ritonavir 
MOP 
Manual of Operations 
MRC CTU 
Medical Research Council Clinical Trials Unit at UCL (UK) 
MUAC 
Mid Upper Arm Circumference 
NHS 
National Health Service (UK) 
NNRTI 
Non-nucleoside Reverse Transcriptase Inhibitor 
NRTI 
Nucleoside Reverse Transcriptase Inhibitor 
QD 
Once daily 
QoL 
Quality of Life Questionnaire 
PENTA 
Paediatric European Network for Treatment of AIDS 
PHPT 
Program for HIV Prevention and Treatment (Thailand) 


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Abbreviation 
Expansion 
PI 
Protease Inhibitor 
PIS 
Patient information Sheet 
PK 
Pharmacokinetics 
pMTCT 
Prevention of Mother to Child Transmission 
QA 
Quality Assurance 
QC 
Quality Control 
R&D 
Research & Development 
RAL 
Raltegravir 
RBC 
Red blood cell 
RPV 
Rilpivirine 
RTV or r 
Ritonavir  
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAR 
Serious Adverse Reaction 
SOC 
Standard Of Care (defined as the antiretroviral regimen routinely prescribed at a 
particular site for an ART-naïve or for an ART-experienced patient) 
SPF 
Summary of Product Characteristics 
SSA 
Sub-Saharan Africa 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TAF 
Tenofovir alafenamide 
TAM 
Thymidine Analogue resistance Mutation 
TB 
Tuberculosis 
TDF 
Tenofovir 
TDM 
Therapeutic Drug Monitoring 
TMF 
Trial Master File 
TMG 
Trial Management Group 
TMT 
Trial Management Team 
TSC 
Trial Steering Committee 
UAR 
Unexpected Adverse Reaction 
ULN 
Upper Limit of Normality 
VL 
Viral Load 
YTB 
Youth Trial Board 
ZDV 
Zidovudine 
3TC 
Lamivudine 


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1 
BACKGROUND 
With the development of new antiretroviral drugs (ARVs), including new drug classes, which offer 
simplified, more potent options for first- and second-line therapy with fewer adverse effects in adults, 
there is a need to evaluate their place in paediatric HIV treatment.  
 
Unique issues for HIV-infected children include: potential for perinatal transmission of viruses 
resistant to antiretroviral therapy (ART) regimens taken by mothers during pregnancy and 
breastfeeding; special consideration of adverse events as children take drugs during growth and 
development and will be on them for much longer than adults; and the need for age appropriate once 
daily formulations, preferably fixed dose scored dispersible combinations which may require different 
ratios of drugs from those used in adults.   
 
Globally, more than 80% of HIV-infected children live in Sub Saharan Africa (SSA). Although there has 
been substantial improvement in ART coverage over the last few years, only half of children in need 
of treatment have access to ART [1, 2]. Rapid disease progression and high early mortality require that 
ART is started early in life and many children still die before they are diagnosed.  Children <3 years in 
low/middle income countries are taking either non-nucleoside reverse transcriptase inhibitors 
(NNRTI)-based ART (e.g. most African countries, India, Eastern Europe) or ritonavir boosted protease 
inhibitor (bPI) lopinavir/ritonavir (LPV/r)-based ART (South Africa; some centres of excellence in SSA).  
Children >3 years in SSA, including South Africa, start NNRTI-based ART.  In both well-resourced and 
resource-limited settings, there is a need for alternative first- and second-line regimens which can be 
given in the face of possible transmitted resistance (from prevention of mother to child transmission 
pMTCT) or resistance arising from first-line ART, whether PI or NNRTI based.  New regimens need to 
be potent, durable, non-toxic and available in acceptable once daily formulations with correct drug 
ratios.  Ideally regimens should be robust with a high barrier to resistance, have minimal cross-
resistance and minimal interactions with anti-tuberculosis drugs.  
 
Dolutegravir (DTG) is a second-generation integrase inhibitor (INSTI) with the advantage of once daily 
dosing, a good short-term safety profile, low pharmacokinetic variability, few drug-to-drug 
interactions, rapid and robust virological response with an optimised background treatment, a distinct 
resistance profile from raltegravir, a high genetic barrier to resistance and high potency at a low 
milligram dose.  Combination regimens with DTG will therefore be attractive for children starting first-
line ART and for those switching to second-line for reasons of toxicity or failure.  
 
1.1 
DTG ADULT TRIALS 
There are encouraging efficacy and safety data from Phase II and III studies of DTG in adults [3-6] with 
reassuring safety data reported at 96 week endpoints [3, 4].  SPRING-2, SINGLE and FLAMINGO Phase 
III studies were conducted on treatment-naïve adults.  SPRING-2 showed that DTG once daily (QD) is 
non-inferior to twice daily (BID) raltegravir in combination with ABC+3TC or TDF+FTC at 96 weeks, and 
superior in patients with VL >100,000 c/ml [4].   SINGLE compared DTG in combination with ABC+3TC 
to efavirenz (EFV) in combination with TDF+FTC.  Results showed that the DTG combination is superior 
in efficacy and safety at 48 weeks and are consistent for patients with VL </>100,000 c/ml and CD4 
count </>200 cells/mm3 [6].  A subsequent analysis of bone marker changes at 48 weeks demonstrated 
that DTG+ABC+3TC was associated with significantly smaller changes compared to Atripla 
(EFV/TDF/FTC) indicating more active bone turnover in patients on Atripla, which may correlate with 
the known TDF-associated effect on bone mineral density over time  [7, 8]. 
FLAMINGO, an open-label, non-inferiority trial compared DTG with darunavir (DRV) boosted with 
ritonavir (/r) plus investigator-selected TDF+FTC or ABC+3TC in previously untreated adults.  The trial 
showed that DTG was superior to DRV/r at 48 and 96 weeks [9].  The difference was most pronounced 


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in participants with baseline viral load ≥100,000 c/ml. There was no treatment-emergent resistance 
to study drugs [9]. Patients randomised to DTG had better lipid profiles with significantly less grade 2 
or above low-density lipoprotein cholesterol results (2% versus 7%, p<0.001).  
 
A recently published systematic reviews and meta-analyses of ART regimens in adults compared 
virological efficacy (HIV-1 RNA <50 c/ml) at 48 and 96 weeks and CD4 change at 48 weeks of DTG-
based ART and other recommended third agents for the first-line treatment .  Results showed that 
DTG has a higher probability of virological suppression and better CD4 cell responses than most 
guideline recommended third agents (standard-dose EFV, atazanavir (ATV)/r, DRV/r and LPV/r) [10, 
11] .   
The studies in treatment-experienced adult patients also showed encouraging results.  SAILING, a 
Phase III trial in treatment-experienced, INSTI-naïve patients, with at least two-class drug resistance, 
compared QD DTG- versus raltegravir-based ART combined with no more than 2 other agents, one of 
which was fully active: by 48 weeks, 71% vs. 64% patients reached undetectable viral load [12].  
VIKING-3, a Phase II study of safety and efficacy of BID DTG in highly treatment-experienced patients 
with previous resistance to INSTI and 2 other classes (70% patients had mutations to PIs), showed that 
69% reached undetectable viral load at 24 weeks and 56% at 48 weeks of treatment.  Only 3% of 
patients discontinued treatment due to adverse events [13].   
 
A single tablet of DTG + 3TC + ABC has been developed, providing an attractive option of a one-pill 
once daily regimen for older children >12 years.  A PK study in healthy volunteers demonstrated that 
FDC DTG 50mg/ABC 600mg/3TC 300mg is bioequivalent to DTG alone in combination with ABC/3TC 
[14].   
 
In order to inform the ODYSSEY design, an exploratory analysis of subjects receiving DTG plus 1-2 NRTIs 
in SAILING was conducted.  None of the 32 subjects in the DTG arm, who received an NRTI-based 
background regimen, experienced protocol defined virological failure by week 48, including no cases 
of virological failure in 13 subjects receiving less than 2 fully active NRTIs by phenotype (12 received 
one fully active NRTI and 1 received two inactive NRTIs)[15].  Based on this exploratory analysis, DTG 
+ 2 NRTIs appears to have good activity through 48 weeks in treatment-experienced patients when at 
least one of the NRTIs was fully active by phenotype.  However, because of the small sample size, an 
increased risk of virological failure in subjects receiving DTG with less than 2 fully active NRTIs cannot 
be ruled out based on these data alone.  
 
1.2 
DTG IN CHILDREN 
A paediatric dose-finding Phase I/II study IMPAACT P1093 is ongoing. The results are available for 
children 6 to 18 years of age. The study enrolled treatment-experienced children failing their regimen 
who were started on DTG with an optimized background regimen containing at least one fully active 
antiretroviral drug [16, 17] . In 23 children aged 12-18 years who received DTG 50 mg PK results were 
comparable to adults [17].  48-week data showed that DTG was well tolerated with two patients 
experiencing grade 3 laboratory adverse events, which were evaluated as not related to DTG; 74% 
children (95% CI 52% to 90%) achieved viral load of <400 c/ml.  There were no drug-related clinical 
adverse events, no grade 3 or 4 clinical events, and no serious adverse events.  48-week results of the 
PK, safety and virological efficacy study in 23 children 6 to 12 years of age were recently reported and 
showed adequate AUC24 and C24 with the dose of ~1 mg/kg [18].  Three subjects experienced grade 3 
laboratory events all of which were unrelated to DTG.  There were no grade 4 AEs, SAEs or study 
discontinuations secondary to AEs. The study in children less than 6 years of age down to 4 weeks of 
age is ongoing. 
 


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1.3 
FIRST- AND SECOND-LINE ART OPTIONS FOR CHILDREN: THE PLACE OF DTG 
DTG-based treatment with two NRTIs offers a potent regimen, with advantages of low toxicity, and 
the potential for once daily dosing. The rapid virological response observed following initiation of ART 
with DTG-based ART will be highly relevant for children with very high viral loads, which is commonly 
observed in younger children.  DTG has high potency at a low milligram dose, and therefore it could 
be particularly attractive for young children in both well-resourced and resource-limited settings, who 
have limited options and may be more likely to be infected with resistant viruses through mother-to-
child transmission (MTCT).  A DTG-based first-line regimen is likely to be better tolerated and 
logistically advantageous for ART programmes currently using liquid LPV/r, as well as needing to be 
dosed once rather than twice daily.   
 
The choice of NRTI backbone depends on the child’s age, history of previous NRTI exposure (for ART 
experienced children) and drug availability in a country. The combination of abacavir (ABC) + 
lamivudine (3TC) is already frequently used as a preferred first-line nucleoside reverse transcriptase 
inhibitors (NRTI) ‘backbone’ and tenofovir disoproxil fumarate (TDF) + emtricitabine (FTC) or TDF + 
3TC are increasingly being used in older children (TDF recently received regulatory approval by both 
Food and Drug Administration (FDA) and European Medicines Agency (EMA) for children >2 years of 
age).  Furthermore, there are reasons to use ABC or TDF as part of a first-line regimen as resistance to 
both these drugs follows the same ‘resistance pathway’ and does not affect potency to zidovudine 
(ZDV) for second-line (and in fact may result in hyper-susceptibility to ZDV), whereas using ZDV in first-
line typically results in accumulation of thymidine analogue resistance mutations (TAMs) which may 
limit second-line NRTI options.  The WHO 2016 guidelines recommend ABC as part of preferred first-
line ART in children 3 to <10 years and ABC or ZDV in children <3 years; if ZDV is used in first-line, then 
ABC + 3TC are recommended in second-line [19].  PK data from PENTA trials [20, 21] and most recently, 
96-week viral load and clinical efficacy data as well as safety data from the paediatric ARROW trial, 
have shown that once daily dosing with ABC + 3TC is non-inferior to twice daily in terms of viral load 
suppression, safety and clinical efficacy [22] .  Thus, with ABC + 3TC, DTG has the potential to be part 
of a potent, safe and simple fixed dose combination (FDC) for both first- and second-line ART in 
children.   
 
DTG can be used as part of a second-line regimen in children failing first-line PI-based therapy; despite 
the presence of viral rebound for long periods, the NRTI backbone remains relatively protected in the 
presence of a boosted PI (bPI).  No TAMs developed in children failing LPV/r-based first line ART in a 
large paediatric study (CHER) [23] and only 3/22 (14%) developed ≤2 TAMs and none developed >2 
TAMs in the PENPACT1 trial [24] when switch was delayed until children had viral load (VL) >30,000 
c/ml.  Children failing NNRTI-based regimens developed TAMs more frequently.  The PENPACT1 study 
showed that 3/20 (15%) children who were randomised to switch their first-line ART at VL of 1000 
c/ml developed one TAM, whereas children randomised to switch at VL of 30,000 c/ml developed 
TAMs at higher rates: 9/22 (41%) developed ≥1 TAM, 5/22 (23%) ≥2 TAMs and 4/22 (18%) had 3 TAMs 
[24]. In small studies in Uganda nearly 10% of children developed a first TAM by 6 months of early 
virological failure on NNRTI-based regimen [25, 26] and 9% developed 2 TAMs by 12 months of 
virological failure [26].  ABC is expected to retain its potency in the presence of no more than two 
TAMs.  Therefore, for children in resource-limited countries in whom ZDV has been used first-line and 
VL and resistance testing are not available, it might still be expected that ABC potency might not be 
unduly compromised when used with DTG (which itself has a high barrier to resistance) and that this 
regimen might have similar potency and greater acceptability compared with a bPI-based second-line 
regimen.  Patients who are failing ABC + 3TC or stavudine (d4T) + 3TC containing first-line ART are at 
risk of accumulating the K65R mutation and thus susceptibility to ABC or TDF containing second-line 
ART may be reduced.  Variable rates of acquiring the K65R mutation are reported in paediatric trials.  
In the PENPACT1 trial 1/14 children on ABC + 3TC developed the K65R mutation [24, 27].  A multi-
centre study in sub-Saharan Africa found that K65R occurred in 3/20 (15%) and 13/47 (28%) adults 


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failing on d4T-or TDF-containing ART respectively, after 12 months of virological failure [27].  However, 
the majority of patients switching empirically to ZDV, ABC or TDF-containing ART would be expected 
to have at least 2 active drugs with a DTG-based regimen, and therefore to have an effective ART 
regimen.  Supporting this, adult studies from Africa showed high rates of virological re-suppression 
with empirically prescribed and re-cycled second-line ART even when switching ART very late [27-30].  
Of note, DTG can be used in liver and renal impairment without dose modification [14, 31].   
 
1.4 
DTG WITH ANTI-TUBERCULOSIS (TB) THERAPY 
A PK study of co-administration of DTG with rifampicin in healthy adult volunteers showed that BID 
DTG overcomes the induction effect of rifampicin [32] and therefore can be used in HIV/TB co-
infection.  A recently reported study in HIV-infected adults with TB treated confirmed that increasing 
DTG dose to 50mg BID co-administered with rifampicin results in a similar DTG exposure to DTG 50mg 
QD without rifampicin [33]. The study showed DTG was effective and well-tolerated in HIV/TB co-
infected adults receiving rifampicin-based TB treatment. It will be important to study the DTG PK in 
children on ART who require anti-TB treatment with rifampicin, as in many settings TB is common in 
HIV-infected children, even when on ART.   
 
1.5 
DTG AND PREGNANCY 
Reproductive toxicology animal studies, including embryofetal development studies in rats and 
rabbits, showed no evidence of adverse developmental outcomes [34] 
 
In May 2018, a National Institutes of Health (NIH)-funded observational surveillance study in Botswana 
(TSEPAMO) evaluating the safety of ART regimens in pregnancy identified an increased risk of neural 
tube defects (NTD) amongst infants of women who initiated DTG-based regimens prior to pregnancy. 
The study reported 4 cases of NTD out of 426 infants in women who conceived on DTG (risk 0.9%), 
this compares to 14 out of 11,173 infants born to women receiving non-DTG-based regimens (risk 
0.13%)[35]. In a further report including all data through to March 2019 there were 5 cases of NTD in 
1683 deliveries where their mother was taking DTG at conception (0.3% of deliveries) (36), suggesting 
the increased risk is ~3-fold, lower than the 10-fold risk initially estimated. 
 
There were no reported NTDs in infants of 1729 women in the TSEPAMO study who started DTG during 
pregnancy, including 280 women who initiated ART during the first trimester of pregnancy [37]. 
 
This study and other surveilance studies are ongoing and other reproductive studies on DTG safety 
have been initiated. More data on safety of DTG for women of childbearing age and their infants are 
expected in the next year. 
 
Following the alert, it was communicated to the ODYSSEY sites that all female participants who are 
sexually active must use highly effective contraception (section 6.8; [38])). 
 
1.6 
DTG FORMULATIONS AND MARKETING AUTHORISATION 
DTG is available as film-coated 10mg, 25mg and 50mg tablets and dispersible 5mg tablets and all 
formulations are provided by ViiV for the ODYSSEY trial. The dispersible tablets are approximately 1.6 
times more bioavailable than the film-coated tablets and are currently being studied in DTG paediatric 
trials (ODYSSEY and IMPAACT P1093[38, 39]). 
 


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FDA and EMA have approved DTG 50mg QD for adolescents ≥40kg and DTG 35mg QD for children 
weighing 30 to <40kg, and EMA has approved DTG 25mg QD for children 20-<25kg and DTG 20mg QD 
for children ≥6 years weighing 15-<20kg. FDC (DTG+3TC+ABC) is approved in paediatric patients 
weighing ≥40kg by EMA and FDA. The dose finding and safety assessment study IMPAACT P1093 in 
younger children is ongoing.   
 
1.7 
RATIONALE AND OBJECTIVES  
DTG is a new drug which offers the potential to be highly effective, safe and simple when used as part 
of first- or second-line ART regimens.  Following adult Phase II/III trials, DTG needs evaluation to 
determine its place as first-line and second-line therapy in adolescent and paediatric HIV treatment.  
 
Standard ART for children is a NNRTI or bPI, plus 2 NRTI and where possible fixed drug combinations 
(FDC) are preferred to support adherence.  Concerns have been raised about the potency of NVP-
based ART in infants [40], and EFV is not readily available for children <3 years.  Neither EFV nor NVP 
are available in a 3-drug once-daily FDC for children <12 years of age.  The most frequently used FDC 
in adolescents is EFV+TDF+FTC (or 3TC).  With currently used doses, EFV may cause significant 
neuropsychological side effects [42].  The commonly available bPI for young children is LPV/r, an 
unpleasant tasting liquid requiring a cold chain.  LPV/r tablets for children are relatively large and need 
to be swallowed whole or they lose bioavailability.  Two other PIs, ATV and DRV, are available for older 
children in high-income countries but need to be boosted with ritonavir tablets.  Adult US and 
European guidelines now recommend integrase inhibitors as part of first-line regimens.  In contrast, 
INSTI are used infrequently in children: raltegravir-based ART is used in some clinics, generally for 
second-line, following treatment failure on LPV/r-based regimens and elvitegravir-based FDC has been 
recently introduced for adolescents in high-income countries, mostly for simplification.  Finally, TDF, 
a preferred NRTI in adults and adolescents [19], has long-term renal and bone toxicity, and therefore 
concerns remain for its use in growing children.   
 
DTG with two NRTIs will potentially offer a potent and safe regimen for both ART-naïve and ART-
experienced children and is available as a FDC with ABC and 3TC for children >12 years.  
No randomised trial has been undertaken comparing this new regimen with standard of care in 
children, who potentially have more to gain in terms of minimising long term HIV and ART 
complications, improving long-term adherence to medication and gaining better quality of life than 
adults. 
 
ODYSSEY will be a pragmatic strategy trial evaluating the efficacy and safety of once daily DTG-based 
ART compared with standard of care in children and adolescents starting first- or second-line ART in 
resource-limited and well-resourced settings.  
 
 


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2 
SELECTION OF SITES/CLINICIANS 
The trial sponsor has overall responsibility for site and investigator selection. 
 
2.1 
SITE/INVESTIGATOR INCLUSION CRITERIA 
Clinical sites invited to enrol children and young people in ODYSSEY will usually have previously 
collaborated in trials with the MRC CTU, INSERM-ANRS, PHPT or IMPAACT.  In the case of a new site 
wishing to participate, the site will need to demonstrate sufficient resources to conduct clinical trial 
research with children and young people.  
 
The principal investigator will sign an Investigator’s Agreement for that institution on behalf of all staff 
at that site who will be working on the ODYSSEY trial.  The principal investigator will sign to confirm 
that: 
 
The institution has an adequate number of qualified staff and adequate facilities for the 
foreseen duration of the trial to conduct the trial properly and safely. 
 
All staff assisting with the trial are adequately informed about the protocol, the investigational 
products and their trial-related duties. 
 
The trial will be conducted in accordance with the current protocol and changes will only be 
made when necessary to protect the safety, rights or welfare of participants. 
 
The trial will be conducted in compliance with the principles of ICH GCP and applicable 
regulatory requirements. 
 
The institution will permit monitoring and auditing by the relevant CTU and inspection by the 
appropriate regulatory authorities.  Direct access will be made available to all trial-related 
sites, data/documents and reports. 
 
The institution will maintain an Investigator Site File (ISF), which will contain essential 
documents for the conduct of the trial. 
 
All trial data will be submitted in a timely manner and as described in the protocol.   
 
All Serious Adverse Events (SAEs) will be reported to the relevant CTU within 24 hours of the 
investigator becoming aware of the event.  The initial SAE report shall be promptly followed 
by detailed follow up reports. 
 
All employees, students or agents engaged in the research shall maintain the confidentiality 
of information. 
 
No data on trial participants will be disclosed without the approval of the Trial Steering 
Committee (TSC). 
 
All trial-related documents will be retained for at least 15 years after the completion of the 
trial. 
 
In addition to the points above and in compliance with the principles of ICH GCP, all institutions 
participating in the trial will complete a delegation log and forward this to the CTU.  Each person 
working on the ODYSSEY trial must complete a section of this log and indicate their responsibilities as 
agreed with the principal investigator.  The CTU must be immediately notified of any changes to trial 
personnel and/or their responsibilities.  An up-to-date copy of this log must be stored in the ISF at the 
institution and also in the Trial Master File (TMF) at the CTU. 
 
2.2 
APPROVAL AND ACTIVATION 
MRC CTU, INSERM-ANRS or PHPT staff will visit new sites prior to the trial commencing at that site in 
order to carry out a site and lab risk assessment and set-up visit.  This visit should be attended by the 


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principal investigator at that site (the clinician), the clinic nurse(s), and representatives from the 
laboratory and pharmacy and any other staff who will be involved in the ODYSSEY trial.  At the trial 
set-up visit the trial management staff should ensure that the following minimum criteria are met 
before the site enrols participants into the trial: 
 
The clinician should be experienced in the management of children/young people with HIV or 
work in close contact with a specialist HIV unit/site. 
 
Staff involved in the trial must have training in Good Clinical Practice (GCP). 
 
Pharmacy staff are able to keep detailed records of the trial medications prescribed. 
 
There exists good communication between all of the above departments. 
 
Laboratories have quality certification procedures, are enrolled with an EQA program and 
have the capacity to run the trial scheduled assays/store trial samples. 
 
Training will be provided for all sites participating in ODYSSEY.  Where sites have participated in 
previous PENTA trials, site initiation training may be conducted via web conferencing or similar. 
Training in the use of ABC will be included in the site initiation.  
 
2.3 
SITE MANAGEMENT 
Sites in the United Kingdom are managed by the MRC CTU.  Sites in Germany, South Africa, Thailand 
(HIV-NAT), Uganda, US and Zimbabwe are managed by the MRC CTU together with national co-
ordinators and local monitors. This includes those sites in Uganda that are supported by IMPAACT. 
Sites in France are managed by INSERM-ANRS; sites in Argentina, Portugal and Spain are managed by 
INSERM-ANRS together with national co-ordinators and local monitors.  PHPT sites in Thailand are 
managed directly by PHPT. 
 
 


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3 
SELECTION OF PATIENTS 
Participants will be selected by medical investigators at the participating sites, who should be aware 
of eligibility criteria in advance of screening participants for the trial.  
Eligible participants (or carers, as appropriate) must: 
 
Be able to understand and comply with protocol requirements, instructions, and restrictions 
 
Be likely to complete the study as planned 
 
Be considered appropriate candidates for participation in an investigative clinical trial with 
oral medication 
 
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 children and adolescents with HIV, it is important that no 
exceptions be made to these criteria for admission to the study. 
 
Participants will be considered eligible for enrolment in this trial only if they fulfil all the inclusion 
criteria and none of the exclusion criteria as defined below.  
 
3.1 
PATIENT INCLUSION CRITERIA 
3.1.1 
ALL PATIENTS:  
 
Children ≥28 days and <18 years weighing ≥3kg with confirmed HIV-1 infection*  
 
Parents/carers and children, where applicable, give informed written consent 
 
Girls who have reached menses must have a negative pregnancy test at screening and 
randomisation and be willing to adhere to effective methods of contraception if sexually 
active 
 
Children with co-infections who need to start ART according to local/national guidelines 
 
Parents/carers and children, where applicable, willing to adhere to a minimum of 96 weeks' 
follow-up 
 
*Children weighing 3 to <14kg must be eligible and willing to participate in the Weight band (WB)-
PK1 substudy unless direct enrolment for the child’s weight band has opened following the WB-PK1 
substudy (see Section 5.3.1 and Appendix XIII) and/or dosing information has become available from 
the IMPAACT P1093 DTG dose-finding study. 
 
 
3.1.2 
ADDITIONAL CRITERIA FOR ODYSSEY A: 
 
Planning to start first-line ART  
 
 
3.1.3 
ADDITIONAL CRITERIA FOR ODYSSEY B: 
 
Planning to start second-line ART defined as either: (i) switch of at least 2 ART drugs due to 
treatment failure; or (ii) switch of only the third agent due to treatment failure where drug 
sensitivity tests show no mutations conferring NRTI resistance  (see Section 5.2.2)   
 
Treated with only one previous ART regimen. Single drug substitutions for toxicity, 
simplification, changes in national guidelines or drug availability are allowed 
 
At least one NRTI with predicted preserved activity available for a background regimen 


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 
In settings where resistance tests are routinely available, at least one active NRTI from 
TDF/TAF, ABC or ZDV should have preserved activity based on cumulative results of resistance 
tests (see Section 5.2.2) 
 
In settings where resistance tests are not routinely available, children who are due to switch 
according to national guidelines should have at least one new NRTI predicted to be available 
from TDF/TAF, ABC or ZDV (see Section 5.2.2) 
 
Viral load ≥500 c/ml at screening visit or within 4 weeks prior to screening 
 
See Section 3.3 for additional considerations for inclusion in the study depending on NRTI 
backbone. 
3.2 
PATIENT EXCLUSION CRITERIA 
 
History or presence of known allergy or contraindications to DTG  
 
History or presence of known allergy or contraindications to proposed available NRTI 
backbone or proposed available SOC third agent.  
 
Alanine aminotransferase (ALT) ≥5 times the upper limit of normal (ULN), OR ALT ≥3xULN and 
bilirubin ≥2xULN 
 
Patients with severe hepatic impairment or unstable liver disease (as defined by the presence 
of ascites, encephalopathy, coagulopathy, hypoalbuminaemia, oesophageal or gastric varices, 
or persistent jaundice), known biliary abnormalities (with the exception of Gilbert's syndrome 
or asymptomatic gallstones) 
 
Anticipated need for Hepatitis C virus (HCV) therapy during the study 
 
Pregnancy or breastfeeding 
 
Evidence of lack of susceptibility to integrase inhibitors or more than a 2-week exposure to 
antiretrovirals of this class  
 
3.3 
CONSIDERATIONS FOR USE OF DIFFERENT NRTI  
3.3.1 
ABC-CONTAINING PRODUCTS 
 
HLA-B*5701 testing 
 
In countries where HLA-B*5701 screening is considered standard of care and HLA-B*5701 status is 
unknown (even if the subject has previously tolerated ABC), investigators must test for HLA-B*5701 
and the results of the test must be received prior to starting ABC.  Children who are HLA-B*5701 
positive must not be given ABC. 
 
In countries where HLA-B*5701 screening is not considered standard of care, investigators must 
obtain a complete history of previous exposure to ABC-containing products. In cases requiring 
discontinuation of abacavir, they should evaluate for the possibility of a clinically suspected 
hypersensitivity reaction (HSR).  If the possibility of a HSR cannot be ruled out then treatment with 
any ABC-containing product should not be started, due to the risk for a potential life-threatening and 
sometimes fatal re-challenge reaction.  Where participants have previously tolerated treatment with 
ABC, restarting ABC treatment as part of this study must be done in a setting where medical assistance 
is readily available. 
 
The use of ABC-containing products in participants should be in accordance with the corresponding 
local product information.   
 
3TC-, FTC- and TDF/TAF-containing products 


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HBV-co-infected patients 
 
Patients known to have chronic HBV infection (HBsAg positive OR anti-HBc positive with HBV DNA 
present) should be treated with TDF ideally in combination with either 3TC or FTC.  Monotherapy with 
either 3TC or FTC for treatment of HBV is not recommended, and 3TC should not be used in 
combination with FTC.  In young patients for whom TDF is not available, consideration should be given 
to use of 3TC- or FTC-sparing regimens to avoid development of 3TC or FTC resistance in HBV. 
 
Some participants with chronic HBV disease may experience clinical or laboratory evidence of 
recurrent hepatitis upon discontinuation of 3TC, FTC or TDF/TAF.  If 3TC, FTC or TDF/TAF is 
discontinued in participants co-infected with HBV, periodic monitoring of liver chemistry tests should 
be considered. 
 
Renal impairment 
 
The use of TDF is not recommended in children with renal impairment.  TDF should be discontinued 
in children who develop renal impairment on TDF therapy. 
 
In patients with moderate-severe renal impairment and creatinine clearance <50 ml/min, the dose of 
3TC or FTC should be adjusted in accordance with the local product information.  
 
ZDV-containing products 
 
Patients with either of the following haematology results at screening should not receive ZDV-
containing products: 
 
Haemoglobin (Hb) concentration <7.5 g/dL or 4.65 mmol/L 
 
Absolute neutrophil count <500/mm3 or 0.5 x 109/L 
 
Alternative causes for anaemia and/or neutropenia, such as concurrent bacterial, mycobacterial or 
fungal infection, malaria, helminthiasis, malignancy and/or malnutrition should be investigated.  ZDV 
should be substituted with an alternative NRTI if alternative causes for anaemia and/or neutropenia 
cannot be identified.   
3.4 
NUMBER OF PATIENTS 
A minimum of 700 children will be enrolled into the main trial over 96-120 weeks.  This will include 
≥310 children starting first-line (ODYSSEY A) and ≥390 children starting second-line ART (ODYSSEY B).  
Children will be recruited from clinical centres in Africa, Europe, Asia, North and South America. 
 
All children randomised into ODYSSEY weighing ≥14kg will contribute to the target numbers of 310 in 
ODYSSEY A and 390 in ODYSSEY B.  
 
 
In addition, over a period of up to 78 weeks (July 2018 to end of 2019) we will recruit a minimum of 
20 children in each of the 3 lower weight bands (3-6kg, 6-10kg, 10-14kg; total ≥60 children).  
 
3.5 
CO-ENROLMENT GUIDELINES 
Co-enrolment in previous or future trials is considered in Section 4.2. 
 


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3.6 
SCREENING PROCEDURES & PRE-RANDOMISATION INVESTIGATIONS 
3.6.1 
SCREENING VISIT 
At screening, parents/carers of HIV-infected children and adolescents will be given an information 
sheet about the ODYSSEY trial and asked to give written consent before any trial-specific procedures 
are performed or any blood is taken for the trial (see Appendices I - II).  
Signed consent forms must be kept by the investigator in the ISF, a copy in the child's clinical records 
and a copy given to the participant or family.  
 
At this visit the patient will be allocated a Trial Number and an anonymous code taken from a 
sequential list included in the ISF. 
 
Screening procedures will include a clinical assessment, T cell lymphocyte subsets (including total 
lymphocytes, CD4, CD8), haematology, biochemistry (see Trial Assessment Schedule, page x) and 
plasma/cell storage.  Stored samples will be discarded if the patient is not randomised into the study; 
HIV-1 RNA viral load is required for ODYSSEY B at screening or within 4 weeks prior to screening.  Girls 
who have started menses will be given information about the risks of pregnancy in the trial and 
advised on how to avoid pregnancy.  A pregnancy test will be performed at screening in girls who have 
started menses.  Any female participant found to be pregnant will not be eligible for the trial.  
 
For children being screened for ODYSSEY B, i.e. children requiring a switch to second-line ART, the 
parent/carer, or any young person who administers their own medication, should complete an 
adherence questionnaire (See Appendix IV). 
 
As soon as the results are received and eligibility has been confirmed, the Screening Form with 
confirmation of eligibility and receipt of informed consent, clinical history and assessment, 
haematology, biochemistry, previous immunology and virology should be entered on the trial 
database or sent to the appropriate CTU.  Eligibility for the study will be confirmed and the 
randomisation visit should be scheduled within 4 weeks after the screening visit.   
 
 


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4 
REGISTRATION & RANDOMISATION 
Randomisation should take place within 4 weeks after the screening visit, ideally within 2 weeks.  
 
The participant’s eligibility for enrolment will be confirmed, including the results of screening 
laboratory tests.  Participants or carers must confirm that they have read the relevant patient 
information sheets (see Appendix I).  Continued agreement to enter in the trial must be confirmed 
from parents/carers after explanation of the aims, methods, benefits and potential hazards (see 
Appendix II).  Older children should give assent to trial participation if they know their HIV status.  
Signed consent forms must be kept by the investigator and documented in the CRF, a copy stored in 
the clinical records and a copy given to the participant or family.  It must be made completely and 
unambiguously clear that the participant (or parent/carer of a child) is free to refuse to participate in 
all or any aspect of the trial, at any time and for any reason, without compromising the care of the 
child.   
 
The randomisation process will be securely embedded within the database, a web-based system 
controlled through an authorised user name and password.  Selected sites will be able to randomise 
patients directly.  An option to fax the Randomisation Form to the appropriate CTU, who will perform 
the randomisation, will also be available.  Patients will be randomised to DTG or SOC arms in a 1:1 
ratio (see Section 4.1 below). 
 
Enrolment assessments will be performed as summarised in the Trial Assessment Schedule.  Blood 
should be taken for plasma storage.  Cells will be stored in selected sites with this capacity.  A repeat 
pregnancy test should be performed in girls who have started menses. Any female participant found 
to be pregnant will not be eligible for the trial.  The questions relating to sleep and mood on the 
Acceptability, Sleep and Mood Questionnaire should be completed at the enrolment visit.  
 
The clinician should complete the Enrolment Form and send to the appropriate CTU once all the 
laboratory results are available, or enter the CRF data directly onto the secure web-based trial 
database. 
 
A clinic visit should be scheduled for 4 weeks after the week 0 visit (week 4 visit).  At the sites where 
children are routinely seen at 2 weeks after the start of new ART, this can be included as an additional 
visit and procedures undertaken as per the Trial Assessment Schedule. 
 
4.1 
RANDOMISATION PRACTICALITIES 
The participant (child) and carer should be physically present together with a study clinician at the 
time of randomisation.   
 
To randomise a participant, the information contained on a completed Randomisation Form will be 
entered into the online trial database accessible from the CTU (or the clinical site if appropriate) to 
automatically check for eligibility.  Only those with completed and verified screening forms on the 
database will be able to be randomised.  The details of the participant’s treatment allocation and trial 
number will be notified to clinical staff.  
 
If a centre’s internet connection to the database is unavailable at the time of randomisation, the 
participant’s details can be provided to staff at the relevant CTU by fax or by telephone.  At the CTU, 
staff will verify eligibility and perform the randomisation using the online system.  The details of the 


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participant’s treatment allocation and trial number will be notified to the trial team at the site by fax 
or phone, with follow-up confirmation. 
 
The clinician should complete a prescription with the participant's details and ART regimen as 
allocated.  The pharmacist or pharmacy technician should ensure that the participant and/or carers 
know how to take/administer the different drugs before they leave the clinic. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
For those sites randomising directly, training will be provided as part of the site initiation and database 
training.  Individual passwords will be provided.   
 
ENROLMENT OF MULTIPLE PARTICIPANTS FROM THE SAME FAMILY/HOUSEHOLD INTO THE TRIAL 
If more than one child from a family/household is to be enrolled at the same time and in the same 
stratum (ODYSSEY A or ODYSSEY B) they will be allocated to the same arm to facilitate their care 
(please refer to Manual of Operations).   
 
4.2 
CO-ENROLMENT GUIDELINES 
Co-enrolment in compatible studies is allowed by the protocol but must first be approved by the CTU 
with previous discussion within the TMG.  Centres should also adhere to local guidelines concerning 
co-enrolment in other trials. 
 
 
RANDOMISATIONS THROUGH A CTU 
To randomise fax or send by password protected email the Randomisation CRF to the 
relevant CTU: 
 
MRC CTU, UK, Monday to Friday 9:00 AM to 17:00 
Tel: +44 (0) 20 7670 4786 
Fax: +44 (0) 20 7670 4814 
Email: mrcctu.trial-odyssey@ucl.ac.uk 
 
 
Inserm-ANRS, France, Monday to Friday 9:00 AM to 17:00 
Tel: + 33 1 45 59 50 83 / 52 55 
Fax: + 33 1 46 58 72 93 
Email: penta.sc10@inserm.fr 
 
 
PHPT, Thailand, Monday to Friday 9:00 AM to 18:00 
Tel: +66 (0) 53 814 633 ext 710 
Fax: +66 53 814 269 
Email: kanchana.than-in-at@phpt.org 
 


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5 
TREATMENT OF PATIENTS 
5.1 
GENERAL INFORMATION 
Participants will be enrolled in two different strata depending on their previous ART experience:  
 
ODYSSEY A: children starting first-line ART 
 
ODYSSEY B: children starting second-line ART.  
 
Within each stratum, children will be randomised 1:1 to either DTG-based ART (DTG arm) or standard 
of care (bPI-, or NNRTI- or INSTI-based ART; SOC arm).   
 
DTG (including Triumeq, as appropriate) will be provided by ViiV for the duration of the randomised 
phase of the ODYSSEY trial. Triumeq will only be supplied in countries where it is licensed. At sites 
where generic DTG-containing FDCs are available through the national programme it may be preferred 
for participants in the DTG arm to be on a once-daily, one-pill regimen, rather than taking DTG supplied 
by ViiV as a separate tablet, in order to aid adherence, but this must not lead to a change to the NRTI 
backbone. If the DTG-containing FDC is to be dispensed from a general clinic/Department of Health 
pharmacy rather than the clinical trial pharmacy it must be ensured that all necessary local 
requirements are met and approvals are in place for the pharmacy to do so. All cases where this may 
apply should be discussed with MRC CTU at UCL prior to switching the participant.  
 
For sites outside Europe, the following NRTIs will also be provided by ViiV where required for the 
duration of the ODYSSEY trial: ABC, 3TC, Kivexa and Combivir.  After the end of the randomised phase 
of the trial, DTG will be provided by ViiV for those children randomised to the DTG arm at the 
discretion of their clinician until it is available and recommended for children in their country of 
residence. For sites in sub-Saharan Africa the Mylan formulation of ABC/3TC 120/60mg will be 
provided for the duration of the randomised phase, if required. 
 
All carers of children starting ABC will receive warning cards and additional information about this 
drug.  In the countries where HLA-B*5701 testing is routinely performed, the test results should be 
received prior to starting ABC.  Children who are HLA-B*5701 positive should not be given ABC.  
 
The NRTI choice in children who are starting second-line ART will depend on the history of previously 
used NRTIs and the resistance profile, if performed.  The decision will be made by the treating clinician 
 
The following should be considered: 
 
1. In countries, where resistance tests are routinely performed, at least one active NRTI from 
TDF/TAF, ABC or ZDV should be chosen based on all resistance test results in the child (historic 
and recent).  The interpretation of the mutations should be based on the up-to-date version 
of the Stanford HIV Drug Resistance Database (http://hivdb.stanford.edu/).  If the child has 
been on ZDV or D4T first-line, and ABC or TDF/TAF are in the planned SOC for second-line, 
then no more than two TAMs or one TAM + M184V are allowed.  If the chosen regimen 
contains ABC or TDF/TAF, no presence (historic or recent) of K65R mutation is allowed.  
 
2. In countries where resistance tests are not routinely performed, clinicians should follow 
national/WHO Guidelines. At least one new NRTI with presumed preserved activity (from ABC, 
TDF or ZDV) should be chosen. 
 
The planned SOC regimen to be used if randomised to SOC should be recorded on the screening and 
randomisation CRFs.  Treatment should start on the day of randomisation or the following morning. 


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Treatment will be open-label and will be dispensed at randomisation for 4 weeks and then at 
maximum 12 weekly intervals.  Where drug has been supplied for the trial, it will be stored separately 
from routine clinic drug supplies in a designated section at the study site. 
 
 
5.1.1 
NRTI BACKBONE CHANGE DURING FOLLOW UP 
 
The proposed NRTI backbone for all participants should be chosen following the considerations in 
sections 3.1 to 3.3 and 5.2 to 5.3. Participants must be prescribed the NRTI backbone that was chosen 
prior to randomisation irrespective of the randomised allocation as randomisation is stratified by NRTI 
backbone.  
 
Additionally participants should remain on the same backbone throughout the duration of the trial 
unless substituting for toxicity, intolerance or switching for treatment failure. Change of NRTI 
backbone for simplification while in the trial should be avoided, if possible. In cases where the clinician 
thinks that this should be done in the patient’s best interest, this should be discussed with the relevant 
CTU and/or TMG. 
 
Upon completion of the randomised phase of the trial clinicians are free to change NRTI backbone as 
per international/national treatment guidelines. 
 
5.2 
SOC ARM 
All participants in the SOC arm will receive ART including either an NNRTI (e.g. NVP, EFV or RPV), a bPI 
(e.g. LPV/r, ATV/r, ATV/c, DRV/r, DRV/c) or an INSTI other than DTG (e.g. RAL, EVG/c), plus 2 (or 3 
(ODYSSEY A only)) NRTIs following international (WHO, PENTA, US), national or local 
recommendations for first- or second-line therapy. See Tables 1 and 2 below for commonly used first- 
and second-line options for standard of care. The exact choice of antiretrovirals will be made by the 
treating clinician, but should take into account what is being used in national programmes, as this will 
ensure that participants can stay on the same regimens long-term.  Inclusion of different regimens in 
the trial increases generalisability, and will form a pre-planned subgroup analysis population. 
 
Participants randomised to SOC must be prescribed the class of non-NRTI drug that was chosen prior 
to randomisation as randomisation is stratified by bPI vs. non-bPI. The doses of antiretrovirals should 
be in accordance to those recommended in the product information or according to international 
(WHO, PENTA, US)/national guidelines as appropriate for the country.  Doses should be recalculated 
at every visit (until the adult dose is reached). 
 
See Section 3.3 for additional considerations that investigators should take into account before 
selecting and initiating the NRTI backbone. 
 
 
5.2.1 
SOC ODYSSEY A 
SOC first-line ART varies across the sites and countries in ODYSSEY.  See Table 1 for commonly used 
first-line ART options.    D4T or ddI may still be an option for young children in whom ZDV and ABC are 
contraindicated and if these NRTIs are included in the national guidelines.   
 
 


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Table 1. ART in ODYSSEY A (First-line treatment) 
Population 
 
Examples of first-line ART regimens for SOC 
NNRTI + 2or3 NRTI 
bPI + 2NRTI 
INSTI +2NRTI 
Children <3 
years 
WHO 2016§ 
preferred first-line 
 
LPV/r + ABC(or ZDV) + 
3TC 
 
Other first line 
options 
NVP + ABC(or ZDV) + 3TC 
 
RAL+ ABC(or ZDV) + 3TC 
NVP + ZDV + ABC + 3TC* 
 
 
Children 3 to 
<10 years 
WHO 2016§ 
preferred first-line 
EFV + ABC + 3TC 
 
 
Other first line 
options 
NVP + ABC + 3TC 
LPV/r + ABC+ 3TC 
RAL + ABC +3TC 
EFV(or NVP) + ZDV +3TC 
ATV/r + ABC + 3TC 
RAL + ZDV +3TC 
EFV(or NVP) + TDF + 
3TC(or FTC) 
LPV/r (or ATV/r) + ZDV 
+ 3TC 
 
Adolescents 
WHO 2016§ 
preferred first-line 
EFV + TDF + 3TC(or FTC) 
 
 
Other first-line 
options 
EFV + ABC + 3TC(or FTC) 
ATV/r (ATV/c or DRV/r 
or DRV/c) + TDF(TAF or 
ABC) + 3TC(or FTC) 
EVG/c+TDF (or TAF)+FTC 
EFV(or NVP) + ZDV + 3TC 
ATV/r(ATV/c or DRV/r 
or DRV/c) + ZDV + 3TC 
RAL + ABC +3TC 
NVP + TDF(TAF or ABC) + 
3TC(or FTC) 
LPV/r + TDF(TAF or 
ABC) + 3TC(or FTC) 
RAL + ZDV +3TC 
RPV + TDF(TAFor ABC) + 
3TC(or FTC) 
LPV/r + ZDV +3TC 
 
§ World Health Organization. Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV 
infection: recommendations for a public health approach – 2nd ed. June 2016. Available: 
http://apps.who.int/iris/bitstream/10665/208825/1/9789241549684_eng.pdf?ua=1    
*For infants and children aged less than 3 years, at the sites where this regimen is routinely used 
 
5.2.2 
SOC ODYSSEY B 
For all children failing their first-line regimen, adherence issues should be addressed prior to switching 
to second-line as per standard practice in the clinic. Children and adolescents are eligible for 
enrolment once their clinician decides to switch them to second-line. Once daily regimens should be 
considered where possible to sustain adherence.  
The choice of second-line ART will be based on international (WHO, PENTA, US) or national guidelines. 
See Table 2 for possible second-line ART options.  
 
 


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Table 2. ART in ODYSSEY B (Second-line treatment) 
§ World Health Organization. Consolidated guidelines on the use of antiretroviral drugs for treating and preventing 
HIV infection: recommendations for a public health approach – 2nd ed. June 2016. Available: 
http://apps.who.int/iris/bitstream/10665/208825/1/9789241549684_eng.pdf?ua=1   
*NRTI for second-line - at least one NRTI with preserved activity (measured by resistance tests or presumed from the 
history of previous ART) from ABC, TDF/TAF or ZDV. Didanosine or d4T may be used in second-line where no other 
drugs are available. 
 
In countries, where resistance tests are routinely performed, the cumulative results of all resistance 
tests should be taken into account. Resistance tests give the most reliable results when collected while 
the patient is still taking the failing regimen or within 4 weeks of stopping the drugs. If the tests are 
taken without drug pressure, they may give false negative results (show no resistance mutations) and 
should not be relied on when choosing the second-line ART. 
 
In general, children with treatment failure on an NNRTI-based regimen are switched to a bPI-based 
regimen.  Children experiencing treatment failure on bPI-based ART may be switched to a more potent 
bPI (for example change of LPV/r to DRV/r in children >3 years) or to an NNRTI-based or INSTI-based 
regimen if adherence can be assured.  
 
5.3 
DTG ARM 
Children randomised to the DTG-containing regimen (DTG-arm) will receive DTG plus 2 NRTIs, with at 
least one NRTI having preserved activity.  The choice of NRTI will be at the clinician’s discretion and 
depend on guidelines and drug availability (See Section 5.2 above on choice of NRTI backbone for the 
first and second-line ART in the participating sites). 
Population 
Examples of sequencing of ART regimens following treatment failure on first-line for 
SOC 
Failed first-line  
WHO 2016§ preferred 
second-line  
Other second-line options 
 Children <3 years 
NVP + 2NRTI 
LPV/r + 2NRTI* 
RAL + 2NRTI* 
LPV/r + 2NRTI 
RAL + 2NRTI* 
NVP + 2NRTI* 
Children 3 to <10 years 
EFV(or NVP) + 2NRTI 
LPV/r + 2NRTI* 
DRV/r(or ATV/r) + 2NRTI* 
LPV/r + 2NRTI 
EFV + 2NRTI* 
RAL + 2NRTI* or 
DRV/r(or ATV/r) + 2NRTI* 
Adolescents 
EFV(or NVP) + 2NRTI 
ATV/r (or LPV/r) + 2NRTI* 
DRV/r (or DRV/c) + 2NRTI* 
or 
EVG/c +TAF + FTC 
 
LPV/r + 2NRTI 
- 
RAL + 2NRTI* or 
DRV/r(or DRV/c) + 2NRTI* 
or 
ATV/r(or ATV/c)+2NRTI* 
or 
EFV (orNVP or RPV) + 
2NRTI* or  
EVG/c +TDF(or TAF) + FTC 


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For children starting second-line ART, the same considerations should be given to addressing 
adherence, as outlined in the previous section (Section 5.2.2).   
 
Options for drug regimens for ODYSSEY A: 
 
 
DTG + ABC + 3TC 
 
DTG + ZDV + 3TC 
 
DTG + TDF + 3TC (or FTC) 
 
DTG + TAF +3TC (or FTC) 
 
Options for drug regimens for ODYSSEY B:  
 
 
DTG + 2 NRTI  
 
At least one of the NRTIs from ZDV, ABC, TDF (or TAF) should have preserved activity (measured by 
resistance tests or presumed from the history of previous ART). D4T or ddi may be used where the 
listed NRTIs are contraindicated or not available.   
 
5.3.1 
DTG 
Dosing will be once daily according to weight bands (Table 3). The dose should be adjusted 
accordingly for a child who moves weight band. Children 3 - <14kg are enrolled via the Lower Weight 
Band PK (WB-PK) substudy (Appendix XIII) until the doses are confirmed acceptable and safe.  
 
On the basis of WB-PK1 part I [43] and WB-PK1 part II [44] results (see Appendix XIII), reviewed by 
the IDMC, TMT, TMG and TSC, the TSC made a recommendation that all children ≥20kg should be 
changed to DTG 50mg FCT. Patients 14-<20kg who participated in PK substudies on 25mg DT should 
continue on the same dose. Participants on 30mg DT who remain in the same weight band should 
complete 24-weeks follow-up before moving to DTG 50mg FCT.  
 
Following the review of the results of the ongoing PK substudies, other DTG doses and formulations 
may be studied with accompanying PK as appropriate. 
 
Based on ODYSSEY WB-PK2 results [45] (see Appendix XIII), reviewed by IDMC, TMT<TMG and TSC, 
the TSC recommended that children in the weight bands 25 - <40kg previously receiving DTG 25mg 
(<30kg) or 35mg (30 - <40kg) should be changed to DTG 50mg QD (film-coated tablet).  
 
Table 3: Dolutegravir dosing in ODYSSEY 
WHO  
Wt bands, kg  
Once daily DTG dose and formulations  in ODYSSEY  
5mg, 
Dispersible tablet 
50mg, 
Film-coated tablet 
3-<6  
1 (5mg) / 2 (10mg)* 
 
6-<10 
3 (15mg)* 
 
10-<14 
4 (20mg)* 
 
14-<20 
5 (25mg)§ 
 
20-<25 
- 
1 (50mg)¥ 
25-<35 
- 
1 (50mg) 
≥35 
- 
1 (50mg) 
 Infants <6 months of age should receive DTG 5mg QD while infants ≥6 months of age should receive DTG 10mg QD, both as dispersible 
tablets.  


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* Children 3-<14kg will be recruited at WB-PK sites and must be willing to go into the PK substudy if randomised to DTG (Lower WB-PK1 
substudy); first children 6-<14kg will be recruited aged ≥6 months (Appendix XIII). The dose may be modified based on data from the ongoing 
P1093 study and the data from this study.  
§ Children 14-<20kg previously receiving either DTG 20mg QD as two 10mg film-coated tablets or DTG 25mg QD as one film-coated tablet 
will be changed to DTG 25mg QD given as five 5mg dispersible tablets.  
¥ Children 20-<25kg previously receiving DTG 25mg QD as one 25mg  film-coated tablet were initially changed to either DTG 30mg QD (six 
5mg dispersible tablets) or DTG 50mg QD (one 50mg film-coated tablet) depending on site. From protocol v5.0, all children 20-<25kg should 
receive DTG 50mg QD as one film-coated tablet. Those who prefer to remain on DTG 30mg DT will be able to do so until they move weight 
band. 
 
Children weighing 3 to <14kg 
Children 3-<14kg will be recruited at PK sites and must be willing to go into the initial PK substudy if 
randomised to DTG (Appendix XIII).  
 
Children weighing 3-<6kg randomised to the DTG arm will receive DTG 5mg or 10mg depending on 
age (<6 months and ≥6 months of age, respectively) as dispersible tablets QD. Children 6-<10kg and 
10-<14kg receive 15mg and 20mg QD as dispersible tablets respectively (Table 3). The dose rationale 
for dosing in these weight bands is provided in Appendix XIII.  These doses (with the exception of the 
5mg DT dose for children <6 months of age and between 3-<6kg) are better aligned to the planned 
paediatric Triumeq dispersible tablet (DTG/ABC/3TC 5/60/30) which is under development  as one of 
the future mid-priority paediatric formulations recommended by WHO-led Paediatric Antiretroviral 
Drug Optimization (PADO) group [46].  
 
Based on available PK and safety data from ODYSSEY and/or P1093 (36), doses in ODYSSEY in the 3 
lowest weight bands will be reviewed and may be modified (with further PK and safety data if 
required) leading to a decision on the appropriate DTG dose for children in these weight bands. 
(Appendix XIII).  
 
Children weighing 14 to <20kg 
Children in the 14 - <20kg weight band previously receiving either DTG 20mg QD (two 10mg film-
coated tablets) or DTG 25mg QD (one 25mg film-coated tablet) will be changed to DTG 25mg QD (five 
5mg dispersible tablets; see rationale in Appendix XIII).  
  
 
Children weighing 20 to <25kg  
Children weighing 20 to <25kg previously receiving DTG 25mg QD as one 25mg  film-coated tablet 
were initially changed to either DTG 30mg QD (six 5mg dispersible tablets) or DTG 50mg QD (one 50mg 
film-coated tablet) depending on site (Appendix XIII). Following the review of PK and safety data from 
WB-PK1 part II, all children 20-<25kg will now receive DTG 50mg QD as one film-coated tablet. Those 
who prefer to remain on DTG 30mg DT will be able to do so until they move weight band.  
 
 
Children weighing 25 to <40kg  
Following the review of PK and safety data from WB-PK2 (Appendix XIII), all children 25-<40kg will 
now receive DTG 50mg QD as one film-coated tablet or as part of a fixed dose combination. 
 
Children weighing ≥40 kg  
Children in this weight band receive DTG 50mg film-coated tablet QD. 
 
In countries where a paediatric licensed DTG dose for a particular weight band differs from the doses 
to be used in ODYSSEY, the DTG dosing to be used at the site should be discussed with the lead CTU. 
 


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5.3.2 
FIXED DOSE COMBINATION OF DTG, ABC AND 3TC 
For all children above 12 years (≥40 kg), whether ART-naïve or ART-experienced (with chosen NRTI 
backbone ABC + 3TC), a three drug fixed dose combination (FDC) tablet containing DTG 50 mg + ABC 
600 mg + 3TC 300 mg (Triumeq) can be provided. 
 
Following the analysis of WB-PK2 results for children weighing 25-<40kg which were reviewed by 
ODYSSEY and ViiV experts and the IDMC, and considered acceptable, children ≥25kg on DTG and 
ABC+3TC in the main trial are able to move to FDC (DTG 50mg + ABC 600 mg + 3TC 300mg) QD provided 
they are able to swallow the large tablet. 
5.4 
DISPENSING 
For all trial drugs, the designated trial pharmacist or nurse will confirm receipt of supplies prior to the 
commencement of the trial.  Inventories will be conducted regularly, and logs returned to the 
appropriate CTU.   
 
All drugs dispensed to participants will be recorded on a dispensing log or logged online.  At each site, 
a named person (trial pharmacist or research nurse) must maintain complete records of all medication 
dispensed and returned.   
 
Throughout the treatment period, carers will be provided with a supply of drugs sufficient to last until 
the next clinic visit and will be requested to return all empty container packs and to bring any container 
packs in use or unused to the follow-up clinic.  
 
On no account should any drug assigned to a participant be used by anyone else.  Unused trial drug 
must be returned to the site if a participant withdraws from treatment. 
 
5.5 
ART MODIFICATIONS, INTERRUPTIONS & DISCONTINUATIONS 
5.5.1 
GENERAL CONSIDERATIONS ON CHANGES OF ARVs DURING THE TRIAL  
 
For both arms, should the study clinician believe ART should be interrupted, discontinued, or that a 
change in treatment is necessary, then the relevant CTU should be notified. 
 
Switching of the current ART regimen in the randomised phase should only occur if there is 
immunological, virological or clinical treatment failure (according to local clinical practice), at which 
point a new regimen should be chosen.  Resistance tests or Therapeutic Drug Monitoring (TDM) may 
be used to inform change of regimen, according to local clinical practice.  In exceptional circumstances 
where standard-of-care third-line is not available at site, and with prior agreement from the relevant 
CTU and the Trial Management Group, study drug may be used as third-line for children in the SOC 
arm who have failed second-line treatment. If simplification of the ART regimen in the randomised 
phase is deemed necessary for clinical reasons during follow-up, this may be allowed, but must first 
be discussed with the appropriate CTU. In the extended follow-up phase simplification is allowed and 
could be done as per routine practice. 
 
If a female participant on DTG-based regimen is identified as pregnant within the first 8 weeks after 
their last menstrual period, the site clinician should discuss the risks and benefits of their current 
regimen. If there are other good options to replace DTG, then switching to a non-DTG ART regimen is 
recommended. 
 


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Toxicity will be managed according to standard clinical practice.  Blood tests additional to those 
described in the trial schedule may be requested for clinical management of the participant.  
Wherever possible and appropriate, side effects will initially be managed by symptomatic measures 
and administration of appropriate (non-contraindicated) medication.  Interruption or substitution of 
drugs should be avoided except in the event of grade 3 or 4 toxicity that is considered at least possibly 
related to one or more of the ARVs.  Wherever possible, an alternative ARV should be substituted 
from the same class in order to maintain the participant’s randomised treatment strategy.  
 
Management of adverse events/toxicity should generally follow the criteria below, but clinicians 
should use their clinical judgment as to the best management for an individual participant.  If in doubt, 
contact the relevant CTU to obtain advice. 
 
NOTE: In the event of a discontinuation of an ABC-containing product for any reason (aside from 
possible hypersensitivity), re-initiation of this drug should be undertaken with caution.  The 
investigator must obtain a complete history of the events surrounding the discontinuation of the ABC-
containing product and evaluate for the possibility of a clinically suspected hypersensitivity reaction 
(HSR) to ABC.  Regardless of a subject’s HLA-B*5701 status, if a hypersensitivity reaction cannot be 
excluded, then ABC must not be restarted. 
 
Grade 1 and 2 
 
Continue ARVs 
 
Manage using symptomatic measures and other concomitant medication, if appropriate 
 
Raised serum aminotransferase ≥3xULN and total serum bilirubin level ≥2xULN (or coagulopathy (INR 
>1.5) without hyperbilirubinemia) may indicate idiosyncratic drug induced liver injury [47] and 
recommendations for Grade 3 or 4 toxicity events as outlined below should be followed. 
 
 
Grade 3 or 4:  
 
Request laboratory results and repeat confirmatory laboratory results within 72 hours if 
relevant 
 
Continue study drugs pending receipt of the confirmatory laboratory tests/repeat 
observations, unless there is an immediate need to substitute ART 
 
Continue to work-up to exclude other causes  
 
Following confirmation of toxicity, and lack of other cause data:  
 
if the child is not too sick, substitute ART immediately  
 
otherwise, stop all drugs and restart with substituted drugs when the child has 
improved  
 
stagger stop NNRTI wherever possible to avoid functional monotherapy and risk of 
resistance (as per PENTA/national guidelines) 
 
   
5.5.2 
ADVERSE REACTIONS & DISCONTINUATIONS OF DTG 
5.5.2.A Liver toxicity 
Stopping criteria based on liver function test thresholds have been designed to assure participant 
safety during administration of the medication and the follow-up period.  It may be necessary to 
substitute DTG should any of the following criteria be met: 
 
ALT ≥3xULN and bilirubin ≥2xULN  
 
ALT ≥5xULN and symptoms of acute hepatitis or hypersensitivity (fatigue, nausea, vomiting, 
right upper quadrant pain, fever, rash or eosinophilia) 


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 
ALT ≥ 5xULN for more than 2 weeks with bilirubin <2xULN and no symptoms of acute hepatitis 
or hypersensitivity 
 
ALT ≥8xULN  
 
Participants who develop ALT ≥5xULN should be followed weekly until resolution or stabilization (ALT 
<5xULN on 2 consecutive evaluations). 
 
When liver chemistry stopping criteria are met, investigator must: 
 
Notify the relevant CTU of the event by e-mail within 24 hours of its occurrence and report 
the event on the Event form (see 7.1.5.A).  Additional information will then be requested from 
the sites.  
 
Discontinue DTG and substitute for an appropriate alternative (the child will continue follow 
up in the study).  If an alternative cause of the raised liver enzymes is more likely (e.g. Hepatitis 
A, anti-TB treatment) then the investigator must contact the MRC CTU.  
 
If DTG is discontinued for liver toxicity, participants should not restart DTG due to the risk of a 
recurrent reaction. If an alternative cause of the raised liver enzymes is more likely, restarting of DTG 
may be permitted but the investigator must have discussed and agreed this with the MRC CTU. 
 
 
5.5.2.B Allergic reaction or rash 
 
Participants may continue DTG for grade 1 or 2 allergic reactions or rash at the discretion of the 
investigator.  Consideration should be made as to whether another ARV or another drug maybe 
causing the reaction.  The carer/participant should be advised to contact the investigator immediately 
if there is any worsening of symptoms if mucosal involvement develops or if further systemic signs or 
symptoms develop.  Antihistamines, topical corticosteroids, or antipruritic agents may be prescribed.   
 
Participants with grade ≥2 rash that is associated with an increase in ALT OR grade ≥3 allergic reactions 
or rash that are considered to be possibly or probably related to DTG should permanently discontinue 
DTG and substitute with an appropriate alternative; the participant will remain in the study.  
Investigators should contact the CTU to discuss cases if there is any uncertainty about the course of 
action.  Participants should be treated as clinically appropriate and follow-up of the AE should be 
reported on CRFs as appropriate. 
 
Participants receiving an ABC-containing product should be evaluated for the possibility of a clinically 
suspected HSR and managed appropriately as outlined in the local product information, regardless of 
a subject’s HLA-B*5701 status. 
 
5.5.2.C Suicidal Ideation Behaviours and Sleep Disorders 
 
Participants with HIV infection may occasionally present with symptoms of depression and/or 
suicidality (suicidal ideation or behaviour). In addition, insomnia and depression have been 
infrequently reported with the use of several antiretroviral drugs, including efavirenz, darunavir, 
atazanavir and integrase inhibitors. Suicidal ideation has also been associated with efavirenz and 
integrase inhibitors, primarily in patients with pre-existing depression or psychiatric conditions.  
Therefore, participants in both arms in ODYSSEY should be monitored appropriately for suicidal 
ideation and behaviour or any other unusual changes in behaviour. It is recommended that the 
subjects who experience signs of suicidal ideation or behaviour have prompt clinical evaluation and 
the investigator considers mental health consultation or referral and discontinuation of the 
corresponding drugs. See section 7.1.5 C for reporting of these events. 
 


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5.6 
ACCOUNTABILITY & UNUSED DRUGS/DEVICES 
Procedures for drug shipping, labelling, resupply, accountability and destruction will be detailed in the 
ODYSSEY Pharmacy MOP.  Drug accountability will be regularly monitored and the remaining stocks 
checked against the amounts dispensed. 
 
5.7 
ADHERENCE & ACCEPTABILITY 
Adherence to ART will be assessed by pill counts and short adherence questions at study visits (see 
Appendix IV).  The importance of adherence should be reinforced at each visit.  Non-adherence should 
prompt the study clinician to identify and address the cause(s) (e.g. side effects, social challenges). 
An acceptability, sleep and mood questionnaire at enrolment and at weeks 4, 12, 24, 48, 72, 96 and 
then 24 weekly until the end of study, will elicit participant opinions about the different regimens, 
particularly with regard to pill burden; complexity and stigma (see Appendices V-VI). At enrolment,  
only the questions about sleep and mood should be answered. 
5.8 
OVERDOSE OF TRIAL MEDICATION 
All participants/carers should be counselled about the importance of taking/administering the 
medications as prescribed.  It is particularly important that participants and carers understand the 
quantity of medicines they should be given.  Participants must be told to contact the clinic immediately 
if they take too much medication.  If the overdose fits the criteria of an SAE (see Section 7.1) it should 
be reported appropriately.   
 
5.9 
PROTOCOL TREATMENT DISCONTINUATION 
In consenting to the trial, participants and carers are consenting to trial treatment, trial follow-up and 
data collection.  However, an individual participant may stop treatment early for any of the following 
reasons: 
 
(i) Unacceptable toxicity (clinical or laboratory) or adverse event 
(ii) Disease progression necessitating change of regimen  
(iii) Virological failure 
(iv) Withdrawal of consent for treatment by the participant or carer 
 
As the child’s participation in the trial is entirely voluntary, they or their carer may choose to 
discontinue the trial treatment at any time without penalty or loss of benefits to which they are 
otherwise entitled.   
 
Although the participant and/or carer are not required to give a reason for discontinuing their trial 
treatment, reasonable effort should be made to establish this reason while fully respecting the 
participant’s rights. 
 
Participants should remain in the trial for the purpose of follow-up and data analysis (unless the 
participant or carer withdraws their consent from all stages of the trial). If a patient is withdrawn 
from follow-up, refer to Section 6.9. 
 
Data will be kept and included for participants who stop follow-up early, up to the point of exit. 
 


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5.10 NON-TRIAL TREATMENT AND SIGNIFICANT DRUG INTERACTIONS 
Families and participants should be advised to notify their clinician of any current or proposed 
concomitant medication, whether prescribed or over-the-counter.  All necessary concomitant 
medications will be recorded in the study CRFs. 
 
Dofetilide, a class III antiarrhythmic agent, not licensed in children <18 years, is the only drug that is 
contraindicated for co-administration with DTG. 
 
A few drugs have important drug interactions with DTG and require dose adjustment of DTG or their 
intake should be separated in time.  Table 4  shows some of the interacting drugs that may be relevant 
for the patients in ODYSSEY. For full information see dolutegravir SPC.   
 
 
Table 4. Significant drug interactions with DTG and recommended actions 
 
Anticonvulsants  
Oxcarbazepine 
Phenytoin 
Phenobarbital 
Weight-appropriate dose of DTG should be doubled (given twice 
daily).  
Sodium valproate 
Careful clinical and adherence monitoring are advised and a 
repeat VL can be considered. 
Herbal products  
St. John's wort  
Weight-appropriate dose of DTG should be doubled (given twice 
daily).  
Antacids and supplements  
Magnesium/ aluminium-
containing antacid  
Calcium supplements  
Iron supplements  
Multivitamin  
Calcium supplements, iron supplements or multivitamins should 
be taken well separated in time from the administration of DTG 
(minimum 2 hours after or 6 hours before DTG). Alternatively DTG 
can be taken with food. 
 
Antimycobacterials  
Rifampicin  
Weight-appropriate dose of DTG should be doubled (given twice 
daily). 
 
Please refer to DTG SmPC (https://www.medicines.org.uk/emc/product/5248/smpc ) and               
the University of Liverpool HIV Drug Interactions site (https://www.hiv-
druginteractions.org/drug_queries/new) for the full list of the possible drug interactions.  


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6 
ASSESSMENTS & FOLLOW-UP 
Trial visit schedules will be prepared for each participant at randomisation, and participants should be 
followed on the same schedule even if their trial medication is discontinued.  The target dates for trial 
visits are determined by the date of randomisation and are not affected by subsequent events.  The 
schedule sent or generated after randomisation defines visit dates (with windows) necessary for data 
collection, but the participant may be seen more frequently for clinical care as needed.   
 
Participants should attend on the scheduled day whenever possible, unless agreed in advance with 
the clinic.  Clinics may choose to re-schedule visits to allow for public holidays or other unavoidable 
circumstances that affect the scheduled visit date.  During the treatment period, if participants are 
unable to attend on the day, every effort should be made to complete the visit as soon as possible and 
within 14 days of the scheduled date.  If a scheduled visit is missed without notice then the research 
team should endeavour to contact the participant by phone or by home visit.   
If a participant is more than 14 days late for a scheduled study visit (during the treatment period), an 
additional visit will be performed as soon as possible, including the appropriate assessments that were 
specified in the trial schedule for the visit week that was missed. 
 
6.1 
TRIAL ASSESSMENT SCHEDULE  
6.1.1 
RANDOMISED PHASE 
All participants will be seen at screening, enrolment (randomisation, week 0) and then at weeks 2 (for 
children 3-<14kg), 4, 12, 24, 36, 48, 60, 72, 84 and at week 96 (see Trial Assessment Schedule).  All 
participants should then be followed-up in clinic every 12 weeks until the last participant enrolled up 
to the end of recruitment for the main trial (see 3.4) reaches week 96 or for a minimum of 96 weeks, 
whichever is greater.  Clinical assessment at week 2 is required for children 3-<14kg and optional for 
children ≥14kg at sites with the standard practice to review participants at 2 weeks after starting new 
antiretrovirals. 
 
A full clinical assessment and the following will be undertaken as specified in the Trial Assessment 
Schedule: 
 
Medical history since last visit including intercurrent illnesses, all AEs, signs and symptoms of 
HIV disease with WHO stage on every visit 
 
Weight, height and mid-upper arm circumference (MUAC) on every visit  
 
Viral load as per local practice (in ODYSSEY B viral load must be measured at screening unless 
the viral load has been done within 4 weeks prior to screening)  
 
Haematology at screening, weeks 0, 2 (for children 3-<14kg), 4, 24, 48, 72, 96 and at the study 
visit at the end of the randomised phase, and at other time points as per local practice. 
 
T cell lymphocyte subsets at screening, weeks 0, 4, 12, 24, 48, 72, 96 and at the study visit at 
the end of the randomised phase, and at other time points as per local practice.  
 
Plasma storage at screening, week 0, 4, 12 and then 12 weekly and at the study visit at the 
end of the randomised phase. 
 
RBC folate/RBC storage and B12/serum storage at week 96 or later 
 
Cell storage (at the selected sites) at week 0, 12, 48, and 96 
 
Biochemistry at screening, 2 (for children 3-<14kg), week 4, 24, 48, 72 and 96 and at the study 
visit at the end of the randomised phase, and if indicated or if required by local practice.  
Participants should be fasting at week 0, 48 and 96, every 48 weeks and at the study visit at 
the end of the randomised phase in order to obtain fasting lipids and glucose values 
 
Bone profile (optional) at randomisation, week 48, 96 and then 48 weekly, and at the study 
visit at the end of the randomised phase at the sites where these tests are done routinely 


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 
Urine dipstick at randomisation, week 48, 96 and then 48 weekly, and at the study visit at the 
end of the randomised phase. 
 
Tanner scales (see Appendix X) should be completed at week 0 and repeated every 24 weeks 
(unless previous scores of 5) until the study visit at the end of the randomised phase in 
children aged 8 or over. 
 
Lipodystrophy clinical assessment should be performed at week 0 and repeated at weeks 48 
and 96 then 48 weekly and at the study visit at the end of the randomised phase. 
 
Pregnancy tests should be performed for all females of childbearing potential at screening, 
randomisation and all trial follow-up visits (including unscheduled visits), regardless of 
whether the participant has recently had her period.  All boys and girls of reproductive age 
will be given continuing advice about avoiding pregnancy; information about contraception 
use will be recorded.  If a pregnancy test performed during the trial is positive, please notify 
the appropriate CTU, following procedures detailed in Sections 6.8 and 7.2.1. 
 
In addition at each visit the following should be recorded: 
 
Assessment of adherence to ART by adherence questionnaire while the participant is on 
treatment  
 
Changes in ART and other concomitant medication 
 
All adverse events since the last protocol visit, including haematological abnormalities, 
pancreatitis, diarrhoea, clinical lipodystrophy, acute illnesses  
 
Change in HIV disease stage since last protocol visit 
 
Inpatient and outpatient attendances with any documented test results 
 
The next supply of drugs to last until the next clinic visit will be dispensed.  Prescriptions of ART and 
any alterations to prescribed doses should be recorded on the CRF.  Doses should be checked at every 
visit and adjusted for body surface area, or weight as appropriate. 
 
Additional study visits, for example if the child develops drug toxicity or other clinical events should 
be recorded using appropriate forms.  At such visits, laboratory tests should be performed as clinically 
indicated.  Participants will also be given a patient card with the contact details for the trial research 
team at their site and information on ABC hypersensitivity if receiving ABC. 
 
For the frequency of the assessments after week 96, see the Trial Assessment Schedule. 
 
6.1.2 
EXTENDED FOLLOW-UP OF ODYSSEY PARTICIPANTS 
When participants attend for their study visit at the end of the randomised phase (after the last patient 
reaches 96 weeks for children recruited weighing ≥14kg or the 96 week visit for children <14kg), 
consent/assent will be requested in order for them to enter into a period of extended follow-up. The 
purpose of this extended follow-up is to collect further safety data for participants who will continue 
to receive ViiV Healthcare supplied dolutegravir (where the formulation that they are taking is not 
available through the country’s national HIV treatment programme) and also to monitor long-term 
safety and effectiveness of dolutegravir versus standard of care (at selected sites, subject to sufficient 
funding). The child’s visit schedule and care will be as per local clinic guidelines with a small amount 
of data to be collected in addition to this. Please see Appendix XX for further details on the 
arrangements for extended follow-up. 
6.2 
PROCEDURES FOR ASSESSING EFFICACY 
6.2.1 
CLINICAL: 
A symptom checklist and targeted physical examination (to evaluate any reported symptoms) will be 
performed at each visit during the randomised phase.  Hospital admissions will be solicited at all visits, 


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regardless of the trial phase.  Where there is any clinical suspicion of a WHO Stage 3 or 4 disease event, 
centres will endeavour to investigate to the full extent possible given local availability of imaging and 
laboratory investigations (particularly microbiology) in order to establish a clear diagnosis of the event.  
The lists of WHO stages and diagnostic criteria are provided (see Appendices VII-IX).  The site will 
report the event and the clinical investigations that support the diagnosis on the Event form in order 
to enable an independent evaluation of the event.  An endpoint review committee will review all 
clinical endpoints occurring during the randomised phase to ensure that they satisfy the diagnostic 
criteria.  
 
6.2.2 
IMMUNOLOGY: 
Blood will be collected according to the appropriate trial assessment schedule, depending on whether 
the participant is in the randomised phase or extended follow-up period of the trial, for the 
determination of total and percentage CD4 and CD8 T cell counts. The T cell subsets will be measured 
using the standard assay in the laboratory operating at each site according to quality-assured 
procedures. 
 
 
6.2.3 
VIRAL LOAD TESTING: 
At sites where plasma HIV viral load (VL) is routinely measured every 12-16 weeks, VL should be 
measured at screening, week 4, 12, 24 and then every 12 weeks until the study visit at the end of the 
randomised phase.   
 
At the sites where VLs are not routinely measured every 12-16 weeks, real-time viral load should be 
measured at the screening visit for participants in ODYSSEY B, unless one has been done within 4 
weeks prior to screening. Viral loads should then be done according to local routine practice.  Viral 
loads will be measured retrospectively on EDTA-plasma samples stored at screening, enrolment 
(ODYSSEY A), week 4, 12, 24, and then every 12 weeks until the end of the randomised phase.  
Retrospective VL measurements will be done in batches using the same assay (lower limit of detection 
of no greater than 50 c/ml) in one or more designated PENTA laboratories.  The Independent Data 
Monitoring Committee (IDMC) (Section 14.3) will review VL results on all patients during the 
randomised phase.   
If the participant meets the definition of treatment failure during the trial (WHO 2016 guidelines), and 
the treating physician wishes to modify treatment, they may perform a VL test at their site, to confirm 
treatment failure prior to switch.  In this situation the management of the participant will be discussed 
with the relevant CTU and the trial Clinical Advice Group.  
 
6.2.4 
RESISTANCE TESTING 
At sites where genotypic resistance testing is part of routine care, for children experiencing virological 
failure tests should be run on the latest sample while the child is still on the same treatment.  At sites 
where genotypic resistance testing is not a part of routine care baseline samples will be tested 
retrospectively using stored EDTA-plasma to assess background regimen activity at baseline and 
batched genotypic resistance testing will be performed on the samples with viral load  reaching 
current threshold for resistance assays.   Additional resistance tests will be performed on stored 
plasma samples in selected participants at the end of the randomised phase of the trial to define in 
more detail the pattern of resistance development. Samples may be assayed locally where possible, 
or moved to another country. 
Drug resistance mutations will be classified using the Stanford database algorithm.  The results of all 
resistance tests performed in individual participants will be given to the treating physician after the 
last participant has completed 96 weeks follow-up, or as soon thereafter as results become available.   
 


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6.3 
PROCEDURES FOR ASSESSING SAFETY 
The clinical examination at each visit will explicitly prompt for symptoms relating to possible drug 
toxicities.  Blood will be drawn at trial visits to assess laboratory safety parameters as per the 
appropriate Trial Assessment Schedule depending on whether the participant is in the randomised 
phase or extended follow-up period of the trial.  Additional safety blood tests or investigations may 
be performed to investigate symptoms or monitor emergent laboratory test abnormalities as clinically 
indicated.  
 
Adverse events will be reported on the case report form.  Adverse events (clinical and laboratory) will 
be graded using the 2014 Division of AIDS toxicity grading scale (see Appendix IX).  Grade 1 and 2 
clinical events do not need to be reported unless resulting in a change of ART regimen.  Serious adverse 
events will be defined according to ICH GCP, and should be reported to the CTU within 24 hours of the 
site being aware (see Section 7 - Safety Reporting).  All adverse events meeting the definitions above 
should be reported on study CRFs, regardless of their relationship to HIV.   
 
6.4 
PROCEDURES FOR ASSESSING QUALITY OF LIFE 
Quality of life questionnaire adapted from EQ-5D questionnaires [48] should be completed by all 
children aged 8 or over, regardless of which arm they are in, at randomisation (week 0), 12, 24, 48 
weeks and then every 48 weeks and at the study visit at the end of the randomised phase. 
6.5 
ADHERENCE ASSESSMENTS 
Adherence issues should be addressed with potential participants in ODYSSEY B before screening for 
the trial and an adherence questionnaire should be completed at the screening visit.  At 4 and 12 
weeks and thereafter every 12 weeks until the end of the randomised phase, carers and children, 
where appropriate, will be asked to complete an adherence questionnaire.  This will include questions 
about adherence to all the antiretrovirals.   
 
6.6 
MANAGEMENT OF PARTICIPANTS WITH TREATMENT FAILURE 
 
In settings where viral load measurement is part of routine care, viral loads will be measured 
locally.  Participants experiencing virological failure should have reasons for virological failure 
investigated as per local practice (addressing problems with adherence, adequate dosing, 
drug interactions, and if available, drug levels, resistance mutations) prior to decisions being 
made about switching ART.  ART management decisions (discontinuation of the previous 
regimen, change to the new regimen) should also be made by the treating clinician as per 
accepted local practice.  Advice from the Clinical Advice Group should be sought during the 
randomised phase of the trial and the CTU also contacted.  The participant should continue to 
be seen 12 weekly until the end of the randomised phase (see Trial Assessment Schedule for 
randomised phase of the trial).  Participants should follow local practice at subsequent visits.  
CRFs should be completed at each follow up visit.   
 
 
In settings where viral load measurement is not routine care, the efficacy of treatment will be 
monitored using clinical assessment and local CD4 cell counts/percentage.  During the 
randomised phase, therapy will be maintained according to the randomised strategy until 
there is clinical or immunological failure, defined for the protocol as after at least 36 weeks 
on the allocated regimen.  Where available, a targeted viral load should be done to confirm 
treatment failure prior to switch.  If the treating clinician decides to switch therapy, then the 


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next regimen should be given according to guidelines and paediatrician choice and based on 
the local availability of antiretrovirals; advice can also be obtained from the Clinical Advice 
Group.  The clinician can at any stage give alternative treatment to that specified in the 
protocol if it is considered to be in the participant’s best interest.  However this should be 
discussed first with the CTU if the participant is in the randomised phase of the trial.  
 
6.7 
MANAGEMENT OF CHILDREN DIAGNOSED WITH TUBERCULOSIS (TB) 
Participants with TB at enrolment or who develop TB during the trial should receive TB treatment 
following national guidelines (usually rifampicin, isoniazid, pyrazinamide, and ethambutol).  Where 
available, cultures should be tested for sensitivity to first-line anti-TB drugs and regimens modified on 
the basis of these results.  
 
Participants may need to be referred to the national TB treatment programme in order to access anti-
tuberculosis medication, and close liaison between the trial team and the TB treatment providers will 
be required.  
 
6.7.1 
MANAGEMENT OF CHILDREN WITH TUBERCULOSIS INFECTION IN THE DTG ARM 
DTG pharmacokinetics are influenced by concomitant treatment with rifampicin. This interaction can 
be overcome by giving the weight-appropriate dose of DTG twice daily, i.e. the protocol daily dose is 
doubled.  
 
Therefore, in a child on rifampicin, the DTG dose needs to be increased from QD to BID and remain 
BID until 2 weeks after the last dose of rifampicin has been given (the enzyme inducing effect of 
rifampicin slowly fades away after discontinuing the drug).  
 
Although not compulsory, at least 12 children in the DTG arm receiving rifampicin as part of anti-TB 
treatment or TB prevention therapy will be invited to participate in the TB substudy for children on 
DTG and rifampicin (see Section 10.1.3 and Appendix XIV).   
 
6.7.2 
MANAGEMENT OF CHILDREN WITH TUBERCULOSIS IN THE SOC ARM 
As rifampicin interacts with some ARVs, including PIs and NNRTIs, change of regimen may be needed 
for co-infected children in SOC arm.  Guidance on the choice of ART for children with TB can be found 
in the WHO 2016 guidelines and in national guidelines and may differ between countries.  Children 
who are on EFV-based ART can continue on the same regimen while those (>3 years) receiving NVP 
should be switched to EFV.  Children receiving LPV/r-based ART can continue on their regimen if they 
receive super-boosted ritonavir (increasing ritonavir to achieve a LPV/r ratio of 1:1), or they can be 
switched to EFV (if >3 years).  As an alternative, children receiving NVP or LPV/r with rifampicin may 
change to triple NRTI (ZDV + 3TC + ABC) [49] or the NVP dose should be increased to the maximum 
recommended, i.e. 200 mg/m2 BID.  In order to obtain better exposure in younger children, the 
maintenance dose can be further increased by 20-30% after two weeks of starting (H Lyall, S Welch, 
unpublished data).  CTUs should be notified and advice sought from the Clinical Advice Group.  
 
6.8 
MANAGEMENT OF PREGNANCY 
Reproductive toxicology animal studies, including embryofoetal development studies in rats and 
rabbits, showed no evidence of adverse developmental outcomes [34].    
 
A National Institutes of Health (NIH)-funded observational surveillance study in Botswana (TSEPAMO) 
evaluating the safety of ART regimens in pregnancy has recently identified an increased risk of neural 


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tube defects (NTD) amongst infants of women who initiated DTG-based regimens prior to pregnancy 
(see Background). This study and other surveillance studies are ongoing and other reproductive 
studies on DTG safety have been initiated. More data on safety of DTG for women of childbearing age 
and their infants are expected in the next year. 
 
All eligible girls with childbearing potential will be counselled about the potential risks associated with 
pregnancy during the trial and the potential risks of antiretroviral therapy on the infant.  If the girl 
then chooses to enter the trial, she will be advised to use highly effective contraception and to report 
to the study site staff as soon as possible if there is a possibility of pregnancy. 
 
Following the safety alert, ODYSSEY sites were advised that all female participants who are sexually 
active must use highly effective contraception [38]. This includes: 
1. Combined (estrogen and progestogen containing) hormonal contraception associated with 
inhibition of ovulation 
a. oral 
b. intravaginal 
c. transdermal 
2. Progestogen-only hormonal contraception associated with inhibition of ovulation 
a. oral (eg. containing 75 micrograms desogestrel) 
b. injectable 
c. implantable 
3. Intrauterine device (IUD) 
4. Intrauterine hormone-releasing system ( IUS) 
 
DTG has no interaction with hormonal contraceptives, and therefore any hormonal contraceptives 
inhibiting ovulation can be used in female participants in the DTG arm. For participants in the SOC 
arm, the site clinician should consider drug interactions between some third agents (nevirapine and 
protease inhibitors) and a number of hormonal contraceptives. Please refer to the table 
‘Recommendations for co-administration of different types of contraception with antiretrovirals in the 
MOP for guidance on prescribing hormonal contraceptives for participants. 
 
Pregnancy testing will be undertaken at screening and randomisation in girls who have reached 
menses.  If pregnant, she will be ineligible for the trial.  For randomised females who have reached 
menses, pregnancy tests will be repeated at all trial follow-up visit and at other time-points as 
required.  Females will be encouraged to disclose missed menses as soon as possible; if this happens, 
a pregnancy test should be done.  
 
Female participants taking DTG who are intending to become pregnant or are identified to be 
pregnant, need to discuss the risks and benefits of their current regimens with their health care 
providers. The neural tube closes within 4 weeks of conception and therefore switching off DTG is 
particularly relevant for women diagnosed with pregnancy early. If women are in very early 
pregnancy (within 8 weeks from last menstrual period) and there are other good options to replace 
DTG, then switching to a non-DTG ART regimen is strongly recommended as per DHHS guidance [50].  
 
Those who are pregnant and are 8 weeks or greater from last menstrual period may continue DTG-
based regimens. Discontinuing DTG-based regimens is unlikely to confer any benefits after the 
neural tube has formed, and medication changes during pregnancy could increase the risk of viremia 
and transmission of HIV to the infant.  
There is also a risk that a young person may become non-adherent if their DTG-based ART regimen is 
well tolerated but this is then changed. The clinician should therefore use his/her judgement about 
whether benefits of continuing a pregnant woman on DTG-containing products are deemed to 
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risk of poor adherence on alternative ART regimen, especially if pregnancy comes to light late and 
near to the time of delivery).  Where local regulatory regulations allow, the woman may continue 
DTG and the case should be discussed with MRC CTU.  Pregnant participants should be encouraged 
to remain in the study whether or not their ART regimen is changed at this time. 
Pregnant participants should receive counselling about their options and receive support to make 
decisions about continuing pregnancy.  Folic acid should be provided to be taken throughout the first 
trimester. For females on DTG who become pregnant, advice on breast-feeding will be given according 
to local or national lactation and treatment guidelines and standard of care.  All infants will receive 
infant prophylaxis according to the current local standard of care. 
 
Reporting of pregnancy and pregnancy-related events are outlined in section 7.1.5.D. 
 
 
6.9 
EARLY STOPPING OF FOLLOW-UP 
If a participant or their carer chooses to discontinue the trial treatment, the participant should 
continue to be followed until the end of the trial providing the participant and their carer are willing; 
that is, they should be encouraged not to leave the trial.  However, if the participant and/or carer do 
not wish to remain on trial follow-up, they should be offered the option of continuing with routine 
follow up and permission to collect minimal routine outcomes from the patient’s notes should be 
requested.  If they do not wish to provide information about routine follow up, their decision must be 
respected and the patient will be withdrawn from the trial completely.  The CTU should be informed 
of this in writing using the appropriate documentation.  Participants stopping early have a negative 
impact on a trial's data. 
 
If the medical data collected during the participant's time in the trial are kept for research and analysis 
purposes, they can be further anonymised if necessary.  Consent for future (but not past) use of stored 
samples already collected can be refused when leaving the trial early (but this should be discouraged 
and should follow a discussion with the patient/carer). 
 
Participants and carers may change their minds about stopping trial follow-up at any time and re-
consent to re-enter participation in the trial. 
 
Participants who stop trial follow-up early will not be replaced, as the total sample size includes an 
adjustment for losses to follow-up. 
 
6.10 PARTICIPANT TRANSFERS 
If a participant moves from the area, reasonable efforts should be made to continue their follow-up, 
e.g. by them continuing to come for visits providing the site has sufficient resources, or by conducting 
nurse only visits over the telephone and providing drugs and clinical care at a local clinic. If a local site 
is conducting the trial, the participant can be transferred there; a copy of the participant’s CRFs should 
be provided to the new site and the parent/carer 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. 
 
If none of the above options are possible, then the participant should be considered as lost to follow-
up.  The participant and/or carer may or may not choose to formally register this as a withdrawal of 
consent.   
 


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6.11 END OF TRIAL 
After target accrual is reached (see Section 3.4 and Analysis Plan Section 9.5) the end of main trial 
recruitment date will be defined. Recruitment will then stop for children ≥14kg. Recruitment will 
continue in the 3 lower weight bands (3-<6kg, 6-<10kg and 10-<14kg) until at least 20 children are 
recruited in each weight band. Follow-up for children recruited up to the end of main trial recruitment 
date will continue during the randomised phase until the last child recruited has completed 96 weeks 
follow-up; all such participants will attend a study visit for the end of the randomised phase after the 
last child reaches 96 weeks.   
 
Analysis of the main trial will be conducted at this time. Results will not be available until 
approximately 6 months after children in the main trial have attended their final study visit (in the 
randomised phase), retrospective viral load testing is complete and the database has been locked.    
Each of the children recruited in the lower weight bands after the end of main trial recruitment date 
will continue to be followed up for 96 weeks.  Children in the lower weight bands should attend for 
their study visit for the end of the randomised phase at or after 96 weeks; they should not attend for 
this visit prior to the ‘diary date’ given in the participant’s visit schedule.   
 
After the end of the randomised phase DTG will be provided by ViiV for those children randomised to 
the DTG arm until it is available and recommended for children in their country of residence. Where 
DTG is available locally, a short supply of trial stock will be provided to enable participants to transition 
smoothly onto the national antiretroviral treatment programme. Participants receiving Triumeq 
should be switched to DTG 50mg plus a separate fixed dose combination of ABC/3TC 600/300mg 
(Kivexa or generic equivalent) on the national programme if Triumeq is not available locally. 
 
Children weighing <20kg at sites in South Africa, Uganda and Zimbabwe still receiving DTG 5mg at the 
end of the randomised phase will continue into extended follow-up until they reach 20kg (and can 
switch to DTG 50mg, available locally) or generic dispersible DTG becomes available locally. Children 
weighing ≥20kg randomised to the DTG arm at these sites are expected to have access to DTG 50mg 
through their country’s national antiretroviral treatment programme by the end of the randomised 
phase of the trial. 
 
Children in Thailand randomised to the DTG arm will continue into extended follow-up so that DTG 
50mg can continue to be provided. Participants receiving Triumeq will be switched to (DTG 50mg 
provided by ViiV) plus a separate fixed dose combination of ABC/3TC 600/300mg (Kivexa or generic 
equivalent available through the national antiretroviral treatment programme) for this period. 
 
All children in DTG and SOC arms at sites in Africa and Thailand may continue into extended follow-
up, subject to sufficient funding. Children in extended follow-up will attend clinic visits as per local 
practice (see Appendix XX for more details). SAEs will continue to be reported as per trial requirements 
(Section 7). 
 
The ODYSSEY trial comprises a randomised phase and an extended follow-up phase. The end of the 
trial will be when all children have attended their final study visit (in randomised or extended follow-
up phase, any retrospective viral load testing is complete and the database has been locked for the 
end of trial. The date of the expected end of the trial will be communicated to the participating centres 
approximately 3-6 months before the trial ends.  The sponsor, or the sponsor’s representative in each 
country, will notify the national regulatory body and ethics committee of the end of the trial.  The 


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Principal Investigator at each site will be responsible for notifying local ethics boards and any other 
local bodies, such as R&D departments.   


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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 trials.  These procedures are described 
in this section of the protocol.  Section 7.1 lists definitions, Section 7.2 gives details of the investigator 
responsibilities and Section 7.3 provides information on MRC CTU responsibilities. 
 
7.1 
DEFINITIONS 
The definitions of the EU Directive 2001/20/EC Article 2 based on the principles of GCP apply to this 
trial protocol.  These definitions are given in Table 5. 
 
Table 5: Definitions 
TERM 
DEFINITION 
Adverse Event (AE) 
Any untoward medical occurrence in a patient or clinical trial 
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 (SPC) 
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 patient 
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 


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emergency treatment, seizures or blood dyscrasias that do not result in hospitalisation or 
development of drug dependency. 
 
7.1.1 
MEDICINAL PRODUCTS 
An investigational medicinal product (IMP) is defined as the tested investigational medicinal product 
and the comparators used in the study (EU guidance ENTR/CT 3, April 2006 revision).  In ODYSSEY DTG, 
Triumeq and 3rd agent comparators prescribed in the SOC arm are the IMP.   
 
Adverse reactions include any untoward or unintended response to drugs.  Reactions to the IMP or 
the other antiretrovirals should be reported appropriately. 
 
7.1.2 
ADVERSE EVENTS 
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 trial) detected 
after trial drug administration 
 
Continuous persistent disease or a symptom present at baseline that worsens following 
administration of the study treatment 
 
Adverse events which do not require reporting in this trial: 
 
Overdose of medication without signs or symptoms 
 
Grade 1 or 2 events which do not result in any changes to ART 
 
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 
 
7.1.3 
DISEASE-RELATED EVENTS 
All adverse events meeting the definitions above should be reported on study CRFs, regardless of their 
relationship to HIV and should be graded.  In particular, all deaths should be reported as fatal SAEs. 
 
7.1.4 
OTHER NOTABLE EVENTS 
7.1.4.A Liver events 
All suspected cases of drug induced liver injury in both arms should be reported as a notable event 
and AE or SAE as appropriate on an Event form and, during the randomised phase, should be sent to 
the relevant CTU within 24 hours of the site becoming aware.  Reporting timelines during extended 
follow-up for notable events which don’t constitute a SAE are outlined in Appendix XX. Additional 
information will be then requested from the sites.  Any results of liver investigations, including liver 
biopsy and/or imaging should be reported. 
 
7.1.4.B ABC Hypersensitivity reaction (HSR) 
Clinically suspected ABC HSR should be reported as a notable event and AE or SAE as appropriate on 
an Event form and, during the randomised phase, should be sent to the relevant CTU within 24 hours 
of the site becoming aware. Reporting timelines during extended follow-up for notable events which 
don’t constitute a SAE are outline in Appendix XX. Additional information will be requested from the 
sites and should be completed within one week of the onset of the hypersensitivity reaction.   
 


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7.1.4.C Suicidal Ideation or Behaviours 
A possible suicidality-related adverse event (PSRAE) should be reported as a notable event and AE or 
SAE as appropriate on an Event form and, during the randomised phase, should be sent to the relevant 
CTU within 24 hours of the site becoming aware.  Reporting timelines during extended follow-up for 
notable events which don’t constitute a SAE are outline in Appendix XX. A PSRAE may include, but is 
not limited to, an event that involves suicidal ideation, a preparatory act toward imminent suicidal 
behaviour, a suicide attempt, or a completed suicide.  The investigator will exercise his or her medical 
and scientific judgment in deciding whether an event is possibly suicide-related.  Following receipt of 
the report, the Investigator will be requested to collect additional information which should be 
reported to the relevant CTU within one week of the investigator diagnosing a possible suicidality-
related adverse event. 
  
7.1.4.D Pregnancy 
Pregnancy occurring during participation in ODYSSEY should be reported as a notable event on an 
Event form and sent to the relevant CTU (see Section 6.8).  All pregnancies will be reported to ViiV and 
registered with the Antiretroviral Pregnancy Register.   
 
Any pregnancy that occurs in a trial participant will be followed up to determine outcome (including 
premature termination) and status of mother and child, which must also be reported to the CTU on a 
Pregnancy Outcome form.  The clinical team responsible will be informed of the mother’s participation 
in the trial and will be asked to inform the relevant CTU if there is any suspicion of any adverse effect 
of the trial medication.   
 
Spontaneous abortions, pregnancy complications and elective terminations for medical reasons must 
be reported on an Event form if the event meets the criteria of a reportable AE or SAE.  
 
Any adverse event occurring in an infant born to a female trial participant within 30 days of delivery 
should be reported in order to evaluate any possible adverse reaction related to in utero exposure to 
the study drugs [51].  
 
Any SAE occurring in association with a pregnancy brought to the investigator´s attention after the 
participant has completed the study and considered by the investigator as possibly related to the 
investigational product, should also be reported as an SAE.  Any event fulfilling the criteria of an SAE 
(e.g. congenital abnormality or birth defect) should be reported within 24 hours of the Investigator 
becoming aware of the event. 
 
Follow-up of a child born to the partner of a male participant (who was taking trial treatment at the 
time of conception) will be according to local practice.  
 
At the end of pregnancy, the investigator will complete an Outcome of Pregnancy CRF. 
 
Reporting timelines during extended follow-up for notable events which don’t constitute a SAE are 
outline in Appendix XX. 
7.2 
INVESTIGATOR RESPONSIBILITIES 
All grade 3 and above clinical and laboratory AEs should be reported in the relevant section of the 
Event Form.  Grade 1 and 2 clinical and laboratory AEs should be reported only if they result in change 
of ART.  All ARs, whether expected or not, should be recorded in the participant’s medical notes and 
reported on the Follow-up Form.  SAEs and SARs and notable events should be reported to the 
relevant CTU within 24 hours of the site becoming aware of the event. Reporting timelines during 
extended follow-up for reportable events which don’t constitute a SAE are outline in Appendix XX. 


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7.2.1 
INVESTIGATOR ASSESSMENT 
 
7.2.1.A Seriousness 
When an AE or AR occurs, the investigator responsible for the care of the patient must first assess 
whether or not the event is serious using the definition given in Table 5.  If the event is serious, then 
an Event Form must be completed and the CTU notified within 24 hours. 
 
7.2.1.B Severity or Grading of Adverse Events 
The severity of all AEs and/or ARs (serious and non-serious) in this trial should be graded using the 
toxicity grading in Appendix IX. 
 
7.2.1.C Causality 
The investigator must assess the causality of all serious events or reactions in relation to the trial 
therapy using the definitions in Table 6.  There are five categories: unrelated, unlikely, possible, 
probable, and definitely related.  If the causality assessment is unrelated or unlikely to be related, the 
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. 
 
 
Table 6: Assigning Type of SAE through Causality 
RELATIONSHIP 
DESCRIPTION 
SAE TYPE 
Definitely 
There is clear evidence to suggest a causal relationship and 
other possible contributing factors can be ruled out. 
SAR 
Probable 
There is evidence to suggest a causal relationship and the 
influence of other factors is unlikely. 
SAR 
Possible 
There is some evidence to suggest a causal relationship (for 
example, because the event occurs within a reasonable time 
after administration of the trial medication). However, the 
influence of other factors may have contributed to the event 
(for example, the patient’s clinical condition, other 
concomitant treatments). 
SAR 
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 trial medication). 
There is another reasonable explanation for the event (for 
example, the patient’s clinical condition, other concomitant 
treatment). 
Unrelated SAE 
Unrelated 
There is no evidence of any causal relationship 
Unrelated SAE 
 
If an SAE is considered to be related to an antiretroviral and drug is stopped or the dose modified, 
refer to Section 5.5. 
 
7.2.1.D Expectedness 
If there is at least a possible involvement of the trial treatment (or comparator), the investigator may 
make an initial assessment of the expectedness of the event, however the Sponsor has the overall 
responsibility for determination of expectedness. An unexpected adverse reaction is one not 
previously reported in the current Reference Safety Information (i.e. the Investigator’s Brochure (for 


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DTG and DTG-containing products), or Summary of Product Characteristics (SPC; for all other ARVs)), 
that should be accessed through the ODYSSEY reserved area on the Penta website (https://penta-
id.org/reserved-area/#odyssey), or one that is more frequent or more severe than previously 
reported.  The definition of an unexpected adverse reaction (UAR) is given in Table 5.  If a SAR is 
assessed as being unexpected, it becomes a SUSAR.  If there is at least a possible involvement of the 
trial treatment, the Investigator should make an initial assessment of the expectedness of the event. 
The Sponsor will have the final responsibility for determination of expectedness (for reporting 
purposes), and this decision will be made on the basis of the above definition and the information 
provided by the Investigator. Please see the Manual of Operations for a summary of expected 
toxicities for ARVs. 
 
7.2.1.E 
Notification 
The relevant CTU should be notified of all SAEs and notable events within 24 hours of the investigator 
becoming aware of the event. Reporting timelines during extended follow-up for notable events which 
don’t constitute a SAE are outlined in Appendix XX. 
 
Investigators should notify the relevant CTU of all reportable AEs (section 7.2), SAEs and notable 
events occurring from the time of randomisation until the end of the trial or end of extended follow 
up, whichever is later.  Any subsequent events that may be attributed to treatment should also be 
reported to national reporting schemes where relevant. 
 
7.2.2 
NOTIFICATION PROCEDURE 
1. The Event Form must be completed by an investigator (a clinician named on the Signature List 
and Delegation of Responsibilities Log who is responsible for the participant’s care; this will 
be either the Principal Investigator or another medically qualified person with delegated 
authority for Event reporting). Due care should be 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 trial team and faxed or 
emailed as appropriate.  The responsible investigator should subsequently check the Event 
Form, make changes as appropriate, sign and then re-fax to the CTU as soon as possible.  The 
initial report must be followed by detailed, written reports as appropriate. 
 
2. The minimum information required for reporting an AE, SAE or notable event are the trial 
number and partial date of birth, name of investigator reporting, the event and why the event 
is considered serious or meets the criteria of a reportable event. 
 
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.  A further Event 
Form, indicated as ‘Follow-up’ should be completed and faxed to the relevant CTU as 
information becomes available.  Extra, annotated information and/or copies of test results 
may be provided separately.  The participant must be identified by trial number, anonymous 
code, and date 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. 
 
 
 


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SAE REPORTING 
Within 24 hours of becoming aware of an SAE or notable event, please fax or email a 
completed Event form to the relevant CTU. Please ensure that an acknowledgment of 
receipt by the CTU is received.   
 
MRC CTU: fax: +44 (0) 20 7670 4814 or email: mrcctu.trial-odyssey@ucl.ac.uk 
 
Inserm-ANRS: fax: + 33 1 46 58 72 93 or email: penta.sc10@inserm.fr 
 
PHPT: fax: +66 53 240 913 or email: suwalai.chalermpantmetagul@phpt.org 
 


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7.3 
CTU RESPONSIBILITIES 
Medically-qualified staff at the CTUs and/or the Chief Investigator (or a medically-qualified delegate) 
will review all event 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. 
 
The CTUs are undertaking the duties of trial sponsor and are responsible for the reporting of SAEs to 
the relevant regulatory authorities (MHRA and competent authorities of other European member 
states and any other countries in which the trial is taking place) and research ethics committees of any 
countries in which the trial is taking place, as appropriate.  This responsibility may be delegated to 
country principal investigators for relevant reporting requirements in individual countries. Fatal and 
life-threatening SUSARs must be reported to the competent authorities within 7 days of the relevant 
CTU becoming aware of the event; other SUSARs must be reported within 15 days. 
 
The relevant CTU will also keep all investigators informed of any safety issues that arise during the 
course of the trial.   
 
MRC CTU will prepare annual Development Safety Update Reports (DSURs) on behalf of the sponsor 
which will be submitted to the Competent Authorities and Ethics Committees in each country 
participating in the trial. 
 
Any drug companies involved will also be notified of reportable (serious and unexpected and drug-
related/unknown relationship) events as per the requirements outlined in the individual contract.   
 
 
 


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8 
QUALITY ASSURANCE & CONTROL 
8.1 
RISK ASSESSMENT 
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 trial and how to address 
them with QA and QC processes.  QA includes all the planned and systematic actions established to 
ensure the trial is performed and data generated, documented and/or recorded and reported in 
compliance with the principles of ICH 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 trial-related activities are fulfilled.  This Risk Assessment has been reviewed by the MRC 
CTU Research Governance Committee (RGC) and has led to the development of a Data Management 
Plan (DMP), Safety Reporting Plan and Monitoring Plan which will be separately reviewed by the 
Quality Management Advisory Group (QMAG).   
 
8.2 
CENTRAL MONITORING AT CTU 
Where local staff have successfully completed training on the trial database, data will be entered into 
the trial database directly at the clinical site.  The site will retain the original CRF.  Data stored on the 
central database will be checked at the CTU 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 entry.  Changes will be made on the original CRF and 
entered into the database at the site.  The CTU will also send reminders for any overdue and/or missing 
data with the regular inconsistency reports of errors.   
 
Alternatively sites can send completed CRFs to the CTU for data entry.  Data received at CTUs will be 
checked and if problems are identified, a missing data report of the problematic data will be sent to 
the local site by secure e-mail for checking and confirmation or correction, as appropriate – any data 
which are changed should be crossed through with a single line, dated and initialled.  The amended 
data should be returned to the appropriate CTU and the amended data should also be filed in the 
notes at site.  The CTUs will send reminders for any overdue and missing data.   
 
Other essential trial issues, events and outputs will be detailed in the Monitoring Plan that is based on 
the trial-specific Risk Assessment.   
 
8.3 
ON-SITE MONITORING 
Staff from the CTUs or local monitors will visit clinical sites to validate and monitor data.  The 
frequency, type and intensity for routine monitoring and the requirements for triggered monitoring 
will be detailed in the Monitoring Plan.  This plan will also detail the procedures for review and sign-
off.  All monitoring will adhere to the principles of ICH GCP.   
 
Monitors will:  
 
 
 
verify completeness of the Investigator Site File  
 
confirm adherence to protocol  
 
review procedures and resources  
o in the trial clinic 
o in the trial pharmacy 


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o in the trial laboratories 
 
advise on additional training as needed  
 
The investigator (or delegated deputy) should work with the monitor to ensure that any problems 
detected are resolved. 
 
8.3.1 
DIRECT ACCESS TO PARTICIPANT RECORDS 
Participating investigators will allow trial-related monitoring, including audits, ethics committee 
review and regulatory inspections by providing direct access to source data and documents as 
required. If required locally, consent for this should be obtained from parents/carers and children, if 
appropriate. 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 
 
all Eligibility and clinical and laboratory data at enrolment  
 
all clinical endpoints and all SAEs 
 
routine patient clinical and laboratory data 
 
trial drug accountability 
 
8.3.2 
CONFIDENTIALITY 
We plan to follow the principles of the UK DPA regardless of the countries where the trial is being 
conducted. 
 
The investigator must assure that the participants’ anonymity will be maintained i.e. their identities 
are protected from unauthorised parties.  Participants will be assigned a trial identification number to 
be used on all CRFs and no names will be used beyond the clinical care of the participant, in order to 
maintain confidentiality.  All trial records, including a participant trial register linking identification 
numbers and names, will be kept in secure locations at each site.  
 


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9 
STATISTICAL CONSIDERATIONS 
9.1 
METHOD OF RANDOMISATION 
Randomisation of children weighing ≥14kg will be stratified by: 
 
antiretroviral treatment: naïve or experienced (ODYSSEY A or ODYSSEY B) 
 
routine availability at site of resistance tests vs. non availability of resistance tests, for children 
failing treatment 
 
bPI vs. non-bPI ART offered as SOC 
 
NRTI backbone : ABC/3TC or ABC/3TC/ZDV vs. TDF/3TC or TDF/FTC  or TAF/3TC or TAF/FTC 
vs. Other  
 
Randomisation of children weighing 3-<14kg will be performed separately stratified by 
 
antiretroviral treatment: naïve or experienced (ODYSSEY A or ODYSSEY B) 
 
weight band at randomisation: 3-<6kg vs. 6-<10kg vs. 10-<14kg 
 
 
The randomisation lists will be prepared by staff at the MRC CTU under the direction of the trial 
statistician.  The randomisation lists will be generated by random permuted blocks and will be securely 
incorporated within the web-enabled trial database.  Randomisation will not take place until after 
informed consent has been confirmed and the participant is ready to receive therapy.   
 
9.2 
OUTCOME MEASURES  
The primary comparison for the study is to compare DTG-based regimen versus SOC for the primary 
efficacy outcome in the combined population (naïve and experienced); subpopulation analyses 
(ODYSSEY A and ODYSSEY B) are key secondary comparisons.  Outcomes are described below for the 
randomised phase.  
 
9.2.1 
PRIMARY EFFICACY OUTCOME (OVER 96 WEEKS) 
Difference in the probability of virological or clinical failure by 96 weeks, estimated by Kaplan-Meier 
methods using time to the first occurrence of any of the following components (note, this does not 
mean VL must be performed in real time):  
 
Insufficient virological response defined as <1 log10 drop at week 24 (or VL≥50c/mL at week 
24 in a participant with VL<500c/mL at baseline) and switch to second/third line ART for 
treatment failure 
 
VL ≥400 c/ml at or after 36 weeks confirmed by next visit 
 
Death due to any cause 
 
Any new or recurrent AIDS defining event (WHO 4) or severe WHO 3 events, confirmed by the 
Endpoint Review Committee 
 
9.2.2 
SECONDARY EFFICACY OUTCOMES  
 
Difference in proportion with clinical or virological failure (as defined above) by 48 weeks 
 
Time to any new or recurrent AIDS defining event (WHO 4) or severe WHO 3 events, confirmed 
by the Endpoint Review Committee  
 
Proportion of children with VL <50 c/ml at 48 and 96 weeks  
 
Proportion of children with VL <400 c/ml at 48 and 96 weeks  
 
Rate of clinical events over 96 weeks: WHO 4, severe WHO 3 events and death 
 
Change in CD4 count and percentage and CD4/CD8 ratio from baseline to weeks 48 and 96 


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 
Proportion developing new resistance mutations  
 
9.2.3 
SECONDARY SAFETY OUTCOMES 
 
Change in total cholesterol, triglycerides and lipid fractions (LDL, HDL) from baseline to weeks 
48 and 96 (change in total cholesterol from baseline to week 96 will be used to formally assess 
superiority of DTG based regimen vs. SOC)  
 
Incidence of serious adverse events 
 
Incidence of new clinical and laboratory grade 3 and 4 adverse events 
 
Incidence of adverse events (of any grade) leading to treatment modification 
 
9.2.4 
OTHER SECONDARY OUTCOMES 
 
 
Quality of life  
Adherence and acceptability  
 
Outcomes in extended follow-up will focus on safety and possible long-term toxicities. See Appendix 
XX for further details. 
9.3 
SAMPLE SIZE 
Based on previous HIV studies a non-inferiority margin (delta) of 10-12% is considered acceptable. 
Assuming a failure rate of 18% overall (both first-line and second-line children combined) in the DTG 
arm and SOC arm by 96 weeks and allowing for 10% loss to follow up, 700 children will provide 90% 
power to exclude (at two-sided 5% significance level) a difference of more than 10% between the two 
arms.  If the upper bound of the two-sided 95% confidence limit for the difference in the proportion 
failing (DTG – SOC) is less than 10% (the margin of non-inferiority) the DTG-regimen will be considered 
to be non-inferior to the SOC.   
Enrolling 310 first-line ART and 390 second-line ART children will provide 80% power to exclude a 
difference of more than 12% between the DTG and SOC arms in both subgroups, assuming a failure 
rate of 15% in ART-naïve (based on previous trials, including the recent ARROW trial [49] in Africa), 
and 20% in ART-experienced with loss to follow up of 10%. 
 
9.4 
INTERIM MONITORING & ANALYSES 
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 (with a description of stopping rules and/or guidelines).  The IDMC will meet within 
6 months after the trial opens; although the IDMC will in general meet annually, the frequency of 
subsequent meetings will be determined by the IDMC and could be more frequent if they deem 
necessary.  The IDMC can recommend premature closure or reporting of the trial, or that recruitment 
be discontinued or modified.  Such recommendations would be made if, in the view of the IDMC, there 
is proof beyond reasonable doubt that one of the allocated strategies is better than its comparator in 
terms of a difference of clinically significant magnitude in a primary outcome.  The guiding statistical 
criteria for “proof beyond reasonable doubt” is a Haybittle-Peto type rule based on the 99.9% 
confidence interval of the relative hazard of death in each interim analysis.   
 
9.5 
ANALYSIS PLAN (BRIEF)  
For the primary analysis of main trial participants, the two treatment groups (DTG and SOC) will be 
compared in terms of the cumulative probability of clinical or virological failure by week 96 (CPF96) 
(as defined above) as estimated by the Kaplan-Meier method, adjusting for stratification factors.  DTG 


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will be considered non-inferior to SOC if the upper limit of the 95% confidence interval of the 
difference in CPF96 (DTG-SOC) is less than the non-inferiority margin of 10%.  The number and 
percentage of participants with at least one component of the primary endpoint and the number and 
percentage for each component will be summarised.   
 
Secondary analyses will summarise the rate of the composite primary endpoint per 100 person years 
by treatment group, and a treatment hazard ratio (HR: DTG to SOC) plus two-sided 95% confidence 
interval estimated by a Cox proportional hazards model.  The primary analysis is by intention to treat 
and includes all randomised participants.  A sensitivity analysis will be done with the per protocol 
population, censoring events after a participant stops the initial randomised trial treatment. 
 
Participants with VL<50 (or <400) c/ml at 48 and 96 weeks will be compared between arms based on 
(i) crude proportions and (ii) using the FDA snapshot algorithm to determine the proportion of 
participants with VL<50 (or <400) c/ml. 
 
The secondary endpoints of change in total cholesterol, triglycerides and lipid fractions (LDL, HDL) 
from baseline to weeks 48 and 96 will be analysed using analysis of covariance to compare the change 
in mean level between the two arms, adjusting for baseline value and stratification factors.  These 
analyses will be carried out on all randomised participants (intention to treat) and change in total 
cholesterol from baseline to week 96 will assess the superiority of DTG compared to SOC for this 
parameter. 
 
There will be a secondary analysis of primary and secondary endpoints in all children recruited 
weighing<14kg (where DTG dose is determined) when this group has completed 96 weeks follow-up. 
The primary endpoint will be re-evaluated in all children including those in the main trial and 
children recruited <14kg (where DTG dose is determined) when follow-up to a minimum of 96 weeks 
is complete.  
 
Intention to treat analyses including all randomised participants will be performed for all other 
endpoints using the following statistical methods: 
 
Descriptive statistics for the summary of baseline characteristics 
 
Fishers Exact test and logistic regression for the analysis of binary variables 
 
Analysis of variance and linear regression models for the analysis of continuous variables, 
adjusting for baseline 
 
Poisson regression for the analysis of incidence of clinical/adverse events 
 
Log-rank test and Cox proportional hazard model for the analysis of time to event variables 
Clinical and adverse events will be summarised using an in-house coding system. 
 
 
Full details of all analyses will be provided in the Statistical Analysis Plan (SAP).  This will include any 
additional pre-planned subgroup analyses.  
 
A second SAP will be written for the extended follow-up phase. 
 
 


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10 ANCILLARY STUDIES 
10.1 PHARMACOKINETIC SUBSTUDIES  
 
10.1.1 WB-PK1 
PHARMACOKINETICS OF DOLUTEGRAVIR IN WHO WEIGHT BANDS 3 TO <6KG, 6 TO <10KG, 10 TO 
<14KG, 14 TO <20KG AND 20 TO <25KG 
 
Children weighing 3 to <25kg randomised to DTG will be recruited to the substudy until at least 8 
children per weight band have evaluable PK curves on the investigated dose/formulation. Children will 
have a single 24h PK curve at least 1 week after starting DTG-based ART or changing to a new 
dose/formulation. Additional children may be recruited if a large interpatient variability in the PK 
parameters (i.e. >50% in AUC0-24, Ctrough or Cmax) within the weight band is seen. PK, safety and 
tolerability will be assessed.  
The substudy will be undertaken at clinical sites in Uganda, South Africa and Zimbabwe. For further 
information see Appendix XIII. 
 
 
10.1.2 WB-PK2 
 A CROSSOVER PHARMACOKINETICS SUBSTUDY OF DOLUTEGRAVIR IN CHILDREN WEIGHING 25 TO 
<40KG WITH DOSE CHANGE TO DTG 50MG QD (the substudy is completed) 
Children weighing 25 to <40kg taking DTG according to the previous version of the protocol (25mg for 
25-<30kg weight band and 35mg for 30-<40kg weight band) were enrolled in the substudy until at 
least 8 children per weight band had evaluable PK curves. Participants had two 24h PK curves 
performed: the first curve on dosing they received prior to the dose change for at least 1 week and 
the second curve at least 1 week after changing to a 50mg tablet.  Following the review of the PK 
results, clinical and laboratory adverse events and treatment discontinuations, children 25-<40kg in 
the main trial were switched to DTG 50mg film-coated tablet QD (Section 5.3). 
 
The substudy was undertaken at clinical sites in Uganda and Zimbabwe. For further information see 
Appendix XIII. 
 
 
10.1.3 TB-PK SUBSTUDY 
PHARMACOKINETICS OF DOLUTEGRAVIR CO-ADMINISTERED WITH RIFAMPICIN IN HIV/TB CO-
INFECTED CHILDREN 
The substudy will evaluate the pharmacokinetics of DTG co-administered with rifampicin in HIV/TB co-
infected children and estimate the impact of rifampicin on DTG plasma concentrations. Children aged 
6 to <18 years treated for TB with rifampicin-containing regimen are enrolled. At least six children per 
age band 6 to <12 years and 12 to <18 years will be enrolled; the number may be increased if 
intersubject variability of DTG PK parameters in children appears much larger than that reported in 
non HIV-infected adults or if less than 2 children per WHO weight band have complete PK data. We 
anticipate few children <6 years being treated for TB with a rifampicin-containing regimen during 
ODYSSEY; however any who receive rifampicin treatment for TB or TB infection will be approached for 
recruitment. Participants will have two PK curves performed: the first curve (12h) during the last 


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month of rifampicin-containing TB treatment and the second curve (24h) four weeks after 
discontinuation of rifampicin (two weeks after changing DTG from BID to QD). Pharmacokinetics of 
BID DTG and QD DTG within participants will be compared and evaluated against the available data in 
children and adults.  
 
The substudy will be undertaken at clinical sites in Uganda, South Africa and Zimbabwe. For further 
information see Appendix XIV. 
10.2 IMMUNOLOGY/VIROLOGY SUBSTUDY 
The substudy will assess the impact of DTG on the mechanisms of CD4 reconstitution, immune 
activation and HIV reservoir and replication. The study aims to collect samples from at least 350 
children (as many as possible from ODYSSEY A). Blood samples for plasma will be collected at each 
study visit according to the trial assessment schedule for the randomised phase of the ODYSSEY trial, 
PBMCs will be collected at enrolment, and at 12, 48 and 96 weeks for sites participating in the 
substudy. Samples will be stored locally and later transferred to the Institute of Child Health, UCL or 
the African Health Research Institute (AHRI) Laboratories for analyses. Changes in thymic output, 
immune activation biomarkers and viral reservoirs and replication will be compared between DTG and 
SOC arms.  
 
The substudy will be undertaken at clinical sites in Uganda, South Africa and Zimbabwe and Europe. 
For further information see Appendix XII. 
10.3 QUALITATIVE SUBSTUDY: OPTIMISING ADHERENCE TO SECOND-LINE TREATMENT. 
The qualitative substudy will explore how moving onto second-line treatment affects young people’s 
treatment engagement and identify how best to support them to maintain optimal treatment 
adherence. Participants enrolled in ODYSSEY B aged 10-18 years who have known about their HIV 
status for a minimum of six months will be recruited. Two ODYSSEY trial sites, JCRC in Uganda and the 
University of Zimbabwe, Harare in Zimbabwe, will be involved; each site will recruit 20 participants 
(40 in total). Two in-depth individual interviews and a series of focus group discussions with trial 
participants at different stages of the trial will be conducted. Consultations with a Youth Trial Board 
(see below) to assist with the dissemination materials will be arranged. 
 
The substudy will be undertaken at clinical sites in Uganda and Zimbabwe. For further information see 
Appendix XV. 
10.4 YOUTH TRIAL BOARD PROJECT 
A MULTI-COUNTRY MODEL OF USER INVOLVEMENT TO ENGAGE ADOLESCENTS LIVING 
WITH HIV IN THE DEVELOPMENT AND DELIVERY OF PAEDIATRIC CLINICAL TRIALS 
 
The project will develop a model of meaningful engagement and participation of adolescent patient 
representatives in paediatric clinical trials and research studies. It will take place in 4 countries 
participating in ODYSSEY: the UK, South Africa, Uganda and Zimbabwe. Children living with HIV, aged 
15-≤19 years will be included. At least half of the children involved will be ODYSSEY trial participants. 
Youth Trial boards (YTB), groups of at least 6 young people in each of the four sites, will be established. 
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they will provide feedback to the ODYSSEY trial investigators on different aspects of the trial, including 
provision of the trial information, consent process, engagement with children and adolescents and 
retention of the participants during the trial. The YTB will be involved in dissemination of the ODYSSEY 
trial materials and the results. They will also participate at the development stage of new clinical trials 
as opportunities arise. At the end of the project the model will be adopted for a wider use in paediatric 
HIV trials and studies.  
 
The substudy will be undertaken at clinical sites in South Africa, Uganda,  Zimbabwe and the UK. For 
further information see Appendix XVI. 
 
10.5 FOLATE AND VITAMIN B12 SUBSTUDY 
DOLUTEGRAVIR AND FOLATE AND B12 LEVELS AMONG CHILDREN AND ADOLESCENTS IN 
THE ODYSSEY TRIAL 
 
Recent concerns have been raised about the use of dolutegravir (DTG) in pregnant women. In a 
preliminary unscheduled analysis of an ongoing NIH-funded birth surveillance study in Botswana, an 
increased risk of neural tube defects (NTDs) among infants of women who became pregnant while 
taking DTG-based regimens has been reported. It is well known that maternal folate deficiency 
increases the risk of NTDs, however it is unknown whether DTG may affect folate levels. 
 
The substudy will compare the folate levels among children and adolescents randomized to DTG 
versus those on a SOC ART regimen. The study aims to collect samples from children enrolled in 
ODYSSEY in sub Saharan sites and to determine whether there is a potential association between DTG 
and folate status. 
 
Folate plasma levels will be assayed at baseline and 4 weeks after commencing trial treatment using 
plasma that is routinely stored as part of the main ODYSSEY protocol (see Trial Assessment Schedule). 
In addition, red cell folate and vitamin B12 levels will be assayed using the same blood draw as for 
plasma isolation at week 96 (or the next clinic visit after this timepoint if collection at week 96 is not 
possible). Where assays cannot be done in real time, the blood samples or lysates will be stored for 
subsequent testing. 
 
The substudy will be undertaken at selected sites in Uganda. For further information see Appendix 
XVIII. 
 
 


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11 REGULATORY & ETHICAL ISSUES 
11.1 COMPLIANCE 
11.1.1 REGULATORY COMPLIANCE 
The trial complies with the principles of the Declaration of Helsinki of 2013. 
 
It will also be conducted in compliance with the approved protocol, the principles of Good Clinical 
Practice (GCP) as laid down by the European Commission Directive 2005/28/EC* with the 
implementation in national legislation in countries in the EU and subsequent amendments and 
appropriate data protection and regulatory legislation in participating countries, the UK Data 
Protection Act (DPA UCL’s number Z6364106), and the National Health Service (NHS) Research 
Governance Framework for Health and Social Care (RGF). 
 
*Until the Clinical Trials Regulation EU No 536/2014 becomes applicable, the trial will be conducted 
in accordance with the Clinical Trials Directive as implemented in the UK statutory instrument. When 
the directive is repealed on the day of entry into application of the Clinical Trial Regulation the trial 
will work towards implementation of the Regulation (536/2014) following any transition period. 
 
 
11.1.2 SITE COMPLIANCE 
The site will comply with the above and with the principles of GCP as laid down by the ICH topic E6 
(Note for Guidance on GCP), Commission Directive 2005/28/EC (the European Directive 2001/20/EC 
[where applicable]) and applicable national regulations.  An agreement will be in place between the 
site, PENTA and the appropriate CTU, setting out respective roles and responsibilities (see Section 13 
- Finance).   
 
The site will inform the relevant CTU as soon as they are aware of a possible serious breach of 
compliance, so that the CTU 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 participants in the trial, or  
• 
The scientific value of the trial 
 
11.1.3 DATA COLLECTION & RETENTION 
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 a minimum period as 
determined by the current clinical trial legislation in effect. Currently this will be for a minimum of 15 
years after the end of the trial.  The EU Clinical Trial Regulation 536/2014 is due to come in to 
application in 2020 and, if still applicable to ODYSSEY following the transition period, the sponsor and 
the investigator shall archive the content of the clinical trial master file for at least 25 years after the 
end of the clinical trial, unless other Union law requires archiving for a longer period. However, the 
medical files of subjects shall be archived in accordance with national law. During this period, all data 
should be accessible, with suitable notice, to the competent or equivalent authorities, the Sponsor, 
and other relevant parties in accordance with the applicable regulations.  The data may be subject to 
an audit by the competent authorities. Medical files of trial participants should be retained in 
accordance with the maximum period of time permitted by the hospital, institution or private practice. 
 


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11.2 ETHICAL CONDUCT OF THE STUDY 
11.2.1 ETHICAL CONSIDERATIONS 
Participation in a randomised controlled trial means that the participant and/or their carer as 
appropriate, agree to randomisation but neither the participant, carer nor clinician are able to choose 
all aspects of the participant's treatment.  Participants will receive different treatments and toxicities 
are different by arm; this will be explained to children/families.  The risks of HIV-1 viral load rebound 
due to a possibly less potent regimen and the use of a novel agent will be explained to 
children/families.  Consent will be sought from parents/carers and from participants where allowed 
by national regulations.  Participants not able to consent for themselves, but deemed able to 
understand about the trial, will be asked to assent.   
 
As described above, the main risks to the participants are from the potential toxicity from integrase 
inhibitors.  However, this possibility needs to be balanced against the risks from SOC ART.  In addition, 
the trial will evaluate the net clinical/virological risk-benefit comparing DTG with SOC.   
 
11.2.1.A Safety Profile of DTG 
DTG has been taken by large numbers of adults in Phase III trials, and is licensed for the treatment of 
HIV infection in adults and children aged 6 and above weighing at least 15 kg.    
 
The most common side effects of DTG in adults are headache, diarrhoea, abdominal pain, feeling sick, 
light headed or weak, worrying often and having sleep problems. Some adults taking dolutegravir have 
reported feeling depressed or having suicidal thoughts; these may not be related to this medicine in 
all cases. There is a small chance that dolutegravir may cause a rash, itching, vomiting, stomach pain, 
sleep problems, lack of energy, an increase in weight, feeling light headed, sad or worried or may 
cause serious liver problems (with signs of vomiting, jaundice or stomach pain).   
 
In May 2018, an observational surveillance study in Botswana (TSEPAMO) evaluating the safety of ART 
regimens in pregnancy identified an increased risk of neural tube defects (NTD) amongst infants of 
women who initiated DTG-based regimens prior to pregnancy (0.9%, which compares to a risk of 
~0.1% in infants born to women on non-DTG based regimens; see Background). In a further report 
including all data through to March 2019 there were 5 cases of NTD in 1683 deliveries where their 
mother was taking DTG at conception (0.3% of deliveries) (36), suggesting the increased risk is ~3-fold, 
lower than the 10-fold risk initially estimated.  To protect female participants and their unborn infants 
from this potential risk, all female participants who are sexually active must use highly effective 
contraception (see section 6.8). Females on DTG identified to be pregnant within 8 weeks after LMP 
should be changed to an alternative non-DTG ART regimen provided optimal options to replace DTG 
are available for them. 
 
At the present time there is limited experience with the use of this drug in the paediatric population.  
Standard procedures are in place to record Serious Adverse Events arising from the use of DTG (or any 
study drug) in the trial, and such events will be evaluated and reported to ethics committees and 
regulatory agencies within specified timelines.  The IDMC will closely monitor Serious Adverse Events 
and grade 3 and 4 events occurring during the randomised phase of the trial in all treatment groups 
and will be able to advise appropriate action if there is a pattern of serious toxicity emerging from one 
or more of the drugs.  
 
11.2.1.B Burden of investigations  
The follow-up study visits coincide with the usual frequency of visits for routine clinical care.  Two 
extra visits are scheduled at the start of the trial to monitor participant’s safety and adherence to 
medication.  Additional tests (over and above routine care) may be required.   
 


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11.2.1.C Post-trial treatment 
Provision of DTG will continue after the randomised phase of the trial, for participants randomised to 
receive DTG who are still receiving it, until it is locally approved and available for the child’s age and 
weight band.  Safety follow-up of those participants receiving DTG after the randomised phase  will 
be performed.   
 
11.2.1.D  Informing potential trial participants of possible benefits and known risks 
Participants and carers will be informed fully of known risks and possible benefits by means of a 
patient information sheet and this will be reinforced by discussions with the trial research teams at 
the individual sites prior to enrolment.  
 
11.2.1.E Confidentiality 
Participants’ confidentiality will be maintained throughout the trial.  Patient data will be identified by 
the trial number and a 3 letter computer generated anonymous code, date of birth and sex; samples 
sent to central testing facilities will be identified only by the trial number and a 3 letter computer 
generated anonymous code, date of collection, type of sample and visit number. 
 
11.2.2 ETHICAL APPROVALS 
Before initiation of the trial at each clinical site, the protocol, all informed consent forms, and 
information materials to be given to the prospective participant and carer will be submitted to 
national/local ethics committees for approval as required.  Any further amendments will be submitted 
and approved by each ethics committee. 
 
The rights of the participant and carer to refuse to participate in the trial without giving a reason must 
be respected.  After the participant has entered into the trial, 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 trial for the purpose of follow-up and for data analysis by the treatment option to 
which they have been allocated.  Similarly, the carer/participant must remain free to change their 
mind at any time about the protocol treatment and trial follow-up without giving a reason and without 
prejudicing his/her further treatment. 
 
11.3 COMPETENT AUTHORITY APPROVALS 
This protocol will be submitted to the national competent or equivalent authority in each country 
where the trial will be conducted. 
 
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 EU.  In countries outside of the EU, local and national 
regulatory requirements will be followed. 
 
The EudraCT number for the trial is 2014-002632-14.   
 
The progress of the trial and safety issues will be reported to the competent authority, regulatory 
agency or equivalent in accordance with local requirements and practices in a timely manner.   
 
Safety reports, including expedited reporting and SUSARs will be submitted to the competent 
authorities in accordance with each authority’s requirements in a timely manner.   
 


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11.4 OTHER APPROVALS 
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 in each country.  A copy of 
the local R&D approval (or other relevant approval as above) and of the PIS and Consent Form (CF) on 
local headed paper should be forwarded to the relevant CTU before any participants are screened for 
eligibility.   
 


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12 INDEMNITY 
In consideration of the agreement by the Principal Investigator at each centre to supervise the trial, 
the PENTA Foundation undertakes to indemnify the Principal Investigator at each centre and the 
institutions which participate in the trial and their employees and agents in respect of any claims made 
against them by any third party which arises out of or as a result of the supervision or conduct of the 
trial (including any claim arising in respect of the technical procedures described in the protocol which 
participants would not have been exposed but for their participation in the trial).  Full details of the 
Indemnity agreement are given in a separate document.  Cover against claims arising from medical 
negligence is not included. 
 
 


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13 FINANCE 
 
Research support will be provided to the clinical centres for additional visits.  In some specific cases 
and agreed by national ethics bodies, transport facilities, payments or vouchers will be given to 
participants or their families in compensation for the time spent in clinic particularly during substudies.   
 
In some countries and as required by national legislation the health service cost of all protocol visits 
will be covered by the sponsor or sponsor’s representative. 
 
DTG (including Triumeq, as appropriate) will be provided by ViiV for the duration of the randomised 
phase of the ODYSSEY trial. DTG 5mg dispersible tablets will only be provided to sites in South Africa, 
Uganda and Zimbabwe, and Triumeq will only be supplied in countries where it is licensed. For sites 
outside Europe, the following NRTIs will also be provided by ViiV where required for the duration of 
the ODYSSEY trial: ABC, 3TC, Kivexa and Combivir.  After the end of the randomised phase, DTG will 
be provided by ViiV for those children randomised to the DTG arm until it is available and 
recommended for children in their country of residence. For sites in sub-Saharan Africa the Mylan 
formulation of ABC/3TC 120/60mg will be provided for the duration of the randomised phase, if 
required. 
 


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14 OVERSIGHT & TRIAL COMMITTEES 
There are a number of committees involved with the oversight of the trial.  These committees are 
detailed below, and the relationship between them is shown (see Appendix XVII). 
14.1 TRIAL MANAGEMENT GROUP (TMG) 
A Trial Management Group (TMG) will be formed comprising Chief Investigator(s), other lead 
investigators (clinical and non-clinical) and members of the CTUs: MRC CTU, INSERM-ANRS and PHPT.  
The TMG will be responsible for the day-to-day running and management of the trial.  It will meet 
monthly during the recruitment phase and thereafter at least every other month.  Part of this trial 
includes a Youth Trial Board (YTB) substudy (see Appendix XVI) and the YTB work with the TMG. 
 
14.2 TRIAL STEERING COMMITTEE (TSC) 
The trial will be supervised by the ODYSSEY TMG who will report to the ODYSSEY Trial Steering 
Committee (TSC).  The TSC has membership from the TMG plus independent members, including a PPI 
representative and the Chair.  The role of the TSC is to provide overall supervision for the trial and 
provide advice through its independent Chair.  The ultimate decision for the continuation of the trial 
lies with the TSC.  Further details of TSC functioning are presented in the TSC Charter.  The ODYSSEY 
TSC may decide to terminate the trial for any reason including the recommendation of the 
Independent Data Monitoring Committee (IDMC). 
 
14.3  INDEPENDENT DATA MONITORING COMMITTEE (IDMC] 
The Independent Data Monitoring Committee (IDMC) which oversees all PENTA trials will be the only 
group who sees the confidential, accumulating data for the trial.  Reports to the IDMC will be produced 
by the CTU statisticians.  The IDMC will meet within 6 months of the trial opening; the frequency of 
meetings will be dictated in the IDMC charter.  The IDMC will consider data using the statistical analysis 
plan (see Section 9.5) and will advise the TSC.  The IDMC can recommend premature closure or 
reporting of the trial, or that recruitment to any research arm is discontinued. 
 
Further details of IDMC functioning and the procedures for interim analysis and monitoring are 
provided in the IDMC Charter. 
 
14.4  ENDPOINT REVIEW COMMITTEE 
An Endpoint Review Committee will be appointed whose remit will be to determine the validity of 
potential clinical endpoints in terms of meeting the standard criteria, as defined by the protocol.  It 
will have an independent Chair.  No member will review endpoints from their own site.  Terms of 
reference for the Endpoint Review Committee will be drawn up.   
14.5  ROLE OF STUDY SPONSOR 
The sponsor of the trial is the PENTA Foundation.  The management of the trial is delegated by the 
sponsor to the CTUs: MRC CTU, INSERM-ANRS and PHPT. 
 


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15 PUBLICATION 
15.1 PUBLICATION 
The ODYSSEY TMG will be responsible for preparing the manuscript for rapid publication.  High priority 
will be given to this and it would be anticipated that a report would be completed within six months 
of the latter of database lock or receipt of retrospective viral loads for participants recruited weighing 
≥14kg into the main trial.  The final publication will require the approval of the ODYSSEY TMG and TSC.  
No other publications, including all or any part of the results, either written or verbal, will be made 
before the definitive manuscript has been agreed and accepted for publication without the prior 
approval of the ODYSSEY TMG and TSC.  Individual clinicians must not publish data concerning their 
participants that are directly relevant to questions posed by the trial until the TMG has published its 
report.  Responsibility for data analysis and publication for ODYSSEY will reside within the PENTA 
network and be governed by PENTA policies.   
 
The trial will be registered with the internationally accepted clinical trials register, clinicaltrials.gov.  
The ISRCTN number will be attached to all publications resulting from this trial.  The ODYSSEY TSC is 
the custodian of the data and specimens generated from the ODYSSEY trial; ODYSSEY trial data are 
not the property of individual participating investigators or health care facilities where the data were 
generated.   
 
 
The data derived from this clinical trial are considered the property of the ODYSSEY TSC.  The 
presentation or publication of any data collected by the participating investigators on 
participants entered into this trial is under the direct control of the TMG and TSC (and the 
IDMC before the end of the trial).  This is true whether the publication or presentation is 
concerned directly with the results of the trial or is associated with the trial in some other 
way. 
 
 
Outcome data by randomised group will not be revealed to the participating investigators 
until the data collection phase and primary full analysis of the trial has been completed.  This 
policy safeguards against possible bias affecting the data collection.  The IDMC will be 
monitoring the outcome results and may recommend that the trial be stopped for safety 
reasons or if a definitive answer is reached earlier than the scheduled end of the trial. 
 
15.2 FEEDBACK TO PARTICIPANTS 
At the end of the study, letters will be sent by trial sites to participants and families to inform them 
when the trial will be closing. 
 
When the trial results are available, an information sheet in lay terms will be provided for every trial 
participant and carers to explain the results of the trial.  This will be distributed to the Principal 
Investigators at each site so that the paediatrician can discuss it with the child and/or parent/carer to 
explain the outcome of the trial.   
 


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16 DATA AND/OR SAMPLE SHARING 
Data will be shared according to the MRC CTU’s controlled access approach, based on the following 
principles: 
 
No data should be released that would compromise an ongoing trial or study.  
 
There must be a strong scientific or other legitimate rationale for the data to be used for 
the requested purpose.  
 
Investigators who have invested time and effort into developing a trial or study should 
have a period of exclusivity in which to pursue their aims with the data, before key trial 
data are made available to other researchers.  
 
The resources required to process requests should not be under-estimated, particularly 
successful requests which lead to preparing data for release. Therefore adequate 
resources must be available in order to comply in a timely manner or at all, and the 
scientific aims of the study must justify the use of such resources.  
 
Data exchange complies with Information Governance and Data Security Policies in all of 
the relevant countries. 
 
Researchers wishing to access ODYSSEY data should contact the Trial Management Group in the first 
instance. 
 
 


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17 PROTOCOL AMENDMENTS 
Changes to protocol version 5.0 creating protocol version 6.0 8th November 2019 
 
Major changes 
1. The following sections have been amended to include information on extended follow-up 
and to clarify the differing requirements between the randomised phase and the extended 
follow-up phase: 
 
Trial Summary: Clarified that trial outcomes are for randomised phase. 
 
Trial Assessment Schedule for Randomised Phase of the Trial: Renamed to clarified 
that it is to be used for the randomised phase of the trial; End of Study visit 
renamed for clarity; footnote added to explain when participants should have their 
study visit for the end of the randomised phase and continue in extended follow-up. 
 
Treatment of patients (including sub-sections 5.1, 5.1.1, 5.5.1): Clarified drug supply 
arrangements for the randomised phase and extended follow-up; clarified that a 
participant’s NRTI backbone may be changed after completion of the randomised 
phase; differences in approach to ART modifications, interruptions and 
discontinuations between the randomised phase and extended follow-up described.  
 
Assessments & Follow-Up (including sub-sections 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.11): 
Described assessments required during randomised phase and directed to Appendix 
XX for those required during extended follow-up. 
 
Safety reporting (including subsections 7.1.4.A, 7.1.4.B, 7.1.4.C, 7.1.4.D, 7.2, 
7.2.1.E): Clarified that reporting timeframes outlined for events that are not SAEs 
are for those occurring during the randomised phase; reporting timeframes for non-
SAEs occurring during extended follow-up are outlined in Appendix XX. 
 
Statistical considerations (including subsections 9.2, 9.5): Updated to clarify that 
trial outcomes documented are for the randomised phase; outcomes in extended 
follow-up will focus on safety and possible long-term toxicities; a second SAP will be 
written for the extended follow-up phase. 
 
Ancillary studies (subsection 10.2): Clarified that time-points for collection of PBMCs 
for immunology virology substudy can be found in the Trial Assessment Schedule 
for the Randomised Phase of the Trial. 
 
Regulatory & Ethical Issues (including subsections 11.2.1.A, 11.2.1.C): Clarified that 
the IDMC will only review events occurring during the randomised phase; clarified 
drug supply arrangements for the randomised phase and extended follow-up. 
 
Finance: Clarified drug supply arrangements for the randomised phase and 
extended follow-up.   
 
Appendix I: Added parent/carer PIS, participant PIS and simplified PIS for younger 
children for extended follow-up. 
 
Appendix II: Added parent/carer ICF, participant ICF and participant assent forms 
for extended follow-up. 
 
Appendix XIII: Clarified that the IDMC will review PK and safety data from the 
randomised phase of the trial. 
 
Appendix XX: New appendix added to describe the arrangements for the extended 
follow-up of ODYSSEY participants 
2. The following section has been amended to describe an update to the end of trial definition: 
 
Assessments & Follow-Up (subsection 6.11): End of Trial definition updated. 
3. Safety Reporting (Section 7.1.1): Correction of trial IMP definition 
 
 


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Minor changes 
 
1. Front page: Logos updated 
2. General Information: Compliance and safety information updated to comply with newly 
released MRC CTU protocol template; Penta, MRC CTU and PHPT details updated, including 
contact details for SAE reporting for PHPT sites. 
3. Trial Assessment Schedule: Clarified that Sleep and Mood section of the Acceptability, Sleep 
and Mood questionnaire should only be completed for children aged 6 years and over, and 
that lipids/glucose tests after week 96 should also be should be performed under fasted 
conditions. 
4. Introduction: Updated information on DTG and pregnancy based on more recent data from 
the TSEPAMO study. 
5. Section 5.3.1: Clarified that DTG dose should be adjusted if a child moves weight band 
(removed reference to moving up a weight band); removed reference to WB-PK1 part III; 
removed that DTG dosing would initially be dependent on age for participants weighing 3-
<6kg; removed that recruitment to lower weight bands may be opened at all sites; removed 
that DTG doses may change again based on PK data. 
6. Section 5.9: Added reference to Section 6.9 for further information if a patient is withdrawn 
from follow-up. 
7. Section 6.1.1: Minor updates to ensure consistency with Trial Assessment Schedule for 
Randomised Phase of the Trial 
8. Section 6.9: Added statement on impact on trial data if participants stop trial follow-up 
early . 
9. Section 7: Minor corrections throughout. 
10. Section 7.1.2: Clarification of adverse event definition and those that require reporting. 
11. Section 7.1.4.D – The timeframe for AEs in infants born to female participants to be 
collected increased to 30 days after delivery. 
12. Section 7.2.1.C: Table 6 reordered to align with that in recently updated MRC CTU protocol 
template.  
13. Section 7.2.1.D: Updated  to clarify that the site investigator should make an initial 
assessment of expectedness but that Sponsor has overall responsibility; location of current 
RSI documentation added. 
14. Section 7.2.2: Clarified that the “investigator” reporting events does not need to be the PI, it 
can be another medically qualified person with delegated responsibility for event reporting; 
contact details for event reporting added to this section 
15. Section 7.3: Clarified that medically-qualified staff at the CTUs and/or the Chief Investigator 
(or a medically-qualified delegate) will review all event reports received, clarified to whom 
SAEs may be reported (regulatory authorities) and applicable timelines; MRC CTU produce 
the annual DSUR, clarified events will be reported to drug companies involved as per the 
individual contract requirements 
16. Section 8: Minor updates throughout as per recently released MRC CTU protocol template. 
17. Section 10.5: Minor correction to folate substudy appendix number 
18. Section 11.1: Updated throughout to reference Clinical Trials Regulation EU No 536/2014 
19. Section 11.2.1.A: Updated information on DTG and pregnancy following recent release of 
results from TSEPAMO study.  
20. Section 14: Minor updates to include information on Patient and Pubic Involvement, as per 
MRC CTU protocol template. 
21. Section 15: Updated to include timeline for reporting trial results. 
22. Section 16: Added as per MRC CTU protocol template. 
23. Appendix II: Corrections made to Participant Re-Consent to ODYSSEY trial. 


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24. Appendix XIII: WB-PK1 part III removed; removed that DTG dosing would initially be 
dependent on age for participants weighing 3-<6kg.  
25. Appendix XIX: Removed DTG dosing for WB-PK participants relating to WB-PK1 part III; 
removed that DTG dosing would initially be dependent on age for participants weighing 3-
<6kg. 
 
Changes to protocol version 4.0 creating protocol version 5.0 1st March 2019 
 
Major changes 
1. Summary: Virological response component of primary outcome measure updated so that 
children who do not respond virologically will not be included as failures unless their 
clinician switches them from first to second-line treatment (ODYSSEY A) or second to third-
line treatment (ODYSSEY B) or they have confirmed viral load ≥400 c/ml at or after 36 
weeks; addition of folate substudy. 
2. Trial assessment schedule and section 6.1: RBC folate/RBC storage and B12/serum storage 
for folate substudy added and footnotes updated accordingly. 
3. Section 5.3.1: Updated to describe changes to DTG dosing within the main trial, based on 
latest PK and safety data, and also ongoing WB-PK doses. Detailed WB-PK substudy 
information removed to avoid duplication as included in Appendix XIII. 
4. Section 5.5.1: Recommended switching female participants on DTG-based regimen 
identified to be pregnant within the first 8 weeks after the last menstrual period to a non-
DTG ART regimen if there are other good options available to replace DTG. 
5. Section 9.2.1: Virological response component of primary outcome measure updated so 
that children who do not respond virologically will not be included as failures unless their 
clinician switches them from first to second-line treatment (ODYSSEY A) or second to third-
line treatment (ODYSSEY B) or they have confirmed viral load ≥400 c/ml at or after 36 
weeks. 
6. Section 10: Addition of folate substudy; minor updates to other substudies. 
7. Appendix I: Updates to main trial PISs to include updated safety information, collection of 
information on babies born to female participants, information on data collection and 
storage; additional Qualitative substudy PISs to include in-depth interviews with caregivers, 
and in-depth interviews with participants on DTG following the safety alert; added PIS for 
YTB facilitators.   
8. Appendix II: Addition of parent/carer and participant re-consent to the ODYSSEY trial and 
participant re-assent to the ODYSSEY trial; additional Qualitative substudy consent forms to 
include in-depth interviews with caregivers and consent/assent forms for in-depth 
interviews with participants on DTG following the safety alert; added consent form for YTB 
facilitators.  
9. Appendix XV: Updated following DTG safety alert and to include caregiver interviews. 
10. Appendix XVIII: Added for folate substudy. 
11. Appendix XIX: Added for tabulation of dolutegravir dosing in the ODYSSEY trial across 
different protocol versions. 
 
Minor changes 
1. General information: Updated email address for contacting MRC CTU regarding 
randomisations & SAE reporting; staff details; collaborating centre details 
2. Summary: Removed that participants 3-<14kg may contribute to the 700 children in the 
main trial as main trial finished recruitment before lower weight bands opened and 
therefore at least 60 additional children will be recruited; clarification of recruitment period 
for children 3-<14kg. 


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3. Trial schema: Added footnote to briefly describe enrolment and follow up of children 3-
<14kg; 
4. Trial assessment schedule: Pregnancy tests to be performed at all trial visits, and other 
time-points if required, for all females of childbearing potential. 
5. Abbreviations: Updated 
6. Section 1.3: Minor update (WHO 2016 no longer most recent guidelines) 
7. Section 1.4: Updated to reference recent study. 
8. Section 1.5: Section added to include information on TSEPAMO study and dolutegravir 
safety alert. Subsequent sections renumbered accordingly. 
9. Section 1.6: Added information on DTG formulations available. 
10. Section 3.1.1: Footnote amended for clarification. 
11. Section 3.4: Clarification and update of recruitment period for children 3-<14kg. 
12. Section 4.1: Updated email address for contacting MRC CTU regarding randomisations. 
13. Section 5.1: Removed US as no longer participating; updated that DTG-containing FDCs may 
be sourced through national programmes where available. 
14. Section 5.3.2: Updated to clarify that participants 25-<40kg whose DTG dose is increased to 
50mg following the results of WB-PK2 and are already receiving ABC 600mg + 3TC 300mg 
may switch to Triumeq. 
15. Section 5.5.2.A: Updated to enable possiblity of restarting DTG if alternative cause for 
explanation of raised liver enzymes is more likely. 
16. Section 5.5.2.C: Updated for clarification. 
17. Section 5.10: Sodium valproate added to list of drugs with significant interactions; update to 
information regarding concomitant calcium/iron/vitamin supplements; added reference to 
link to University of Liverpool HIV Drug Interactions website added. 
18. Section 6.1: Pregnancy tests to be performed at all trial visits, and other time-points if 
required, for all females of childbearing potential; information about contraception use to 
be recorded; RBC folate/RBC storage and B12/serum storage for folate substudy added. 
19. Section 6.7.1: Children in the DTG arm receiving rifampicin as part of TB prevention therapy 
may also participate in the TB-PK substudy. 
20. Section 6.8: Updated to include information on TSEPAMO study; list of highly effective 
contraception that must be used if female participants are sexually active; updated 
guidance to sites if female participants taking DTG are intending to/become pregnant 
during the trial. 
21. Section 7.1.5.D: Reporting of events in infants born to female trial participants added; other 
minor update for clarification. 
22. Section 7.2.1.D: Updated to clarify that the most recently approved IB should be used for 
assessing expectedness for DTG and DTG-containing products but that SPC should be used 
for all other ARVs. 
23. Section 9.5: Clarified primary analysis refers to main trial participants; clinical and adverse 
events will be summarised using an in-house coding system  
24. Section 11.2.1.A: Updated with information on common side effects and dolutegravir in 
pregnancy safety alert. 
25. Section 13: Clarification of the drugs provided for the trial and to which sites/countries. 
26. Appendix I: Updates to WB-PK1 PISs to include children 3-<14kg; updates to Qualitative 
substudy focus group PISs; updates to YTB PIS. 
27. Appendix II: Updates to parent/carer main study consent to randomisation, participant 
main study consent to continued participation for young people who reach the age of 
consent whilst in the trial; updates to WB-PK1 consent/assent forms to include children 3-
<14kg; update to title of consent form for Qualitative focus group discussions (young people 
18-19 years); updated YTB consent/assent forms. 


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28. Appendix XIII: Updated to include results and outcomes of the WB-PK substudies to date 
and to fully describe updates to the WB-PK1 substudy (parts II & III). Rearrangement of 
some sections and other minor amendments for clarification purposes; Table 10 moved to 
appendix XIX. 
29. Appendix XIV: Children in the DTG arm receiving rifampicin as part of TB prevention therapy 
may also participate in the TB-PK substudy; clarified that children <6 years may be 
recruited. 
30. Appendix XVI: Updated to include interviews and to clarify that ≥32 young people will take 
part. 
31. Appendix XVII: Odyssey structure updated with sites added/deleted as appropriate. 
 
Changes to protocol 3.0 creating version 4.0 22nd December 2017 
 
Major changes 
1. Summary: In the number of patients, added that 60 additional children 3-<14kg will be 
enrolled, some of whom may contribute to the 700 children in the main trial (see below 
changes in sections 9.1 and 9.5).    
2. Section 6.1 and Trial assessment schedule footnote t: Clinical assessment, haematology and 
biochemistry tests at week 2 are required for all children 3-<14kg. 
3. Section 3.1.1: Inclusion criteria expanded to include children aged ≥28 days and weighing 3-
<14kg. 
4. Section 3.4: Explanation that 60 additional children 3-<14kg will be enrolled as a separate 
group, some of whom may contribute to the 700 children in the main trial. Recruitment 
period increased to 96-120 weeks, to allow recruitment of younger/lighter children. 
5. Section 5.3.1: Table 3 and the text are updated to include formulations and dosing 
information on children 3-<14kg recruited via an updated WB-PK1 substudy. Added 
information about the lead-in PK substudy for the weight band 3 to <14kg. Children 14-
<20kg will receive DTG 25mg to simplify the dosing to one DTG 25mg tablet QD instead of 
two DTG 10mg tablets QD and to avoid confusion with two different dosing for this weight 
band in the trial. Added that ViiV Healthcare is confirming the suggested dose for children 3-
<6kg. Also added that children 14-<25kg who are able to swallow tablets will be taking DTG 
25mg tablets and those who cannot swallow will take dispersible tablets. Information on 
WB-PK1 is removed as repeated in Appendix XIII.  
6. Section 6.11: The end of the main trial recruitment is defined. Explained that recruitment of 
children 3-<14kg may be continued after the end of the main trial recruitment reached and 
that all children will be followed up for a minimum of 96 weeks. 
7. Section 9.1: Added that children 3-<14kg will be recruited and randomised as a separate 
group stratified by A/B and the 3 weight bands. Randomisation of children ≥14kg continues 
as previously. 
8. Section 9.5: Added that children recruited in the 3 lower weight bands before recruitment 
targets have been achieved will contribute to the total accrual numbers for the main trial if 
their doses are confirmed to be optimal doses. Added that there will be a separate 
secondary analysis of all children <14kg when this group has completed 96 weeks follow-up.  
9. Appendix XIII: WB-PK1 substudy is updated to include children 3-<14kg. Table 9 updated. 
References updated.  
 
Minor changes 
 
1. General information: Updated staff details; CTU address; added address of new 
collaborating centre. 
2. Summary: Recruitment period increased to 96-120 weeks. 


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3. Trial assessment schedule footnote d: For clarity and consistency added that the screening 
viral load test for ODYSSEY B participants may be omitted if a result of ≥500 copies is 
available up to 4 weeks prior to the screening visit. (This change was included as part of the 
previous protocol version 3.0 and the details can be found elsewhere in sections 3.1.3 and 
3.6.1. and for completeness and consistency is now added to the assessment schedule 
footnotes). 
4. List of abbreviations: DT (dispersible tablet) added 
5. Section 1.5: Information on marketing authorisation is updated. 
6. Section 2.3: Deleted sites no longer participating, including Brazil and an IMPAACT-
supported site in South Africa. 
7. Section 3.1.3: TAF added to the list of drugs in the additional inclusion criteria for ODYSSEY 
B. 
8. Section 3.3.1: TAF added to section on considerations of use of different NRTI. 
9. Section 4 and Section 5.7 and Trial assessment Schedule:  Updated that the Sleep and mood 
section of Acceptability, Sleep and Mood Questionnaire is to be completed at enrolment. 
10. Section 5.1: Added TAF to list of NRTIs. 
11. Section 5.2: – Added ATV/c to list of bPIs and added “e.g.” in order to clarify other less 
common drugs not listed may also be included. 
12. Section 5.2.1 Table 1 and Section 5.2.2 Table 2: ATV/c, DRV/c and TDF or TAF are added in 
the examples of ART regimens for the SOC arm.  
13. Section 5.3: TAF is added in the examples of NRTI backbone for the DTG arm.  
14. Section 5.3.1: For children 20-<25kg added that doses in this weight band will be reviewed 
and, if necessary, modified based on PK and safety data from ODYSSEY and/or P1093. 
Clarified information on all weight bands in the WBPK substudies. Information on WB-PK1 is 
removed as repeated in Appendix XIII. 
15. Section 5.5.1: Added that in exceptional circumstances study drug may be provided as third-
line treatment for children in the SOC arm who have failed second-line treatment. 
16. Section 5.5.2.C: Added that prompt clinical evaluation should be done (instead of 
considered) for participants who experience signs of suicidal ideation or behaviour.  
17. Section 6.3: – Corrected typo - version of DAIDS from 2010 to 2014 
18. Section 6.8: Information on reporting of pregnancy moved to the relevant section on safety 
reporting 7.1.5.  
19. Section 7.1.5: Reporting of notable events is clarified. Added that the suspected cases of 
drug induced liver injury should be reported in both arms. 
20. Section 7.2: clarified reporting of laboratory AEs, SAEs, SARs and notable events.  
21. Sections 7.2.1 and 7.2.2: Clarified that notable events should be reported within 24 hours of 
the investigator becoming aware of the event.  
22. Section 7.3: Clarified that the CTUs will review all reported notable events. 
23. Section 8.3: Updated to clarify monitoring processes. Removed repetition on permission 
and consent to access patient data. 
24. Section 8.3.2: Confidentiality section clarified. 
25. Section 10.1: Updated information on PK substudies. 
26. Section 17: References updated. 
27. Appendix I: Titles of Patient Information Sheets are updated to include children weighing 
≥3kg. 
28. Appendix II: Titles of Template Consent and Assent Forms are updated to include children 
weighing ≥3kg. Main study consent to continued participation for young people who reach 
the age of consent whilst in the trial added. 
29. Appendix XIII: Updated list of sites participating in WB-PK substudies. 
30. Appendix XIV: Clarified that younger children <6 years may be recruited once the 
appropriate DTG doses are confirmed for them in WB-PK1 substudy. Updated information 


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in study design paragraph and Figure 1 that the 1st PK day (TB-PK1, 12h curve) may be 
performed within the last month of co-administration. Removed details of specific sites as 
the TB-PK will take place at all sites in Uganda, South Africa and Zimbabwe. 
31. Appendix XVII: Odyssey structure updated with sites added/deleted as appropriate. 
Minor corrections 
 
Changes to protocol version 2.0 creating version 3.0 18th January 2017 
 
Major changes 
 
10. Summary of Trial and section 5.2: Added that INSTIs (other than DTG) can be included as a 
SOC third agent option. Clarified that PI means a boosted PI. 
11. Summary of Trial secondary outcomes: Changed from ≥50 and ≥400 copies to <50 and <400 
copies.  
12. Summary of Trial and section 10 Ancillary substudies: Added WB-PK1 and WB-PK2 
substudies. Renamed TB-PK substudy to differentiate from new PK substudies. Added 
Qualitative and Youth Trial Board substudies. 
13. Updated Trial Schema to include INSTI in SOC Arm for ODYSSEY A and replace RAL with 
INSTI in SOC for ODYSSEY B. 
14. Trial Assessment Schedule and accompanying notes: Added that the glucose test can be 
optional at the randomisation visit if there is a medical justification to limit the amount of 
blood drawn.  Renamed EQ-5D questionnaire as Quality of Life questionnaire (as using an 
adapted version of the EQ-5D). Changed frequency of plasma storage after 96 weeks from 
every 24 weeks to every 12 weeks. Removed PBMC storage at screening, week 2 and the 
end of study visit.  Changed acceptability questionnaire to acceptability, sleep and mood 
questionnaire and added that this will be done at week 12. Revised volumes for blood 
collection, differentiating for blood to be used for tests and for storage. Added that 
lipodystrophy and bone profile (optional) to be done at the end of study visit. Added 
clarifications regarding mandatory and optional tests. Clarified that adherence 
questionnaire for ODYSSEY B at screening visit only to be done if participant is currently on 
treatment. Added that BIA measurements will be done at selected sites. Added that, if not 
already scheduled, plasma storage, adherence and acceptability questionnaires should be 
done at point of treatment failure, and adherence and acceptability questionnaires if ART 
regimen changes. 
15. Background: Updates and clarifications made. 
16. Section 3.1.1 Patient inclusion criteria all patients: Replaced DTG dose known for 
age/weight band with “weighing ≥14 kg and DTG dose known for the child’s weight-band”, 
and added details regarding the inclusion criteria for children weighing 14 to <20kg.  
17. Section 3.1.3 Additional criteria for ODYSSEY B: Additional definition of starting second-line 
ART as switch of only the third agent due to treatment failure where resistance tests show 
no NRTI mutations. Clarification that reasons for substitutions could also include changes in 
national guidelines or drug availability. Removed time period for cumulative results of 
resistance testing. Replaced viral load of >1000 copies with >500 copies at screening visit, 
and added that can also be within 4 weeks prior to screening.  
18. Section 3.6.1: Removed words “for screening” and “screening” in order to comply with local 
requirements for consent procedures. 
19. Section 3.6.1: Added viral load for ODYSSEY B may be done at screening or within 4 weeks 
prior to screening. 
20. Section 4: Amended wording “written informed consent… must then be obtained” with 
“Continued agreement… must be confirmed” in order to comply with local requirements for 
consent procedures. 


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21. Section 5: Major reorganisation to this section: Added a general information section to 
clarify information relevant to all participants, regardless of treatment allocation. Moved 
text previously in either ODYSSEY A or B sections to this section as applicable to all 
participants (e.g. ABC warning cards). 
22. Section 5.1.1: Added section 5.1.1 to clarify that participants must be prescribed the NRTI 
backbone selected prior to randomisation and added further guidance regarding changes to 
the NRTI backbone during the trial. 
23. Section 5.1 and 5.2: Updated SOC drug options to include RPV and INSTIs. Tables 1 and 2 
updated and moved to sections 5.2.1 and 5.2.2. Added for clarification that participants 
randomised to SOC must be prescribed the class of non-NRTI drug that was chosen prior to 
randomisation. 
24. Section 5.2.2: Added further guidance regarding addressing adherence issues. 
25. Section 5.2.2: Further guidance on interpretation of resistance test results added. Added 
that ddi or d4T may be used in second-line where no other drugs are available. 
26. Section 5.3.1: Added information about DTG dosing according to the following weight 
bands: 14 to <20kg, 20 to <25kg, 25 to <40kg, and >40kg. Added information about the lead-
in PK substudy (WB-PK1) for the weight bands 14 to <20kg and 20 to <25kg; and about the 
cross-over PK substudy (WB-PK2) for the weight band 25 to <40kg. Added table 3 
summarising DTG dosing and formulations to be used in ODYSSEY. 
27. Section 5.3.2: Added that (subject to satisfactory PK results) children ≥25kg  in the main trial 
on DTG+ABC+3TC would be able to move to an FDC. 
28. Added Section 5.5.2.C Suicidal Ideation Behaviours and Sleep Disorders. 
29. Section 5.7: Acceptability questionnaire now incorporates questions on sleep and mood and 
week 12 now added (which was previously missing in error).  
30. Section 5.10: Added information and table 4 on significant drug interactions with DTG. 
31. Section 6.1 and 6.2.3: Added that for ODYSSEY B the viral load can be done at screening or 4 
weeks prior. 
32. Section 6.1: Removed PBMC storage at screening. 
33. Section 6.2.4: Clarification that for children experiencing virological failure. Replaced >1000 
c/ml with current threshold for resistance assays. 
34. Section 6.4: Renamed EQ-5D questionnaire as Quality of Life questionnaire (as using an 
adapted version of the EQ-5D). 
35. Section 6.7.1: Changed from at least ‘10’ children to ‘12’. 
36. Section 7.2: Added that Grade 1 clinical AEs should be reported only if they result in change 
of ART, (as well as Grade 2). 
37. Section 9.1: Clarification that availability of resistance tests is for each particular site and is 
with respect to children who are failing treatment. 
38. Section 9.1: Added TAF/3TC and TAF/FTC to TDF stratification group. 
39. Section 9.1: Added that randomisation will be stratified by NRTI backbone. 
40. Section 9.2.2: Changed, (<50 and <400 copies rather than ≥). Deleted “with a subgroup 
analyses according to the activity of the background regimen”. 
41. Appendix I Template information sheets Main study:  Reworded explanation of second-line 
treatment. Updated volumes of blood collection from 2 to 3 teaspoons to 3 to 6 teaspoons. 
Deleted the visit schedule. Added sentence regarding depression or having suicidal thoughts 
in possible disadvantages of taking part. Added more detail on section “what will happen to 
information about me/my child collected during the study”. 
42. Appendix I: Added information sheet for the WB-PK 1 substudy (also incorporating the main 
trial). 
43. Appendix I: Added information sheet for the WB-PK 2 substudy (also incorporating the main 
trial). 


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44. Appendix I: Renamed information sheet for TB PK substudy. Added further details to “what 
will happen to information about me/my child collected during this substudy”. Reduced 
number of samples collected from 10 to 7. Changed wording from hospital to clinic. 
45. Appendix I: Added information sheets for Qualitative substudy. 
46. Appendix I: Added information sheets for Youth Trial Board substudy. 
47. Appendix II: Added consent and assent forms for WB-PK 1 and WB-PK 2 substudies. 
48. Appendix II: Added consent and assent forms for Qualitative substudy. 
49. Appendix II: Added consent and assent forms for Youth Trial Board substudy. 
50. Appendix IV: Updated adherence questionnaires. 
51. Appendices V and VI: Updated acceptability questionnaires and also incorporated additional 
questions on sleep and mood. No longer different questionnaires for ODYSSEY A and B 
therefore Appendix VI deleted. 
52. Added Appendix XI and Table 7 on safe limits of blood sample volumes in children. 
53. Updated Appendix XII on the Immunology/virology substudy. 
54. Added Appendix XIII on the Weight band pharmacokinetics substudies WB-PK 1 & 2. 
55. Updated Appendix XIV on the TB PK substudy. 
56. Added Appendix XV on the Qualitative Substudy. 
57. Added Appendix XVI on the Youth Trials Board project. 
 
 
Minor changes 
 
1. Cover page: Mylan logo added. 
2. General information: Updated phone number and e-mail address for MRC CTU 
randomisations. 
3. General information: Updated e-mail address for SAE reporting for MRC CTU coordinated 
sites. 
4. General information: Updated staff details at PENTA foundation, MRC CTU, INSERM-ANRS 
and PHPT. 
5. General information: Updated details of staff at collaborating centres and removed 
countries and centres no longer participating. Updated and added new collaborating 
centres. 
6. General information:  Added e-mail addresses for David Burger, Nigel Klein and Maria 
Munoz Ferndandez. 
7. Summary of Trial: Clarified that PI means a boosted PI. 
8. Summary of Trial and sections 9.2.1 to 9.2.3; Primary and secondary outcomes: 
clarifications made to how endpoints will be assessed.  
9. Summary of Trial: Secondary outcome measures, deleted word “suppression”. 
10. Summary of Trial and sections 9.2.3 and 9.5 Added that change in total cholesterol from 
baseline to week 96 will be used to assess superiority of DTG arm vs SOC arm. 
11. Summary of Trial and section 10, ancillary substudies: Added “see section 10 for 
participating countries”. Reworded summary Immunology/virology substudy for clarity and 
consistency. 
12. Abbreviations: List updated. Removed EQ-5D and replaced with QoL. 
13. Section 2.3 Site Management: Removed countries no longer participating. 
14. Section 3.2 Patient exclusion criteria. Minor rewording for clarification regarding history of 
presence of known allergy or contraindications to DTG, proposed available SOC third agent 
or NRTI backbone. 
15. Section 4 Registration & Randomisation: Minor rewording for clarity. Updated the MRC CTU 
contact details for randomisations. Clarified that family also can mean household for 
enrolment of multiple participants. 


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16. Section 5.1: Clarifications regarding drug supply added, and that that the Mylan formulation 
of ABC/3TC 120/60mg will be provided in sub-Saharan Africa if required. 
17. Section 5.4: Clarification that refers to trial drugs. 
18. Section 5.5: Renamed section title for clarity (deleted word “dose”). 
19. Section 5.5.1: Renamed section title for clarity. Moved sentence on “if simplification…is 
deemed necessary” to the end of the section. Added word “treatment”. Minor clarification 
regarding recommendations if possible drug induced liver injury. 
20. Section 5.5.2: Renamed section title for clarity.  Added word “appropriate” before CTU. 
21. Section 5.7 Heading reworded for clarity from Compliance and adherence to adherence and 
acceptability. Deleted words “participant-reported” in first sentence for clarity. 
22. Section 5.8: Reworded “pills” as may include liquid formulations. 
23. Section 6.1: Clarification that if previous Tanner scores of 5, no need to continue doing 
Tanner scores at subsequent visits. Added “and then 48 weekly” and “and at end of study” 
to those measurements where this was missing, in order to match the Trial Assessment 
Schedule. 
24. Section 6.2.4: Added that samples may be assayed locally where possible, or moved to 
another country. 
25. Section 6.4 Added “and at end of study” for the quality of life questionnaire”. 
26. Sections 6.7 to 6.7.2. Clarification that participants may either have TB at enrolment or 
develop TB during the trial. Clarification that not compulsory to enter the substudy if 
participant has TB. Other minor rewording for clarification. 
27. Section 6.11: Clarification that the trial will be considered closed when the last patient to be 
enrolled reaches 96 weeks. 
28. Sections 7.1, 7.1.5 and 7.2.1: Table 4 renumbered as Table 5. 
29. Section 7.2.1: Table 5 renumbered as Table 6. 
30. Section 7.1.5: Renamed section title as other notable events, renumbered some section 
titles from 7.3.x to 7.2.x 
31. Section 7.3: Corrected spelling error. 
32. Section 8.2: Deleted MRC as relevant to all CTUs. 
33. Section 9.1: Clarification that availability of resistance testing is relevant to “before switch 
to second line”. 
34. Section 9.2.3: Added “change in total cholesterol from baseline to week 96”. 
35. Section 9.2.4:  Removed “as assessed by patient completed questionnaires”. 
36. Section 9.5: Added paragraph on how the proportion of participants with VL <50 or <400 
will be determined. 
37. Section 10: Added a short summary of the ancillary studies details of which countries are 
participating. 
38. Section 11.2.1.E:  Corrected that computer generated anonymous codes will be three letters 
not four. Corrected that full date of birth, not just month and year of birth will be used. 
Added further details on identifiers for stored samples. 
39. Section 13: Clarification regarding arrangements for drug supply. 
40. Appendix I: Grammar correction in patient/carer information sheet “what happens at the 
end of the study” section. 
41. TB-PK information sheet – changed wording from “Rifampicin” to “anti-TB medicine” to 
make easier to understand. Changed blood sample amount from “less than” half a teaspoon 
to “about” half a teaspoon. 
42. Appendix II: Parent/carer – main trial consent to screening, corrected typo on last 
statement. 
43. Appendix II: Added screening assent form. 
44. Appendix II: Added participant consent to storage of blood samples for future testing form. 
45. Appendix II: Renamed consent form for TB PK substudy (added “TB”). 


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46. Renumbering of Appendices throughout document following deletion of appendix VI. 
47. Appendix IX: Updated DAIDS Tables to 2014 version. 
48. Appendix XVII updated ODYSSEY structure to remove countries and collaborating sites no 
longer participating and to include new collaborating sites. 
 
 
Changes to protocol version 1.1 creating version 2.0 6th March 2015 
Cover page: IMPAACT logo updated. 
General Information: Details for collaborating centres in Klerksdorp, South Africa (PHRU) and 
Memphis, US (St Jude Children’s Research Hospital) added  
General Information & Section 2.3 Site Management: US removed in relation to IMPAACT and 
added as a MRC collaborator.   
General Information: MRC CTU at UCL staff details updated. 
Trial Assessment Schedule: Timing of urine dipstick tests corrected – tests at end of study visit 
added. 
Trial Assessment Schedule & Section 6.4 Procedures for Assessing Quality of Life: Removal of 
reference to EQ-5D-Y questionnaire, replaced with EQ-5D. EuroQol website link added to section 
6.4. 
Trial Assessment Schedule: Total blood volume to be collected clarified. 
Abbreviations: List updated to include EQ-5D. 
Section 6.8 Management of Pregnancy: Clarified that pregnant participants should be encouraged 
to remain in the study even if ART regimen is changed. 
Section 7.3.1.D Expectedness:  Updated information on responsibilities for determination of 
expectedness of serious adverse events. 
 
Changes to protocol version 1.0 creating version 1.1 11 December 2014 (the protocol was still a 
draft document at this stage but a “final” version was required for review by Viiv resulting in version 
numbers taking this format. Neither protocol version 1.0 nor version 1.1 have been reviewed by an 
ethics committee or competent authority). 
General Information, Summary of Trial, Section 2 Selection of Sites/Clinicians & Section 14 Oversight 
& Trial Committees: Details of IMPAACT involvement added. 
General Information: Funding information corrected to reflect current status. 
General Information: Sponsor details added. 
General Information: Immunology/Virology Committee member details updated. 
Summary of Trial: Updated for consistency and minor amendments for clarification. 
Trial Schema, Section 5.1 Introduction & Section 5.2 SOC Arm: Addition of raltegravir to SOC arm of 
ODYSSEY B. 
Trial Assessment Schedule & Section 6.1 Trial Assessment Schedule: Addition of urine dipstick tests. 
Trial Assessment Schedule, Section 3.1.1 Patient Inclusion Criteria, Section 6.1 Trial Assessment 
Schedule & Section 6.8 Management of Pregnancy: Pregnancy test requirements clarified.  
Trial Assessment Schedule: Timing of Tanner scale measurements, lipodystrophy assessments and 
study drug supply clarified. 
Trial Assessment Schedule: Timing of screening and randomisation visits clarified. 
Abbreviations: List updated accordingly. 
Section 1 Background: Updated 
Section 2 Selection of Sites: General wording updated  and update to laboratory requirements.  
Clarified that a site and lab risk assessment will be carried out prior to site activation. 
Section 3.2 Patient Exclusion Criteria: Bilirubin must be ≥2xULN. 
Section 5 Treatment of Patients & Section 13 Finance: Triumeq can be provided by Viiv Healthcare 
as appropriate. 


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Section 5.5.2.A Liver Toxicity: Stopping criteria updated to include that DTG should be substituted if 
ALT ≥3xULN and bilirubin ≥2xULN, or that ALT ≥5xULN for more than 2 weeks with bilirubin <2xULN 
and no symptoms of acute hepatitis or hypersensitivity. 
Section 6.2.2 Immunology, Section 8.3.1 Direct Access to Participant Records & Section 9.2.2 
Secondary Efficacy Outcomes: Clarification that total and percentage CD8 T cell counts should also 
be measured and access will be required to a random sample of this data. This data will be used to 
provide CD4/CD8 ratios required as a secondary efficacy outcome. 
Section 6.2.4 Resistance Testing: At sites where genotypic resistance testing is not performed as 
standard of care baseline samples will be tested retrospectively and batched genotypic resistance 
testing will be performed on samples with viral load >1000 c/ml. 
Section 6.7.1 Management of Children with Tuberculosis in the DTG Arm & Section 10.2 
Pharmacokinetic Substudy in Participants Developing TB while on DTG: At least 10 children with TB 
receiving DTG and rifampicin will be invited to participate in the PK substudy. 
Section 6.8 Management of Pregnancy: Clarification that all infants born to female participants will 
receive infant prophylaxis according to current local standard of care. 
Section 6.8 Management of Pregnancy:  Clarification that any pregnancy that occurs during study 
participation must be reported as a notable event. 
Section 6.10 Participant Transfers: Patients can continue to attend visits at original site if sufficient 
resources are available, or nurse only telephone visits can be conducted with drugs and clinical care 
provided at a local clinic. Participant should be considered lost to follow-up if none of the options 
are possible. 
Section 7.4 CTU Responsibilities: Modified for general applicability. CTUS are responsible for 
reporting of SAEs to relevant regulatory authorities and research ethics committees. This 
responsibility may be delegated to country principal investigators. 
Section 8.3 On-Site Monitoring:  Monitors will evaluate laboratory procedures and sample storage. 
Section 9 Statistical Considerations: Randomisation will be stratified by bPI/non-bPI-base ART 
offered as SOC (to include RAL). 
Section 13 Finance: Drugs provided by Viiv Healthcare corrected. 
Minor corrections 


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AIDSinfo. Recommendations Regarding the Use of Dolutegravir in Adults and Adolescents 
with HIV who are Pregnant or of Child-Bearing Potential. 2018 May 30, 2018; Available from: 
https://aidsinfo.nih.gov/news/2109/recommendations-regarding-the-use-of-dolutegravir-in-adults-
and-adolescents-with-hiv-who-are-pregnant-or-of-child-bearing-potential. 
51. 
EMA. Guideline on good pharmacovigilance practices (GVP) Module VI – Collection, 
management and submission of reports of suspected adverse reactions to medicinal products (Rev 
2), in Guideline on good pharmacovigilance practices (GVP). 2017: EMA. 
 
 


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19 APPENDIX I  TEMPLATE PATIENT INFORMATION SHEETS 
PARENT/CARER INFORMATION SHEET - MAIN STUDY ONLY 
ODYSSEY STUDY  
 
We are inviting you and your child to take part in a research study 
 
 Before you decide whether to take part, it is important for you and your child to understand why we 
want to carry out this study and what it will mean for you both. 
 Please take time to read the following information and to discuss it with friends, family and with your 
doctor or clinic nurse if you wish.  
 You are free to decide if you want your child to take part in this research study. If you choose not to 
take part, this will not affect the care your child gets from your doctor or nurse. 
 If you decide to take part in the study you can stop taking part at any time without giving a reason. 
 Ask your study doctor or nurse if anything is not clear or if you would like more information. 
 Thank you for reading this information.  
 
Important to know 
  
 If you decide to take part your child will have some extra visits to the clinic at the beginning of the 
study. 
 A computer program will choose which treatment your child will take. Neither you nor your doctor 
will be able to choose which group your child is in. 
 
 
Contents 
 
1. Why are we doing this study?  
2. Why has my child been asked to take part? 
3. What will happen if we decide not to take part? 
4. What will happen if my child takes part? 
5. What medicines will my child be given if we take part? 
6. What are the possible benefits and disadvantages of taking part? 
7. Study questionnaires 
8. More information about taking part 
 
 
 


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1 Why are we doing this study? 
 
Dolutegravir is a new medicine being used to treat adults with HIV.  
In adults it has been shown to be effective and safe, with few side effects, and it only needs to be 
taken once a day.  
Sometimes a medicine works differently in growing children than in adults, so we need to check how 
it works in children as well. Dolutegravir could be an excellent option for children if the study finds it 
works as well as it does in adults. 
ODYSSEY will see how children and adolescents taking dolutegravir as part of their anti-HIV medicines 
compare to others taking different anti-HIV medicines.   
 
 
2 Why has my child been asked to take part? 
 
We are aiming to ask 700 children and young people from many countries to take part.  
Your child has been asked to participate because:  
A. He/She is about to start taking anti-HIV medicine for the first time. 
Or 
B. He/She is already taking one set of anti-HIV medicine that is no longer working well and your 
doctor has decided it is time your child changes to a new combination.  This is known as “second-
line” treatment. 
 
 
3 What will happen if we decide not to take part? 
 
It is totally up to you and your child whether or not he/she takes part in this study.  
It is your right to decide not to take part if you wish.  
This will not affect your child’s care now or in the future in any way. 
 
 
4 What will happen if my child takes part? 
 
If you decide to take part, we will go through this information sheet together.  We will give a copy to 
you to keep. You will be asked to sign a consent form to show you have understood the information 
and have agreed for your child to have some blood tests and a check-up to see whether they can go 
into the study.  
If the results show that your child can participate, we will invite him/her to enter the study.  We need 
to know that you have fully understood the study and then we will ask you to sign a second consent 
form for your child to join.  
Your child’s health will be watched closely during the study.  


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In the first 2 months you will need to come for 3 appointments.  Once your doctor is happy that your 
child has no side effects from the medicines and is doing well, they will change to having 3-monthly 
appointments.   
These visits are to make sure your child is continuing to do well. If for any reason your doctor has any 
concerns, they will change your child’s treatment in the normal way.  
In addition to blood tests to check for any side effects, a small amount of extra blood will be collected 
at each visit. The total amount of blood taken will never exceed a safe limit and will be between 3 and 
6 teaspoons depending upon the age of your child. Part of this sample will be stored to be used to 
check the amount of virus in the blood and to look at how the body fights HIV. We would like your 
agreement that we can store these samples anonymously (without your child’s name or exact date 
of birth) for up to 15 years. 
Your child will be in the study for at least 2 years. When the study ends, if your child is doing well they 
may be able to remain on the same anti-HIV medicines they have been taking during the study, but 
you will need to discuss this with your doctor.  
It is important that you know that this is a voluntary study so if at any time you decide that your 
child does not want to be involved anymore, you can stop and it will not affect the care that your 
child receives in the future. 
 
 
5 What medicines will my child be given if we take part? 
 
If your child joins the study, a computer will choose which group he/she will be in so it is fair and we 
can truly compare the treatments.  
There will be two groups in the study:   
 Standard of care group: meaning your child will receive the usual, nationally approved anti-HIV 
medicine.  
 Dolutegravir group: meaning your child will take a combination of anti-HIV medicines that 
includes the new medicine, dolutegravir.   
 
 
6 What are the possible benefits and disadvantages of taking part? 
 
What are the possible benefits of taking part in this study? 
We cannot promise that participating in the study will directly help your child. Compared to other 
anti-HIV medicines dolutegravir may have fewer side effects and needs to be taken only once a day 
which may make it easier to take medicines long-term. 
However, if your child is in the ‘standard of care’ group they will receive the same anti-HIV medicines 
as children not taking part in ODYSSEY, although your child will be watched very carefully for any side 
effects and responses to the treatment. All the information we get will help children and young people 
across the world with HIV and in the future it may mean your child has the chance to change to 
medicines that are easier to take. 
 
What are the possible disadvantages and risks of taking part in this study? 
Whichever group they are in your child will have 3 extra visits to the clinic.  


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Anti-HIV medicines, like all medicines, can have side effects; most common are nausea, vomiting, 
abdominal discomfort, diarrhoea, rash or may affect the liver. If your child feels unwell, you should 
contact the clinic as soon as possible. 
The new medicine, dolutegravir, has been shown to be effective, with few side effects in adults, but 
we don’t know if this will be the same in children (which is why we need to do this study). The most 
common side effects in adults are headache, diarrhoea, abdominal pain feeling sick, light headed or 
weak, worrying often and having sleep problems. Some adults taking dolutegravir have reported 
feeling depressed or having suicidal thoughts, these may not be related to this medicine in all cases. 
There is a small chance that dolutegravir may cause a rash, itching, vomiting, stomach pain, sleep 
problems, lack of energy, an increase in weight, feeling light headed, sad or worried or may cause 
serious liver problems (with signs of vomiting, jaundice or stomach pain), which is why the doctor 
needs to follow your child closely. If your child has these signs for more than a day you should inform 
your doctor straight away. 
 
Risks in Pregnancy and anti-HIV medicines 
There is very little information about the effect of dolutegravir in unborn babies. In a recent study 
from Botswana, approximately 1 in 100 women who were taking dolutegravir when they became 
pregnant had babies with serious brain and/or spine problems. In the same study, approximately 1 in 
1000 women who were taking other antiretrovirals had babies with brain and/or  spine problems, 
which is similar to what is seen in women without HIV. These problems happen very early in 
pregnancy, before many women even know that they are pregnant. We do not know for sure if these 
problems are because of dolutegravir. The study in Botswana and other similar studies are ongoing. 
We expect more information about this in the near future. In the meantime, we would like to tell you 
about this possible risk. 
If your child could become pregnant, she will need a pregnancy test before entering the study. She 
will not be able to join the study if the test shows she is pregnant.  She should avoid getting pregnant 
while in the study, and use effective contraceptives if she is having sex. While in the study, please let 
us know if she is thinking about having a baby before she starts trying, or if she thinks she is pregnant. 
Pregnancy tests will be done regularly during the study to find out early if she is pregnant or not and 
to give her the appropriate medical care. If she does get pregnant, she will be able to stay in the study 
and her doctor will talk to you both about whether she needs to change her medicine.  Once she 
delivers, her baby will be assessed by a doctor for any problems and the baby will be followed for 
approximately 4 weeks to monitor their health. Health information, including HIV status, will be 
collected about the baby. If she has already had a baby whilst being on the study, health information 
captured by the hospital during this time period will be collected for the study.  
 
7 Study questionnaires 
 
We are very interested in finding out what children, young people and families feel about the study 
and how it is affecting their wellbeing. Over the course of the study we will ask you and your child to 
complete questionnaires asking how your child takes their medicines, what it’s like taking medicine 
and how they feel in general.  
 


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8 More information about taking part 
 
Additional studies 
There are some additional studies that are part of ODYSSEY. If they are run at your clinic your doctor 
may talk to you and your child about taking part.  
Who is organising the study? 
ODYSSEY is organised by the PENTA Foundation, an independent organisation that concentrates 
specifically on treatment issues for children and young people infected with HIV.  
Who has checked this study is safe? 
The information about this study has been checked by an independent group of people (a Research 
Ethics Committee) to make sure that, as far as possible, the safety and wellbeing of anyone taking 
part in the study is protected.  
A second group (the Independent Data Monitoring Committee) will meet regularly during the study 
to review the results as they come out and will recommend if the study is safe to continue.  This is 
standard for all studies looking at medicines for adults or children. 
 
What if something goes wrong? 
The PENTA Foundation has made arrangements for compensation should your child come to any 
harm from participating in this study. If your child is harmed due to someone’s negligence then you 
may have reasons for legal action for compensation against the clinic where this occurred. 
 
With your permission your child’s GP will be informed of his/her participation in the study. Your 
hospital doctor is not receiving any personal payment for carrying out this research. [Country specific, 
delete if not applicable] 
 
What will happen to information about my child collected during the study? 
The Fondazione PENTA Onlus, based in Italy and Sponsor for this study, is the owner of data and acts 
as Joint Data Controller. University College London (UCL) through the MRC Clinical Trial Unit at UCL, 
will be using information from your child and your child’s medical records in order to undertake this 
study and will act, along with the Sponsor, as Joint Data Controller for this study and Data Processor. 
This means that PENTA and UCL are responsible for looking after your child’s information and using 
it properly. UCL and the sponsor designated trial co-ordinating units will keep information about your 
child for a minimum of 15 years after the study has finished.  
 
Your and your child’s rights to access, change, move or erase their information are limited, as we need 
to manage information in specific ways in order for the research to be reliable and accurate. If your 
child withdraws from the study, we will keep the information about your child that we have already 
obtained. To safeguard your child’s rights, we will use the minimum personally identifiable 
information possible.  
 
All ODYSSEY study information received by the above organisations and other authorised 
independent individuals will be kept completely confidential and names will not be used. Your child 
will only be identified using a study number, an anonymous code and their date of birth.  
Your child’s clinic notes may be looked at by the above organisations and authorised independent 
individuals to make sure that the ODYSSEY study is being properly carried out. They may also be seen 
by the companies who are supplying medicine for the study or relevant international regulatory 
authorities. Confidentiality will be maintained at all times.  


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If the results of this study are reported or published your child’s name will not be used nor any 
information that could be used to identify your child. The study will be conducted in agreement with 
the country specific data protection regulations.  
You 
can 
find 
out 
more 
about 
how 
we 
use 
your 
child’s 
information 
at 
www.ctu.mrc.ac.uk/general/privacy-policy and www.penta-id.org/study-participants-privacy. 
 
How your child’s data will be stored and collected 
Your child’s clinic will collect information from your child and your child’s medical records for this 
research study in accordance with our instructions.  
 
Your child’s clinic will keep your child’s name, NHS Number and contact details confidential and will 
not pass this information to anyone outside of the clinic. Your child’s clinic will use this information 
as needed, to contact your child about the research study, and make sure that relevant information 
about the study is recorded for your child’s care, and to oversee the quality of the study. Certain 
individuals from UCL, authorised regulatory organisations and authorised independent individuals 
may look at your child’s medical and research records to check the accuracy of the research study. 
They may also be seen by the companies who are supplying medicines for the study or relevant 
international regulatory authorities. The people who analyse the information will not be able to 
identify your child and will not be able to find out your child’s name, NHS number or contact details.  
 
UCL will collect information about your child for this research study from your child’s clinic. This 
information will include health information. This data may be used by UCL and other authorised 
research collaborators to conduct the trial and associated sub-studies. 
 
How your data will be used in future & other research  
When your child agrees to take part in a research study, the information about your child’s health 
and care may be provided to researchers running other research studies in this organisation and in 
other organisations. These organisations may be universities, NHS organisations or companies 
involved in health and care research in this country or abroad. Your child’s information will only be 
used by organisations and researchers to conduct research in accordance with the relevant 
legislation, ethics and NHS research policy requirements.  
 
We won't share information with others that can identify your child. The information will only be used 
for the purpose of health and care research, and cannot be used to contact you or to affect your 
child’s care. It will not be used to make decisions about future services available to your child, such 
as insurance. 
 
What happens at the end of the study? 
You and your child and their doctor will continue to make decisions about your child’s medicines once 
the study has finished. If your child is in the dolutegravir group and treatment with dolutegravir 
appears to be a safe and effective way of treating children and young people with HIV then they may 
be able to stay on these medicines. We would also like to continue to collect routine information 
about your child after the study has ended so we can look at the long term effects of the new 
medicines. 
 
What if new information about dolutegravir becomes available during the 
study? 
Sometimes during a study, new information becomes available about the medicines that are being 
studied. An independent committee will look at any new information and will also look at the 


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information collected so far in the study and decide if any changes are needed. If this happens, your 
doctor will tell you about it and discuss whether you want your child to continue in the study. If you 
decide to stop taking part in the study, your doctor will continue your child’s regular care.  
 
How can my child join the study? 
If your child would like to join the ODYSSEY study please speak to the staff at your nearest clinic where 
the study is run during your next appointment.  
 
How to contact us? 
  
Contact:   ____________________________  
Tel: 
 ____________________________  


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PARTICIPANT INFORMATION SHEET - MAIN STUDY ONLY 
ODYSSEY STUDY 
 
We are inviting you to take part in a research study 
 
 Before you decide whether to take part, it is important for you to understand why we want to carry 
out this study and what it will mean for you. 
 Please take time to read the following information and to discuss it with friends, family and with your 
doctor or clinic nurse if you wish.  
 You are free to decide if you want to take part in this research study. If you choose not to take part, 
this will not affect the care you get from your doctor or nurse. 
 If you decide to take part in the study you can stop taking part at any time without giving a reason. 
 Ask your study doctor or nurse if anything is not clear or if you would like more information. 
 Thank you for reading this information.  
 
Important to know 
 
 If you decide to take part you will have some extra visits to the clinic at the beginning of the 
study. 
 A computer program will choose which treatment you will take. Neither you nor your doctor 
will be able to choose which group you are in. 
 
Contents 
 
1. 
Why are we doing this study? 
2. 
Why have I been asked to take part? 
3. 
 What will happen if I decide not to take part? 
4. 
What will happen if I take part? 
5. 
What medicines will I be given? 
6. 
 What are the possible benefits and disadvantages of taking part? 
7. 
Study questionnaires 
8. 
More information about taking part 
 
 
 


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1 Why are we doing this study? 
 
Dolutegravir is a new medicine being used to treat adults with HIV.  
In adults it has been shown to be effective and safe, with few side effects and it only needs to be 
taken once a day.  
Sometimes a medicine works differently in growing children than in adults, so we need to check how 
it works in children as well. Dolutegravir could be an excellent option for children if the study finds it 
works as well as it does in adults. 
ODYSSEY will see how children and adolescents taking dolutegravir as part of their anti-HIV medicines 
compare to others taking different anti-HIV medicines.   
 
2 Why have I been asked to take part? 
 
 We are aiming to ask 700 young people like yourself, from many countries to take part.  
You have been asked to participate because:  
A: You are about to start taking anti-HIV medicine for the first time  
or 
B: You are already taking one set of anti-HIV medicine that is no longer working well and your doctor 
has decided it is time you change to a new combination. This is known as “second-line” treatment. 
  
3 What will happen if I decide not to take part? 
 
It is totally up to you whether or not you take part in this study.  
It is your right to decide not to take part if you wish.  
This will not affect your care now or in the future in any way.  
 
 
4 What will happen if I take part? 
If you decide to take part we will go through this information sheet together.  We will give a copy to 
you to keep. Your parent/carer will be asked to sign a consent form to show you have both 
understood the information and agreed to have some blood tests and a check-up to see whether you 
can go into the study. 
If the results show that you can participate we will invite you to enter the study. We need to know 
that you have fully understood the study and then we will ask your parent/carer to sign a second 
consent form for you to join. We will also ask you to sign a form giving your assent to join the study. 
Your health will be watched closely during the study. In the first 2 months you will need to come for 
3 appointments.  Once your doctor is happy that you have no side effects from the medicines and you 
are doing well, you will change to having 3-monthly appointments.   
These visits are to make sure you are continuing to do well. If for any reason your doctor has any 


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concerns, they will change your treatment in the normal way.  
In addition to blood tests to check for any side effects, a small amount of extra blood will be collected 
at each visit. The total amount of blood taken will never exceed a safe limit and will be between 3 and 
6 teaspoons depending on your age. Part of this sample will be stored to be used to check the amount 
of virus in the blood and to look at how the body fights HIV. We would like your agreement that we 
can store these samples anonymously (without your name or exact date of birth) for up to 15 years. 
You will be on the study for at least 2 years.  When the study ends, if you are doing well, you may be 
able to remain on the treatment you have been taking during the study, but you will need to discuss 
this with your doctor.  
It is important that you know that this is a voluntary study so if at any time you decide that you do 
not want to be involved anymore, you can stop and it will not affect the care that you receive in the 
future. 
 
5 What medicines will I be given? 
 
If you join the study, a computer will choose which group you will be in so it is fair and we can truly 
compare the treatments.  
There will be two groups in the study:  
Standard of Care group: meaning you will receive the usual, nationally approved anti-HIV medicine.  
Dolutegravir group: meaning you will take a combination of anti-HIV medicines that includes the new 
medicine, dolutegravir.   
 
6 What are the possible benefits and disadvantages of taking part? 
 
What are the possible benefits of taking part in this study? 
We cannot promise that participating in the study will directly help you. Compared to other anti-HIV 
medicines, dolutegravir may have fewer side effects and needs to be taken only once a day which 
may make it easier to take medicines long-term. 
If you are in the ‘standard of care’ group you will receive the same anti-HIV medicines as children not 
taking part in ODYSSEY although you will still be watched very carefully for any side effects and 
responses to the treatment. All the information we get will help children and young people across the 
world with HIV, and in the future it may mean you have the chance to change to medicines that are 
easier to take. 
What are the possible disadvantages and risks of taking part in this study? 
Whichever group you are in you will have 3 extra visits to the clinic.   
Anti-HIV medicines, like all medicines, can have side effects; most common are nausea, vomiting, 
abdominal discomfort, diarrhoea, rash or may affect the liver. If you feel unwell, you should contact 
the clinic as soon as possible. 
The new medicine, dolutegravir, has been shown to be effective with few side effects in adults, but 
we don’t know if this will be the same in children (which is why we need to do this study).  The most 
common side effects in adults are headache, diarrhoea, abdominal pain feeling sick, light headed or 
weak, worrying often and having sleep problems. Some adults taking dolutegravir have reported 
feeling depressed or having suicidal thoughts, these may not be related to this medicine in all cases.  
There is a small chance that dolutegravir may cause a rash, itching, vomiting, stomach pain, sleep 


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Page 106 of 324 
problems, lack of energy, an increase in weight, feeling light headed, sad or worried or may cause 
serious liver problems (with signs of vomiting, jaundice or stomach pain), which is why the doctor 
needs to follow you closely. If you have these signs for more than a day you should inform your doctor 
straight away. 
 
Risks in Pregnancy and anti-HIV medicines 
There is very little information about the effect of dolutegravir in unborn babies. In a recent study 
from Botswana, approximately 1 in 100 women who were taking dolutegravir when they became 
pregnant had babies with serious brain and/or spine problems. In the same study, approximately 1 in 
1000 women who were taking other antiretrovirals had babies with brain and/or spine problems, 
which is similar to what is seen in women without HIV. These problems happen very early in 
pregnancy, before many women even know that they are pregnant. We do not know for sure if these 
problems are because of dolutegravir. The study in Botswana and other similar studies are ongoing. 
We expect more information about this in the near future. In the meantime, we would like to tell you 
about this possible risk. 
 
If you are a girl who has started your period you will need a pregnancy test before entering the study. 
You will not be able to join the study if the test shows you are pregnant. You should avoid getting 
pregnant while in the study, and use effective if you are having sex. While in the study, please let us 
know if you are thinking about having a baby before you start trying, or if you think you are pregnant. 
Pregnancy tests will be done regularly during the study to find out early if you are pregnant or not 
and to give you the appropriate medical care. If you do get pregnant, you will be able to stay in the 
study and your doctor will talk to you about whether you need to change your medicine. Once you 
deliver, your baby will be assessed by a doctor for any problems and the baby will be followed for 
approximately 4 weeks to monitor their health. Health information, including HIV status, will be 
collected about the baby. If you have already had a baby whilst being on the study, health information 
captured by the hospital during this time period will be collected for the study.  
 
7 Study questionnaires 
 
We are very interested in finding out what children, young people and families feel about the study 
and how it is affecting their wellbeing. Over the course of the study we will ask you to complete 
questionnaires asking how you take your medicines, what it’s like taking medicine and how you feel 
in general.  
8 More information about taking part 
 
Additional studies 
There are some additional studies that are part of ODYSSEY. If they are run at your clinic your doctor 
may talk to you about taking part.  
 Who is organising the study? 
ODYSSEY is organised by the PENTA Foundation, an independent organisation that concentrates 
specifically on treatment issues for children and young people infected with HIV.  
Who has checked this study is safe? 
The information about this study has been checked by an independent group of people (a 
Research Ethics Committee) to make sure that as far as possible, the safety and wellbeing of 
anyone taking part in the study is protected.  


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Page 107 of 324 
A second group (the Independent Data Monitoring Committee) will meet regularly during the study 
to review the results as they come out and will recommend if the trial is safe to continue. This is 
standard for all studies looking at medicines for adults or children. 
  
What if something goes wrong? 
The PENTA Foundation has made arrangements for compensation should you come to any harm from 
participating in this study.   If you are harmed due to someone’s negligence then you may have 
reasons for legal action for compensation against the clinic where this occurred. 
With your permission your GP will be informed of your participation in the study. Your hospital doctor 
is not receiving any personal payment for carrying out this research. [Country specific, delete if not 
applicable]  
 
What will happen to information about me collected during the study? 
The Fondazione PENTA Onlus, based in Italy and Sponsor for this study, is the owner of data and acts 
as Joint Data Controller. University College London (UCL) through the MRC Clinical Trial Unit at UCL, 
will be using information from you and your medical records in order to undertake this study and will 
act, along with the Sponsor, as Joint Data Controller for this study and Data Processor. This means 
that PENTA and UCL are responsible for looking after your information and using it properly. UCL and 
the sponsor designated trial co-ordinating units will keep information about you for a minimum of 15 
years after the study has finished.  
 
You and your parent/carer’s rights to access, change, move or erase your information are limited, as 
we need to manage information in specific ways in order for the research to be reliable and accurate. 
If you withdraw from the study, we will keep the information about your child that we have already 
obtained. To safeguard your rights, we will use the minimum personally identifiable information 
possible.  
All ODYSSEY study information received by the above organisations and other authorised 
independent individuals will be kept completely confidential and names will not be used. You will only 
be identified using a study number, an anonymous code and your date of birth.  
Your clinic notes may be looked at by the above organisations and authorised independent individuals 
to make sure that the ODYSSEY study is being properly carried out. They may also be seen by the 
companies who are supplying medicine for the study or relevant international regulatory authorities. 
Confidentiality will be maintained at all times.  
If the results of this study are reported or published your name will not be used nor any information 
that could be used to identify you. The study will be conducted in agreement with the country specific 
data protection regulations. 
You can find out more about how we use your information at www.ctu.mrc.ac.uk/general/privacy-
policy and www.penta-id.org/study-participants-privacy. 
 
How your data will be stored and collected 
Your clinic will collect information from you and your medical records for this research study in 
accordance with our instructions.  
 
Your clinic will keep your name, NHS Number and contact details confidential and will not pass this 
information to anyone outside of the clinic. Your clinic will use this information as needed, to contact 
you or your parent/carer about the research study, and make sure that relevant information about 


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the study is recorded for your care, and to oversee the quality of the study. Certain individuals from 
UCL, authorised regulatory organisations and authorised independent individuals may look at your 
medical and research records to check the accuracy of the research study. They may also be seen by 
the companies who are supplying medicines for the study or relevant international regulatory 
authorities. The people who analyse the information will not be able to identify you and will not be 
able to find out your name, NHS number or contact details.  
 
UCL will collect information about you for this research study from your clinic. This information will 
include health information, This data may be used by UCL and other authorised research collaborators 
to conduct the trial and associated sub-studies. 
 
How your data will be used in future & other research  
When you agree to take part in a research study, the information about your health and care may be 
provided to researchers running other research studies in this organisation and in other organisations. 
These organisations may be universities, NHS organisations or companies involved in health and care 
research in this country or abroad. Your information will only be used by organisations and 
researchers to conduct research in accordance with the relevant legislation, ethics and NHS research 
policy requirements.  
 
We won't share information with others that can identify you. The information will only be used for 
the purpose of health and care research, and cannot be used to contact you or to affect your care. It 
will not be used to make decisions about future services available to you, such as insurance. 
  
What happens at the end of the study? 
You, your parent/carer and your doctor will continue to make decisions about your medicines once 
the study has finished.  
If you are in the dolutegravir group and treatment with dolutegravir appears to be a safe and effective 
way of treating children and young people with HIV then you may stay on these medicines. 
We would also like to continue to collect your routine information after the study has ended so we 
can look at the long term effects of the new medications. 
  
What if new information about dolutegravir becomes available during the 
course of the study? 
Sometimes during a study, new information becomes available about the medicines that are being 
studied. An independent committee will look at any new information and will also look at the data 
collected so far in the study and decide if any changes are needed. If this happens, your doctor will 
tell you about it and discuss whether you want to continue in the study. If you decide to stop taking 
part in the study, your doctor will continue your regular care.  
  
How can I join the study? 
If you would like to join the ODYSSEY study please speak to the staff at your nearest clinic where the 
study is run during your next appointment.  
 
How to contact us? 
  
Contact:_________________________ 
 
Tel:_____________________________ 


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CHILDREN’S INFORMATION SHEET - MAIN STUDY ONLY 
 
 


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PARENT/CARER INFORMATION SHEET – EXTENDED FOLLOW-UP 
ODYSSEY STUDY  
 
Contents 
 
1. Why are we requesting extended follow-up?  
2. Why has my child been asked to take part? 
3. What will happen if we decide not to take part? 
4. What will happen if my child takes part? 
5. What are the possible benefits and disadvantages of taking part? 
6. More information about taking part 
 
1 Why are we requesting extended follow-up? 
 
We are requesting extended follow-up so that we can continue to collect safety information from children 
and adolescents enrolled in ODYSSEY. This information is important as it will enable the long term safety 
and effectiveness of dolutegravir in children and adolescents to be assessed.  
 
If your child is currently taking dolutegravir in a form that is not currently available through your country’s 
national treatment programme, we are also required to collect further safety information.  
 
 
 
2 Why has my child been asked to take part? 
 
Your child has been asked to take part in extended follow-up because he/she is enrolled in the ODYSSEY 
trial and we would like to collect further information on the treatment that they receive in order to assess 
the safety of dolutegravir over a longer period of time. 
 
 
3 What will happen if we decide not to take part? 
 
It is totally up to you and your child whether or not he/she takes part in extended follow-up.  
If you choose that your child will not take part, but your child is currently taking a form of dolutegravir that 
is not available through your country’s national treatment programme, then it may be necessary for your 
doctor to change your child’s anti-HIV medicine so that they will take another appropriate drug in place of 
dolutegravir. If your child is taking anti-HIV medicines that are available through your country’s national 
treatment programme then their treatment may not need to be changed if you choose not to take part. 
This will not affect your child’s care now or in the future in any way. 
 
 
 


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4 What will happen if my child takes part? 
 
If you decide to take part, we will go through this information sheet together. We will give you a copy to 
keep. You will be asked to sign a consent form to show you have understood the information and have agreed 
for your child to continue in extended follow-up.  
Once your child is in the extended follow-up period they will attend for regular clinic visits which will be 
similar to routine care in your country. Blood tests will be performed as per local practice and, if your child 
could become pregnant, a pregnancy test will be performed at every visit. Sleep and Mood Questionnaire 
data will be collected annually. Your child will remain in extended follow-up for a period of up to 3 years (until 
May 2023)  
It is important that you know that this is a voluntary study so if at any time you decide that you do not want 
to be involved anymore, you can stop and it will not affect the care that you receive in the future. 
 
5 What are the possible benefits and disadvantages of taking part? 
 
What are the possible benefits of taking part in extended follow-up? 
Although there may not be any direct benefits to you or your child of taking part, the information collected 
will help us to improve the treatment of other children and adolescents who are living with HIV. 
 
If your child is taking a form of dolutegravir that is not available through your country’s national HIV 
treatment programme then taking part will enable them to continue taking the same treatment. In these 
circumstances the medicine will continue to be provided to your clinic, by a drug company working with the 
study team, free of charge to your child. 
 
What are the possible disadvantages and risks of taking part in this study? 
Anti-HIV medicines, like all medicines, can have side effects; most common are nausea, vomiting, abdominal 
discomfort, diarrhoea, rash or may affect the liver. If your child feels unwell, you should contact the clinic as 
soon as possible. 
Dolutegravir has been shown to be effective, with few side effects in adults, but we don’t know if this will be 
the same in children (which is why we need to do this study). The most common side effects in adults are 
headache, diarrhoea, abdominal pain, feeling sick, light headed or weak, worrying often and having sleep 
problems. Some adults taking dolutegravir have reported feeling depressed or having suicidal thoughts, these 
may not be related to this medicine in all cases. There is a small chance that dolutegravir may cause a rash, 
itching, vomiting, stomach pain, sleep problems, lack of energy, an increase in weight, feeling light headed, 
sad or worried or may cause serious liver problems (with signs of vomiting, jaundice or stomach pain), which 
is why the doctor needs to follow your child closely. If your child has these signs for more than a day you 
should inform your doctor straight away. 
 
Risks in Pregnancy and anti-HIV medicines 
There is very little information about the effect of dolutegravir in unborn babies. In a recent study from 
Botswana, approximately 3 in 1000 women who were taking dolutegravir when they became pregnant had 
babies with serious brain and/or spine problems. In the same study, approximately 1 in 1000 women who 
were taking other antiretrovirals had babies with brain and/or  spine problems, which is similar to what is 
seen in women without HIV. These problems happen very early in pregnancy, before many women even 
know that they are pregnant. We do not know for sure if these problems are because of dolutegravir. The 
study in Botswana and other similar studies are ongoing. We expect more information about this in the near 
future. In the meantime, we would like to tell you about this possible risk. 


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If your child could become pregnant, she should avoid getting pregnant while in extended trial follow-up, and 
use effective contraceptives if she is having sex. While in extended follow-up, please let us know if she is 
thinking about having a baby before she starts trying, or if she thinks she is pregnant. Pregnancy tests will 
continue to be done regularly during extended follow-up to find out early if she is pregnant or not and to give 
her the appropriate medical care. If she does get pregnant, she will be able to stay in extended follow-up and 
her doctor will talk to you both about whether she needs to change her medicine.  Once she delivers, her 
baby will be assessed by a doctor for any problems and the baby will be followed for approximately 4 weeks 
to monitor their health. Health information, including HIV status, will be collected about the baby. If she has 
already had a baby whilst being on the study, health information captured by the hospital during this time 
period will be collected for the study.  
 
6 More information about taking part 
 
What if something goes wrong? 
The PENTA Foundation has made arrangements for compensation should your child come to any harm from 
participating in this study. If your child is harmed due to someone’s negligence then you may have reasons 
for legal action for compensation against the clinic where this occurred. 
 
What will happen to information about my child collected during follow-up? 
The Fondazione PENTA Onlus, based in Italy and Sponsor for this study, is the owner of data and acts as Joint 
Data Controller. University College London (UCL) through the MRC Clinical Trial Unit at UCL, will be using 
information from your child and your child’s medical records in order to undertake this study and will act, 
along with the Sponsor, as Joint Data Controller for this study and Data Processor. This means that PENTA 
and UCL are responsible for looking after your child’s information and using it properly. UCL and the sponsor 
designated trial co-ordinating units will keep information about your child for a minimum of 15 years after 
the study has finished.  
 
Your and your child’s rights to access, change, move or erase their information are limited, as we need to 
manage information in specific ways in order for the research to be reliable and accurate. If your child 
withdraws from the study, we will keep the information about your child that we have already obtained. To 
safeguard your child’s rights, we will use the minimum personally identifiable information possible.  
 
All ODYSSEY study information received by the above organisations and other authorised independent 
individuals will be kept completely confidential and names will not be used. Your child will only be identified 
using a study number, an anonymous code and their date of birth.  
Your child’s clinic notes may be looked at by the above organisations and authorised independent individuals 
to make sure that the ODYSSEY study is being properly carried out. They may also be seen by the companies 
who are supplying medicine for the study or relevant international regulatory authorities. Confidentiality will 
be maintained at all times.  
If the results of this study are reported or published your child’s name will not be used nor any information 
that could be used to identify your child. The study will be conducted in agreement with the country specific 
data protection regulations.  
You can find out more about how we use your child’s information at www.ctu.mrc.ac.uk/general/privacy-
policy and www.penta-id.org/study-participants-privacy. 
 
How your child’s data will be stored and collected 
Your child’s clinic will collect information from your child and your child’s medical records for this research 
study in accordance with our instructions.  
 


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Your child’s clinic will keep your child’s name and contact details confidential and will not pass this 
information to anyone outside of the clinic. Your child’s clinic will use this information as needed, to contact 
your child about the research study, and make sure that relevant information about the study is recorded for 
your child’s care, and to oversee the quality of the study. Certain individuals from UCL, authorised regulatory 
organisations and authorised independent individuals may look at your child’s medical and research records 
to check the accuracy of the research study. They may also be seen by the companies who are supplying 
medicines for the study or relevant international regulatory authorities. The people who analyse the 
information will not be able to identify your child and will not be able to find out your child’s name or contact 
details.  
 
UCL will collect information about your child for this research study from your child’s clinic. This information 
will include health information. This data may be used by UCL and other authorised research collaborators 
to conduct the trial and associated sub-studies. 
 
How your data will be used in future & other research  
When your child agrees to take part in a research study, the information about your child’s health and care 
may be provided to researchers running other research studies in this organisation and in other 
organisations. These organisations may be universities, hospitals or companies involved in health and care 
research in this country or abroad. Your child’s information will only be used by organisations and researchers 
to conduct research in accordance with the relevant legislation and ethics requirements.  
 
We won't share information with others that can identify your child. The information will only be used for 
the purpose of health and care research, and cannot be used to contact you or to affect your child’s care. It 
will not be used to make decisions about future services available to your child, such as insurance. 
 
What happens at the end of extended follow-up? 
You, your child and their doctor will continue to make decisions about your child’s medicines once extended 
follow-up has finished. If, at the end of this follow-up period, dolutegravir is still not available through your 
country’s national treatment programme, your child may have to change to different anti-HIV medicines. 
 
How to contact us? 
  
Contact:   ____________________________  
Tel: 
 ____________________________  
 
 


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PARTICIPANT INFORMATION SHEET – EXTENDED FOLLOW-UP 
ODYSSEY STUDY 
 
Contents 
 
1. Why are we requesting extended follow-up?  
2. Why have I been asked to take part? 
3. What will happen if I decide not to take part? 
4. What will happen if I take part? 
5. What are the possible benefits and disadvantages of taking part? 
6. More information about taking part 
 
1 Why are we requesting extended follow-up? 
 
We are requesting extended follow-up so that we can continue to collect safety information from children 
and young people taking part in ODYSSEY. This information is important as it will enable the long term 
safety and effectiveness of dolutegravir in children and adolescents to be assessed.  
 
If you are currently taking dolutegravir in a form that is not currently available through your country’s 
national treatment programme, we are also required to collect further safety information.  
 
2 Why have I been asked to take part? 
 
You have been asked to take part in extended follow-up because you are taking part in the ODYSSEY trial 
and we would like to collect further information on the treatment that you receive in order to assess the 
safety of dolutegravir over a longer period of time. 
  
3 What will happen if I decide not to take part? 
 
It is totally up to you whether or not you take part in extended follow-up.  
If you choose not to take part, but you are currently taking a form of dolutegravir that is not available through 
your country’s national treatment programme, then it may be necessary for your doctor to change your anti-
HIV medicine so that you will take another appropriate drug in place of dolutegravir. If you are taking anti-
HIV medicines that are available through your country’s national treatment programme then your treatment 
may not need to be changed if you choose not to take part. 
This will not affect your care now or in the future in any way. 
 
4 What will happen if I take part? 
If you decide to take part, we will go through this information sheet together. We will give you a copy to 
keep. If you are not old enough to give consent yourself, your parent/carer will be asked to sign a consent 


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form to show you have both understood the information and have agreed to continue in extended follow-
up.  
Once you are in the extended follow-up period you will attend for regular clinic visits which will be similar to 
routine care in your country. Blood tests will be performed as per local practice and, if you could become 
pregnant, a pregnancy test will be performed at every visit. Sleep and Mood Questionnaire data will be 
collected annually. You will remain in extended follow-up for a period of up to 3 years (until May 2023)  
It is important that you know that this is a voluntary study so if at any time you decide that you do not want 
to be involved anymore, you can stop and it will not affect the care that you receive in the future. 
 
5 What are the possible benefits and disadvantages of taking part? 
 
What are the possible benefits of taking part in extended follow-up? 
Although there may not be any direct benefits to you of taking part, the information collected will help us to 
improve the treatment of other children and adolescents who are living with HIV. 
 
If you are taking a form of dolutegravir that is not available through your country’s national HIV treatment 
programme then taking part will enable you to continue taking the same treatment. If this is the case, the 
medicine will continue to be provided to your clinic, by a drug company working with the study team, free of 
charge. 
 
What are the possible disadvantages and risks of taking part in this study? 
Anti-HIV medicines, like all medicines, can have side effects; most common are nausea, vomiting, abdominal 
discomfort, diarrhoea, rash or may affect the liver. If you feel unwell, you should contact the clinic as soon 
as possible. 
Dolutegravir has been shown to be effective with few side effects in adults, but we don’t know if this will be 
the same in children (which is why we need to do this study).  The most common side effects in adults are 
headache, diarrhoea, abdominal pain, feeling sick, light headed or weak, worrying often and having sleep 
problems. Some adults taking dolutegravir have reported feeling depressed or having suicidal thoughts, these 
may not be related to this medicine in all cases.  There is a small chance that dolutegravir may cause a rash, 
itching, vomiting, stomach pain, sleep problems, lack of energy, an increase in weight, feeling light headed, 
sad or worried or may cause serious liver problems (with signs of vomiting, jaundice or stomach pain), which 
is why the doctor needs to follow you closely. If you have these signs for more than a day you should inform 
your doctor straight away. 
 
Risks in Pregnancy and anti-HIV medicines 
There is very little information about the effect of dolutegravir in unborn babies. In a recent study from 
Botswana, approximately 3 in 1000 women who were taking dolutegravir when they became pregnant had 
babies with serious brain and/or spine problems. In the same study, approximately 1 in 1000 women who 
were taking other antiretrovirals had babies with brain and/or spine problems, which is similar to what is 
seen in women without HIV. These problems happen very early in pregnancy, before many women even 
know that they are pregnant. We do not know for sure if these problems are because of dolutegravir. The 
study in Botswana and other similar studies are ongoing. We expect more information about this in the near 
future. In the meantime, we would like to tell you about this possible risk. 
 
If you are a girl who has started your period you should avoid getting pregnant while in extended trial follow-
up, and use effective contraceptives if you are having sex. While in extended follow-up, please let us know if 
you are thinking about having a baby before you start trying, or if you think you are pregnant. Pregnancy 
tests will continue to be done regularly during extended follow-up to find out early if you are pregnant or not 


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and to give you the appropriate medical care. If you do get pregnant, you will be able to stay in extended 
follow-up and your doctor will talk to you about whether you need to change your medicine. Once you 
deliver, your baby will be assessed by a doctor for any problems and the baby will be followed for 
approximately 4 weeks to monitor their health. Health information, including HIV status, will be collected 
about the baby. If you have already had a baby whilst being on the study, health information captured by the 
hospital during this time period will be collected for the study.  
6 More information about taking part 
 
What if something goes wrong? 
The PENTA Foundation has made arrangements for compensation should you come to any harm from 
participating in this study.   If you are harmed due to someone’s negligence then you may have reasons for 
legal action for compensation against the clinic where this occurred. 
 
What will happen to information about me collected during the study? 
The Fondazione PENTA Onlus, based in Italy and Sponsor for this study, is the owner of data and acts as Joint 
Data Controller. University College London (UCL) through the MRC Clinical Trial Unit at UCL, will be using 
information from you and your medical records in order to undertake this study and will act, along with the 
Sponsor, as Joint Data Controller for this study and Data Processor. This means that PENTA and UCL are 
responsible for looking after your information and using it properly. UCL and the sponsor designated trial co-
ordinating units will keep information about you for a minimum of 15 years after the study has finished.  
 
You and your parent/carer’s rights to access, change, move or erase your information are limited, as we need 
to manage information in specific ways in order for the research to be reliable and accurate. If you withdraw 
from the study, we will keep the information about your child that we have already obtained. To safeguard 
your rights, we will use the minimum personally identifiable information possible.  
All ODYSSEY study information received by the above organisations and other authorised independent 
individuals will be kept completely confidential and names will not be used. You will only be identified using 
a study number, an anonymous code and your date of birth.  
Your clinic notes may be looked at by the above organisations and authorised independent individuals to 
make sure that the ODYSSEY study is being properly carried out. They may also be seen by the companies 
who are supplying medicine for the study or relevant international regulatory authorities. Confidentiality will 
be maintained at all times.  
If the results of this study are reported or published your name will not be used nor any information that 
could be used to identify you. The study will be conducted in agreement with the country specific data 
protection regulations. 
You can find out more about how we use your information at www.ctu.mrc.ac.uk/general/privacy-policy and 
www.penta-id.org/study-participants-privacy. 
 
 
How your data will be stored and collected 
Your clinic will collect information from you and your medical records for this research study in accordance 
with our instructions.  
 
Your clinic will keep your name and contact details confidential and will not pass this information to anyone 
outside of the clinic. Your clinic will use this information as needed, to contact you or your parent/carer about 
the research study, and make sure that relevant information about the study is recorded for your care, and 


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to oversee the quality of the study. Certain individuals from UCL, authorised regulatory organisations and 
authorised independent individuals may look at your medical and research records to check the accuracy of 
the research study. They may also be seen by the companies who are supplying medicines for the study or 
relevant international regulatory authorities. The people who analyse the information will not be able to 
identify you and will not be able to find out your name or contact details.  
 
UCL will collect information about you for this research study from your clinic. This information will include 
health information, This data may be used by UCL and other authorised research collaborators to conduct 
the trial and associated sub-studies. 
 
How your data will be used in future & other research  
When you agree to take part in a research study, the information about your health and care may be provided 
to researchers running other research studies in this organisation and in other organisations. These 
organisations may be universities, NHS organisations or companies involved in health and care research in 
this country or abroad. Your information will only be used by organisations and researchers to conduct 
research in accordance with the relevant legislation, ethics and NHS research policy requirements.  
 
We won't share information with others that can identify you. The information will only be used for the 
purpose of health and care research, and cannot be used to contact you or to affect your care. It will not be 
used to make decisions about future services available to you, such as insurance. 
  
What happens at the end of extended follow-up? 
You, your parent/carer and your doctor will continue to make decisions about your medicines once extended 
follow-up has finished. If, at the end of this follow-up period, dolutegravir is still not available through your 
country’s national treatment programme, you may have to change to different anti-HIV medicines. 
 
How to contact us? 
  
Contact:_________________________ 
 
Tel:_____________________________ 


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CHILDREN’S INFORMATION SHEET – EXTENDED FOLLOW-UP 
 
ODYSSEY STUDY  
(PENTA 20)  
 
You are taking part in a study called ODYSSEY. In ODYSSEY we have been looking at 
a new medicine for children called dolutegravir. 
 
We would like to collect more information on dolutegravir and the other medicines 
that children in ODYSSEY are taking. To do this we would like you to stay in the 
ODYSSEY study until May 2023 (up to an extra 3 years after you would have finished 
taking part). 
 
The information that we collect will help us find out if dolutegravir is still safe and 
working well even after children have been taking it for a long time. 
 
The doctors will still watch you closely but now you will only need to attend for 
visits at the same times that you would if you were not taking part in the study.  
 
Most of the tests that you will have are the same as those you would have outside 
of the study but you or your carer will sometimes also be asked to answer some 
questions on how easy you find it to take your medicine. 
 
It is still up to you whether you take part in the study. If you say yes now you can 
change your mind at any time and stop being part of the study. It is up to you. 
 
 
 
 


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PARENT/CARER INFORMATION SHEET – MAIN STUDY & WEIGHT BAND PK 1 (3 TO <14KG) 
ODYSSEY STUDY  
 
We are inviting you and your child to take part in a research study 
 
 Before you decide whether to take part, it is important for you and your child to understand why we want to 
carry out this study and what it will mean for you both. 
 Please take time to read the following information and to discuss it with friends, family and with your doctor 
or clinic nurse if you wish.  
 You are free to decide if you want your child to take part in this research study. If you choose not to take 
part, this will not affect the care your child gets from your doctor or nurse. 
 If you decide to take part in the study you can stop taking part at any time without giving a reason. 
 Ask your study doctor or nurse if anything is not clear or if you would like more information. 
 Thank you for reading this information.  
 
Important to know 
 If you decide to take part your child will have some extra visits to the clinic at the beginning of the study. 
 A computer program will choose which treatment your child will take. Neither you nor your doctor will be 
able to choose which group your child is in 
 If your child is in the dolutegravir group they will be asked to come into the clinic and stay for a whole day at 
least 1 week after starting the new medicine. He/she will have up to 7 blood samples taken during the day 
(over a 24 hour period) to test the level of medicine in their blood. We will also need to take a blood sample 
the next morning. Your child can stay overnight or we will provide transport for you to come back the next 
day. 
 
Contents 
1. Why are we doing this study?  
2. Why has my child been asked to take part? 
3. What will happen if we decide not to take part? 
4. What will happen if my child takes part? 
5. What medicines will my child be given if we take part? 
6. What are the possible benefits and disadvantages of taking part? 
7. Study questionnaires 
8. More information about taking part 


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1 Why are we doing this study? 
 
Dolutegravir is a new medicine being used to treat adults with HIV.  
In adults it has been shown to be effective and safe, with few side effects, and it only needs to be 
taken once a day.  
Sometimes a medicine works differently in growing children than in adults, so we need to check how 
it works in children as well. Dolutegravir could be an excellent option for children if the study finds it 
works as well as it does in adults. 
ODYSSEY will see how children and adolescents taking dolutegravir as part of their anti-HIV medicines 
compare to others taking different anti-HIV medicines.   
Weight band Pharmacokinetic (PK) Study (checking the level of medicine in the blood): 
We need to check that the dose of the new medicine is correct for younger children. If your child joins 
the study and is put in the dolutegravir group he/she will come into the clinic for a PK blood sampling 
day. 
 
 
2 Why has my child been asked to take part? 
 
We are aiming to ask 700 children and young people from many countries to take part.  
Your child has been asked to participate because:  
A. He/She is about to start taking anti-HIV medicine for the first time. 
Or 
B. He/She is already taking one set of anti-HIV medicine that is no longer working well and your doctor 
has decided it is time your child changes to a new combination.  This is known as “second-line” 
treatment. 
 
3 What will happen if we decide not to take part? 
 
It is totally up to you and your child whether or not he/she takes part in this study.  
It is your right to decide not to take part if you wish.  
This will not affect your child’s care now or in the future in any way. 
 
4 What will happen if my child takes part? 
 
If you decide to take part, we will go through this information sheet together.  We will give a copy to 
you to keep. You will be asked to sign a consent form to show you have understood the information 
and have agreed for your child to have some blood tests and a check-up to see whether they can go 
into the study.  
If the results show that your child can participate, we will invite him/her to enter the study.  We need 
to know that you have fully understood the study and then we will ask you to sign a second consent 
form for your child to join.  
Your child’s health will be watched closely during the study.  


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In the first 2 months you will need to come for 3 or 4 appointments.  Once your doctor is happy that 
your child has no side effects from the medicines and is doing well, they will change to having 3-
monthly appointments.  
These visits are to make sure your child is continuing to do well. If for any reason your doctor has any 
concerns, they will change your child’s treatment in the normal way.  
In addition to blood tests to check for any side effects, a small amount of extra blood will be collected 
at each visit. The total amount of blood taken will never exceed a safe limit and will be between 3 and 
6 teaspoons depending upon the age of your child. Part of this sample will be stored to be used to 
check the amount of virus in the blood and to look at how the body fights HIV. We would like your 
agreement that we can store these samples anonymously (without your child’s name or exact date of 
birth) for up to 15 years. 
Your child will be in the study for at least 2 years. When the study ends, if your child is doing well they 
may be able to remain on the same anti-HIV medicines they have been taking during the study, but 
you will need to discuss this with your doctor.  
It is important that you know that this is a voluntary study so if at any time you decide that your 
child does not want to be involved anymore, you can stop and it will not affect the care that your 
child receives in the future. 
 
PK (blood levels) Study (only to be done in children allocated to the dolutegravir group) 
If your child is in the dolutegravir group they will be asked to come into the clinic and stay for a whole 
day at least 1 week after starting the new medicine. He/she will have up to 7 blood samples taken 
during the day (over a 24 hour period) to test the level of medicine in their blood. A local anaesthetic 
cream will be used to make the skin numb and a thin tube (called a cannula) will be inserted into a 
vein for the day to enable the blood samples to be taken. All blood samples will be taken from the 
cannula, so only one needle prick is required. Each blood sample will be small (less than half a 
teaspoon) and is an amount which is safe for your child’s age and weight. 
We will also need to take a blood sample the next morning. Your child can stay overnight or we will 
provide transport for you to come back the next day. 
The laboratory needs to know exactly when your child took their medicine so you will be asked to 
record the time of giving the medicine the day before.  Immediately after the first blood sample is 
taken your child will be given breakfast (we will provide all their meals during the day) with their usual 
dose of medicine. 
 
5 What medicines will my child be given if we take part? 
 
If your child joins the study, a computer will choose which group he/she will be in so it is fair and we 
can truly compare the treatments.  
There will be two groups in the study:   
 Standard of care group: meaning your child will receive the usual, nationally approved anti-HIV 
medicine.  
 Dolutegravir group: meaning your child will take a combination of anti-HIV medicines that includes 
the new medicine, dolutegravir.  Children in this group will also take part in PK (blood levels) study.  
 
6 What are the possible benefits and disadvantages of taking part? 
 
What are the possible benefits of taking part in this study? 


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We cannot promise that participating in the study will directly help your child. Compared to other anti-
HIV medicines dolutegravir may have fewer side effects and needs to be taken only once a day which 
may make it easier to take medicines long-term. 
However, if your child is in the ‘standard of care’ group they will receive the same anti-HIV medicines 
as children not taking part in ODYSSEY, although your child will be watched very carefully for any side 
effects and responses to the treatment. All the information we get will help children and young people 
across the world with HIV and in the future it may mean your child has the chance to change to 
medicines that are easier to take. 
 
What are the possible disadvantages and risks of taking part in this study? 
Whichever group they are in your child will have 3 or 4 extra visits to the clinic and if they are in the 
dolutegravir group, they will come in for a full day (and possibly an overnight stay) at clinic for the 
blood sampling day.  
Anti-HIV medicines, like all medicines, can have side effects; most common are nausea, vomiting, 
abdominal discomfort, diarrhoea, rash or may affect the liver. If your child feels unwell, you should 
contact the clinic as soon as possible. 
The new medicine, dolutegravir, has been shown to be effective, with few side effects in adults, but 
we don’t know if this will be the same in children (which is why we need to do this study). The most 
common side effects in adults are headache, diarrhoea, abdominal pain feeling sick, light headed or 
weak, worrying often and having sleep problems. Some adults taking dolutegravir have reported 
feeling depressed or having suicidal thoughts, these may not be related to this medicine in all cases. 
In most of these cases the person had a history of similar problems before starting dolutegravir. There 
is a small chance that dolutegravir may cause a rash, itching, vomiting, stomach pain, sleep problems, 
lack of energy, an increase in weight, feeling light headed, sad or worried or may cause serious liver 
problems  (with signs of vomiting, jaundice or stomach pain), which is why the doctor needs to follow 
your child closely. If your child has these signs for more than a day you should inform your doctor 
straight away. 
 
Pregnancy and anti-HIV medicines 
There is very little information about the effect of dolutegravir in unborn babies. If your child could 
become pregnant, she will need a pregnancy test before entering the study. She will not be able to 
join the study if the test shows she is pregnant.  We encourage her to use effective contraceptives and 
for her to let us know straightaway if at any time she thinks she may have become pregnant. If this is 
confirmed with a pregnancy test her treatment will be reviewed by the doctor. She will be able to stay 
in the study if she becomes pregnant. 
 
7 Study questionnaires 
 
We are very interested in finding out what children, young people and families feel about the study 
and how it is affecting their wellbeing. Over the course of the study we will ask you and your child to 
complete questionnaires asking how your child takes their medicines, what it’s like taking medicine 
and how they feel in general.  
 
8 More information about taking part 
 
Additional studies 


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There are some additional studies that are part of ODYSSEY. If they are run at your clinic your doctor 
may talk to you and your child about taking part.  
Who is organising the study? 
ODYSSEY is organised by the PENTA Foundation, an independent organisation that concentrates 
specifically on treatment issues for children and young people infected with HIV.  
Who has checked this study is safe? 
The information about this study has been checked by an independent group of people (a Research 
Ethics Committee) to make sure that, as far as possible, the safety and wellbeing of anyone taking part 
in the study is protected.  
A second group (the Independent Data Monitoring Committee) will meet regularly during the study 
to review the results as they come out and will recommend if the study is safe to continue.  This is 
standard for all studies looking at medicines for adults or children. 
 
What if something goes wrong? 
The PENTA Foundation has made arrangements for compensation should your child come to any harm 
from participating in this study. If your child is harmed due to someone’s negligence then you may 
have reasons for legal action for compensation against the clinic where this occurred. 
 
With your permission your child’s GP will be informed of his/her participation in the study. Your 
hospital doctor is not receiving any personal payment for carrying out this research. [Country specific, 
delete if not applicable] 
 
What will happen to information about my child collected during the study? 
The Fondazione PENTA Onlus, based in Italy and Sponsor for this study, is the owner of data and acts 
as Joint Data Controller. University College London (UCL) through the MRC Clinical Trial Unit at UCL, 
will be using information from your child and your child’s medical records in order to undertake this 
study and will act, along with the Sponsor, as Joint Data Controller for this study and Data Processor. 
This means that PENTA and UCL are responsible for looking after your child’s information and using it 
properly. UCL and the sponsor designated trial co-ordinating units will keep information about your 
child for a minimum of 15 years after the study has finished.  
 
Your and your child’s rights to access, change, move or erase their information are limited, as we need 
to manage information in specific ways in order for the research to be reliable and accurate. If your 
child withdraws from the study, we will keep the information about your child that we have already 
obtained. To safeguard your child’s rights, we will use the minimum personally identifiable 
information possible.  
 
All ODYSSEY study information received by the above organisations and other authorised independent 
individuals will be kept completely confidential and names will not be used. Your child will only be 
identified using a study number, an anonymous code and their date of birth.  
Your child’s clinic notes may be looked at by the above organisations and authorised independent 
individuals to make sure that the ODYSSEY study is being properly carried out. They may also be seen 
by the companies who are supplying medicine for the study or relevant international regulatory 
authorities. Confidentiality will be maintained at all times.  
If the results of this study are reported or published your child’s name will not be used nor any 
information that could be used to identify your child. The study will be conducted in agreement with 
the country specific data protection regulations.  
You 
can 
find 
out 
more 
about 
how 
we 
use 
your 
child’s 
information 
at 
www.ctu.mrc.ac.uk/general/privacy-policy and www.penta-id.org/study-participants-privacy. 


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How your child’s data will be stored and collected 
Your child’s clinic will collect information from your child and your child’s medical records for this 
research study in accordance with our instructions.  
 
Your child’s clinic will keep your child’s name, NHS Number and contact details confidential and will 
not pass this information to anyone outside of the clinic. Your child’s clinic will use this information as 
needed, to contact your child about the research study, and make sure that relevant information 
about the study is recorded for your child’s care, and to oversee the quality of the study. Certain 
individuals from UCL, authorised regulatory organisations and authorised independent individuals 
may look at your child’s medical and research records to check the accuracy of the research study. 
They may also be seen by the companies who are supplying medicines for the study or relevant 
international regulatory authorities. The people who analyse the information will not be able to 
identify your child and will not be able to find out your child’s name, NHS number or contact details.  
 
UCL will collect information about your child for this research study from your child’s clinic. This 
information will include health information. This data may be used by UCL and other authorised 
research collaborators to conduct the trial and associated sub-studies. 
 
How your data will be used in future & other research  
When your child agrees to take part in a research study, the information about your child’s health and 
care may be provided to researchers running other research studies in this organisation and in other 
organisations. These organisations may be universities, NHS organisations or companies involved in 
health and care research in this country or abroad. Your child’s information will only be used by 
organisations and researchers to conduct research in accordance with the relevant legislation, ethics 
and NHS research policy requirements.  
 
We won't share information with others that can identify your child. The information will only be used 
for the purpose of health and care research, and cannot be used to contact you or to affect your child’s 
care. It will not be used to make decisions about future services available to your child, such as 
insurance. 
 
What happens at the end of the study? 
You and your child and their doctor will continue to make decisions about your child’s medicines once 
the study has finished. If your child is in the dolutegravir group and treatment with dolutegravir 
appears to be a safe and effective way of treating children and young people with HIV then they may 
be able to stay on these medicines. We would also like to continue to collect routine information about 
your child after the study has ended so we can look at the long term effects of the new medicines. 
 
What if new information about dolutegravir becomes available during the 
study? 
Sometimes during a study, new information becomes available about the medicines that are being 
studied. An independent committee will look at any new information and will also look at the 
information collected so far in the study and decide if any changes are needed. If this happens, your 
doctor will tell you about it and discuss whether you want your child to continue in the study. If you 
decide to stop taking part in the study, your doctor will continue your child’s regular care.  
 
How can my child join the study? 
If your child would like to join the ODYSSEY study please speak to the staff at your nearest clinic where 
the study is run during your next appointment.  
 


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How to contact us? 
  
Contact:  _________________________ 
Tel: 
 _________________________ 
 


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CHILDREN’S INFORMATION SHEET – MAIN STUDY & WEIGHT BAND PK 1 (3 TO <14KG) 
ODYSSEY STUDY  
Odyssey is a study.  Studies take groups of people and ask them to do something and 
then see if there are any changes.  This study is looking at some new medicine for 
children  
 
Dolutegravir is the name of the new medicine, we know it works very well with adults 
but we don’t know how it works with children  
 
You have been asked to take part because you need to start taking medicine or you 
need to change the medicine you are on.  
 
So why be involved?  Well, this new medicine is exciting as it will mean a big difference 
for lots of children around the world, so you can be part of something that makes a 
big difference. 
 
Studies run in different ways.  This one has two groups: one will take the new medicine 
and the other will take the medicine your doctor has given to lots of children like you. 
This is so both groups can be watched to see any differences.  This is decided randomly 
– like pulling names out of a hat – so you can’t choose which one you are in.  
 
Everyone taking part will be closely watched by doctors, so you will need to come to 
some extra clinic visits in the first two months and after that it’ll be every three 
months.  
 
You can say yes now, but if you change your mind at any point, you can stop being part 
of the study, it’s up to you. 
 
BLOOD LEVELS STUDY 
If you are in the group taking the new medicine, after at least one week of taking this 
new medicine you will be asked to spend a whole day at the clinic so we can check how 
much of the medicine is in your blood.  We will take up to 7 small blood samples during 
the day (over a 24 hour period).  Each blood sample will be small (less than half a 
teaspoon) and the amount of blood taken will be safe for your age and weight. 
 
After the first blood sample is taken you will be given breakfast (we will provide all 
your meals during this day) with your usual dose of medicine.  
 
We also need a sample the next morning. Your clinic team will let you know whether 
you need to stay overnight or come back the next day to have this sample taken. 


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PARENT/CARER INFORMATION SHEET –WEIGHT BAND PK 1 (3KG TO <25KG) 
ODYSSEY WEIGHT BAND PK 1 –
BLOOD LEVELS STUDY  
1 Why are we doing this study? 
 
We need to confirm that the dose of the new medicine is suitable for children who weigh 3kg 
to 25kg. If your child joins this study he/she will need to come into the clinic for a whole day 
(over a 24 hour period) when samples will be taken to check the pharmacokinetics (PK) which 
means the levels of medicine in their blood. 
 
2 Why has my child been asked to take part? 
  
Children being asked to take part in this study are taking part in ODYSSEY, weigh between 3kg 
to 25kg and are taking dolutegravir.  We are aiming to ask a small group of children to take 
part. 
 
Your child has been asked to take part either because: 
 
A. 
he/she is already taking part in ODYSSEY 
 
OR 
 
B. 
you and your child may be thinking about taking part in ODYSSEY; in this case your 
child may only take part in this additional study if they join the ODYSSEY trial and they 
are allocated dolutegravir. 
 
3 
What will happen if we decide not to take part? 
 
It is totally up to you and your child whether or not he/she takes part in this study.  
 
If you or your child decides not to take part in the PK (blood levels) study this will not stop 
your child from taking part in ODYSSEY or affect your child’s care now or in the future in any 
way.  
 
 
4 What will happen if my child takes part? 
If you decide to take part, we will go through this information sheet together.  We will give 
you a copy to keep. You will be asked to sign a consent form to show you understand the 
information and agree to take part.  
If your child does take part, blood samples will be taken from your child and stored so 
researchers can learn more about anti-HIV medicines. If at any point your child wants to stop 


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being in the study we hope that you will still allow us to use these samples. If, however, you 
do not give your permission then we will destroy them. 
 
 
Your child’s wellbeing will be monitored closely during the study. If for any reason his/her 
medicine needs to be changed this will be done by their doctor. 
 
Important to know 
 If your child is eligible and does take part they will need to spend one whole day in 
the clinic after at least 1 week of taking dolutegravir.  
 
On the day booked for the blood sampling visit your child will be asked to come to the clinic 
for a whole day. He/she will have up to 7 blood samples taken during the day (over a 24 hour 
period) to test the level of medicine in their blood. A cream with local pain-killing effect will 
be used to make the skin numb and a thin flexible tube (called a cannula) will be inserted into 
a vein for the day to enable the blood samples to be taken more easily. All blood samples will 
be taken from the cannula so only one needle prick is required. Each blood sample will be 
small (less than half a teaspoon), and the amount will be is safe for your child’s age and 
weight. 
 
We will also need to take a blood sample the next morning. Your child can stay overnight or 
we will provide transport for you to come back the next day. 
 
At this point the PK (Blood Levels) study will end. However, usual clinic ODYSSEY visits will 
continue for routine monitoring of your child’s health. 
 
5 What are the possible benefits and disadvantages of taking part? 
 
What are the possible benefits of taking part in this study? 
We cannot promise that participating in the study will directly help your child but the results 
of this study will give us more information about the dosing of dolutegravir for children and 
young people. It is very important that we have this information so we can make sure that 
children are given the correct amount of medicine. 
 
This information will help children and young people across the world with HIV and in the 
future it may mean your child has the chance to get the most appropriate amount of 
medicine. 
  
What are the possible disadvantages and risks of taking part in this study? 
It’s important to think about these before deciding to take part.   
 
This study will not result in any risk to your child’s health. However, your child will have to 
spend one day at the clinic and may need to stay overnight on this day. 
 
On the PK day, up to 7 small blood samples will be taken but only one needle prick will be 
needed. 
 


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 6 More information about taking part 
 
Who has checked this study is safe? 
This study has been looked at by an independent group of people (a Research Ethics 
Committee) to make sure that, as far as possible, the safety and wellbeing of anyone taking 
part in the study is protected.  
 
A second group (the Independent Data Monitoring Committee) will review the results as they 
come out and will recommend if the study is safe to continue. This is standard for all studies 
looking at medicines for adults or children. 
 
What if something goes wrong? 
The PENTA Foundation has made arrangements for compensation should your child come to 
any harm from participating in this study. However, if your child is harmed due to someone’s 
negligence then you may have reasons for legal action for compensation against the hospital 
where the negligence occurred. 
 
With your permission your child’s GP will be informed of his/her participation in the study. 
Your hospital doctor is not receiving any personal payment for carrying out this research. 
[Country specific, delete if not applicable]   
 
What will happen to information about my child collected during this study? 
All information collected during the ODYSSEY study will be kept completely confidential and 
names will not be used. Your child will only be identified using a study number, an         
anonymous code and their date of birth. Your child’s clinic notes may be looked at by study 
staff from the PENTA Foundation, the trials units co-ordinating the study or other 
independent people authorised to make sure that the ODYSSEY study is being properly carried 
out. They may also be seen by the companies who are supplying medicine for the study or 
relevant international regulatory authorities. Confidentiality will be maintained at all times. 
 
If the results of this study are reported or published no information will be included that could 
identify your child (no name or date of birth). The study will be conducted in agreement with 
the country specific data protection regulations. 
 
 
7 Contacts for more information 
 
If you would like more information about the study please ask the doctor or nurse at your 
clinic. If you still need more information please call: 
 
Contact: _________________________ 
Tel: _____________________________ 


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CHILDREN’S INFORMATION SHEET – WEIGHT BAND PK 1 (3 TO <25KG) 
ODYSSEY PK (BLOOD LEVELS) STUDY  
 
We need to confirm that the dose of the new medicine is suitable for children who are 
about the same weight as you. If you join this study you will need to come into the 
clinic for a whole day when samples will be taken to check the levels of medicine in 
the blood. 
 
You have been asked to take part because either 
A. you are part of the ODYSSEY study and are taking the new medicine  
OR 
B. you may be taking part in ODYSSEY and could be starting to take the new 
medicine if and when you start the study. 
You can say yes now, but if you change your mind at any point, you can stop being 
part of the study, it’s up to you. 
 
After at least one week in the study and taking the new medicine you will be asked to 
spend a whole day at the clinic so we can check how much of the medicine is in your 
blood.  We will take up to 7 small blood samples during the day (over a 24 hour period).  
Each blood sample will be small (less than half a teaspoon), and the amount will be is 
safe for your age and weight. 
 
After the first blood sample is taken you will be given breakfast (we will provide all your 
meals during this day) with your usual dose of medicine.  
 
We also need a sample the next morning. Your clinic team will let you know whether 
you need to stay overnight or come back the next day to have this sample taken. 
 
 


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PARENT/CARER INFORMATION SHEET – WEIGHT BAND PK 2 (25KG TO <40KG) 
ODYSSEY WEIGHT BAND PK 2 – 
BLOOD LEVELS STUDY  
1 Why are we doing this study? 
 
We need to check that a different dose of dolutegravir is suitable for children who weigh 25kg to 40kg.  
 
2 Why has my child been asked to take part? 
Children being asked to take part in this study are taking part in ODYSSEY, weigh between 25kg and 
40kg and are taking dolutegravir.  We are aiming to ask a small group of children to take part. 
 
Your child has been asked to take part either because: 
 
A. 
he/she is already taking part in ODYSSEY 
 
OR 
 
B. 
you and your child may be thinking about taking part in ODYSSEY; in this case your child may 
only take part in this additional study if they join the ODYSSEY trial and they are allocated 
dolutegravir. 
 
3 What will happen if we decide not to take part? 
 
It is totally up to you and your child whether or not he/she takes part in this study.  
 
If you or your child decides not to take part this will not stop your child from taking part in ODYSSEY 
or affect your child’s care now or in the future in any way.  
 
4 What will happen if my child takes part? 
If you decide to take part, we will go through this information sheet together.  We will give you a copy 
to keep. You will be asked to sign a consent form to show you understand the information and agree 
to take part.  
 
If your child does take part, blood samples will be taken from your child and stored so researchers can 
learn more about anti-HIV medicines. If at any point your child wants to stop being in the study we 
hope that you will still allow us to use these samples. If, however, you do not give your permission 
then we will destroy them. 
 
Your child’s wellbeing will be monitored closely during the study. If for any reason his/her medicine 
needs to be changed this will be done by their doctor. 
 
Important to know 


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 
If your child is eligible and does take part in the blood levels study they will need to spend 
one whole day at the clinic after at least 1 week of taking dolutegravir.  
 
 
Your child’s dose will be changed after the first PK (blood sampling) day. 
 
 
At least 1 week after your child has been changed to the new dose of dolutegravir, he/she 
will spend a second day at the clinic.   
 
 
Your child will also have to come in for a clinic visit at 2, 4 and 12 weeks after starting the 
new dose of dolutegravir. Where possible these visits will be timed to coincide with 
scheduled ODYSSEY study visits to minimise additional clinic visits. 
 
On the day booked for the first blood sampling visit your child will be asked to come to the clinic for a 
whole day. He/she will have up to 7 blood samples taken during the day (over a 24 hour period) to 
test the level of medicine in their blood. A cream with local pain-killing effect will be used to make the 
skin numb and a thin flexible tube (called a cannula) will be inserted into a vein for the day to enable 
the blood samples to be taken more easily. All blood samples will be taken from the cannula so only 
one needle prick is required. Each blood sample will be small (less than half a teaspoon), and the 
amount will be is safe for your child’s age and weight. 
 
We will also need to take a blood sample the next morning. Your child may stay overnight or we will 
provide transport for you to come back the next day. 
 
At least one week after your child has switched to the new dose of dolutegravir he/she will be asked 
to spend a second day at the clinic and another set of blood samples will be taken. Like for the first PK 
day this may also require an overnight stay in hospital.  
 
2, 4 and 12 weeks after starting the new dose of dolutegravir your child will be asked to come to clinic 
for clinical assessment, some blood tests and we will ask you and your child to complete a short 
questionnaire.  These visits are to make sure that your child is doing well and is healthy whilst taking 
the new dose.  
 
At this point the PK (Blood Levels) study will end. However, usual clinic ODYSSEY visits will continue 
for routine monitoring of your child’s health. 
 
5 What are the possible benefits and disadvantages of taking part? 
 
What are the possible benefits of taking part in this study? 
We cannot promise that participating in the study will directly help your child but the results of this 
study will give us more information about which dose of dolutegravir works better for children and 
young people. It is very important that we have this information so we can make sure that children 
are given the correct amount of medicine. 
 
This information will help children and young people across the world with HIV and in the future it 
may mean your child has the chance to get the most appropriate amount of medicine. 
What are the possible disadvantages and risks of taking part in this study? 
It’s important to think about these before deciding to take part.   
 
This study will not result in any risk to your child’s health. However, your child will have to spend two 
days at the clinic and may need to stay overnight on these days. 


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On each PK day, up to 7 small blood samples will be taken but only one needle prick will be needed. 
 
Your child will have to attend at least 1 or 2 additional visits after starting the new dose in order to 
check they are doing well. 
 
 6 More information about taking part 
 
Who has checked this study is safe? 
This study has been looked at by an independent group of people (a Research Ethics Committee) to 
make sure that, as far as possible, the safety and wellbeing of anyone taking part in the study is 
protected.  
 
A second group (the Independent Data Monitoring Committee) will review the results as they come 
out and will recommend if the study is safe to continue. This is standard for all studies looking at 
medicines for adults or children. 
 
What if something goes wrong? 
The PENTA Foundation has made arrangements for compensation should your child come to any harm 
from participating in this study. However, if your child is harmed due to someone’s negligence then 
you may have reasons for legal action for compensation against the hospital where the negligence 
occurred. 
 
With your permission your child’s GP will be informed of his/her participation in the study. Your 
hospital doctor is not receiving any personal payment for carrying out this research. [Country specific, 
delete if not applicable]   
 
What will happen to information about my child collected during this study? 
All information collected during the ODYSSEY study will be kept completely confidential and names 
will not be used. Your child will only be identified using a study number an         anonymous code and 
their date of birth. Your child’s clinic notes may be looked at by study staff from the PENTA Foundation, 
the trials units co-ordinating the study or other independent people authorised to make sure that the 
ODYSSEY study is being properly carried out. They may also be seen by the companies who are 
supplying medicine for the study or relevant international regulatory authorities. Confidentiality will 
be maintained at all times. 
 
If the results of this study are reported or published no information will be included that could identify 
your child (no name or date of birth). The study will be conducted in agreement with the country 
specific data protection regulations. 
 
7 Contacts for more information 
 
If you would like more information about the study please ask the doctor or nurse at your clinic. If you 
still need more information please call: 
 
 
Contact: _________________________ 
Tel: _____________________________ 
 
 


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PARTICIPANT INFORMATION SHEET –WEIGHT BAND PK 2 (25KG TO <40KG) 
ODYSSEY WEIGHT BAND PK 2 -  
BLOOD LEVELS STUDY  
 
1 Why are we doing this study? 
 
We need to check that a different dose of the new medicine is suitable for children who weigh about 
the same as you.  
 
2 Why have I been asked to take part? 
  
You have been asked to take part because either 
 
A. you are part of the ODYSSEY study and are taking the new medicine  
OR 
B. you may be taking part in ODYSSEY and could be starting to take the new medicine if and 
when you start the study. 
 
3 What will happen if we decide not to take part? 
 
It is totally up to you whether or not to take part in this study. 
  
If you decide not to take part this will not stop you from taking part in ODYSSEY or affect your care 
now or in the future in any way.  
 
4 What will happen if I take part? 
If you decide you would like to take part, we will go through this information sheet together.  We will 
give you a copy to keep. You will be asked to sign an assent form to show you understand the 
information and agree to take part.  
 
Important to know 
 
If you do take part you will need to spend one whole day in the clinic after at least 1 week 
of taking the new medicine.  
 
 
Your dose will be changed after the first blood sampling day. 
 
 
After at least 1 week of being on the new dose of your medicine you will spend a second day 
at the clinic.   
 
 
You will also have to come in for a clinic visit at 2, 4 and 12 weeks after starting the new 
dose of medicine.  
 


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On the day booked for the first blood sampling visit you will be asked to come to the clinic for a whole 
day.  
 
You will have up to 7 blood samples taken during the day (over a 24 hour period) to test the level of 
medicine in your blood. A cream will be used to make the skin numb and a thin flexible tube (called a 
cannula) will be inserted into a vein for the day to enable the blood samples to be taken more easily. 
All blood samples will be taken from the cannula so only one needle prick is required.  
 
Each blood sample will be small (less than half a teaspoon), and the amount will be is safe for your age 
and weight. 
 
We will also need to take a blood sample the next morning. You can stay overnight or we will provide 
transport for you to come back the next day. 
 
At least one week after you have switched to the new dose of medicine you will be asked to spend a 
second day at the clinic and another set of blood samples will be taken. Like the first blood sampling 
day, this may also require an overnight stay in the clinic.  
 
2, 4 and 12 weeks after starting the new dose you will be asked to come to clinic to make sure that 
you are doing well and are healthy whilst taking the new dose.  
 
At this point the blood levels study will end. However, usual clinic ODYSSEY visits will continue for 
routine monitoring of your health. 


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PARENT/CARER INFORMATION SHEET FOR TB PHARMACOKINETIC (PK) SUBSTUDY 
 
ODYSSEY TB PK STUDY: 
DOLUTEGRAVIR + anti-TB medicines  
 
1 Why are we doing this study? 
 
Many people taking dolutegravir also need to take anti-TB medicines. 
 
Studies looking at this in adults have shown the amount of dolutegravir needs to be doubled 
if anti-TB medicines are taken at the same time.  
 
In children there isn't enough information about how much we need to increase the amount 
of dolutegravir if anti-TB medicines are taken. 
 
We hope this study will help us to find the best treatment for children like yours. 
 
2 Why has my child been asked to take part? 
  
Your child has been asked to participate because he/she is part of the ODYSSEY study and is 
taking dolutegravir and anti-TB medicines.  
 
We are asking at least 12 children and young people to take part.  
 
3 What will happen if we decide not to take part? 
 
It is totally up to you and your child whether or not he/she takes part in this study. It is your 
right to decide not to take part if you wish.  
 
If you or your child decides not to take part this will not stop your child from taking part in 
ODYSSEY or affect your child’s care now or in the future in any way.  
 
If you do decide to take part, blood samples will be taken and stored from your child so 
researchers can learn more about anti-HIV medicines. If at any point your child wants to stop 
being in the study we hope that you will still allow us to use these samples. If, however, you 
do not give your permission then we will destroy them. 
 
 
 
 
4 What will happen if my child takes part? 


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If you do decide to take part, we will go through this information sheet together.  We will give 
you a copy to keep. You will be asked to sign a consent form to show you understand the 
information and agree to take part.  
 
Your child’s wellbeing will be monitored closely during the study. If for any reason his/her 
medicine needs to be changed this will be done by their doctor in the usual way. 
 
Important to know 
 
If you decide to take part your child will need to spend one day in clinic while 
taking anti-TB medicines.  
 
At least a month after your child stops taking anti-TB medicines, he/she will spend 
a second day at the clinic and may need to stay overnight. 
 
At the start of the study your child will be taking dolutegravir and anti-TB medicines. At this 
point we will take some blood samples to measure the level of dolutegravir in the blood.  
 
Your child will be asked to come into clinic for a whole day. He/she will have up to 7 blood 
samples taken during the day (over a 12 hour period) to test the level of dolutegravir and anti-
TB medicine in their blood. A cream with local pain-killing effect will be used to make the skin 
numb and a thin flexible tube (called a cannula) will be inserted into a vein for the day to 
enable the blood samples to be taken. All blood samples will be taken from the cannula so 
only one needle prick is required. Each blood sample will be small (about half a teaspoon), 
and the amount will be is safe for your child’s age and weight. 
 
At least a month after your child has completed his/her anti-TB treatment he/she will be 
asked to spend a second day at the clinic and another 7 blood samples will be taken (over 24 
hours). This may require an overnight stay in hospital.  
 
At this point the dolutegravir-anti-TB medicines study will end. However, usual clinic ODYSSEY 
visits will continue for routine monitoring of your child’s health. 
 
5 What are the possible benefits and disadvantages of taking part? 
What are the possible benefits of taking part in this study? 
We cannot promise that participating in the study will directly help your child but the results 
of this study will give us more information about how dolutegravir and anti-TB medicines 
work together in children. It is very important that we have this information so we can make 
sure that children are given the correct amount of medicine. 
This information will help children and young people across the world with HIV and TB and in 
the future it may mean your child has the chance to get the most appropriate amount of           
medicines. 
  
What are the possible disadvantages and risks of taking part in this study? 
It’s important to think about these before deciding to take part.   
This study will not result in any risk to your child’s health. However, your child will have to 
spend separate two days at the clinic and may need to stay overnight on the second day. 
Each day, up to 7 small blood samples will be taken but only one needle prick will be needed 
each day. 


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 6 More information about taking part 
Who has checked this study is safe? 
This study has been looked at by an independent group of people (a Research Ethics 
Committee) to make sure that, as far as possible, the safety and wellbeing of anyone taking 
part in the study is protected.  
 
A second group (the Independent Data Monitoring Committee) will meet regularly during the 
study to review the results as they come out and will recommend if the study is safe to 
continue. This is standard for all studies looking at medicines for adults or children. 
 
What if something goes wrong? 
The PENTA Foundation has made arrangements for compensation should your child come to 
any harm from participating in this study. However, if your child is harmed due to someone’s 
negligence then you may have reasons for legal action for compensation against the hospital 
where the negligence occurred. 
 
With your permission your child’s GP will be informed of his/her participation in the study. 
Your hospital doctor is not receiving any personal payment for carrying out this research. 
[Country specific, delete if not applicable]   
 
What will happen to information about my child collected during this study? 
All information collected during the ODYSSEY study will be kept completely confidential and 
names will not be used. Your child will only be identified using a study number, an         
anonymous code and their date of birth. Your child’s clinic notes may be looked at by study 
staff from the PENTA Foundation, the trials units co-ordinating the study or other 
independent people authorised to ensure that the ODYSSEY study is being properly carried 
out. They may also be seen by the companies who are supplying medicine for the study or 
relevant international regulatory authorities. Confidentiality will be maintained at all times. 
 
If the results of this study are reported or published no information will be included that could 
identify your child (no name or date of birth). The study will be conducted in agreement with 
the country specific data protection regulations. 
 
7 Contacts for more information 
 
If you would like more information about the study please ask the doctor or nurse at your 
clinic. If you still need more information please call: 
 
Contact: _________________________ 
Tel: _____________________________ 
 
 


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PARTICIPANT INFORMATION SHEET FOR TB PHARMACOKINETIC (PK) SUBSTUDY 
ODYSSEY TB PK STUDY: 
DOLUTEGRAVIR + anti-TB medicines  
 
1 Why are we doing this study? 
 
Many people taking dolutegravir also need to take anti-TB medicines. 
 
Studies looking at this in adults have shown the amount of dolutegravir needs to be doubled if anti-
TB medicines are taken at the same time.  
 
In children there isn't enough information about how much we need to increase the amount of 
dolutegravir if anti-TB medicines are taken. 
 
We hope this study will help us to find the best treatment for young people like you. 
 
2 Why have I been asked to take part? 
  
You have been asked to participate because you are part of the ODYSSEY study and are taking 
dolutegravir and anti-TB medicines.  
 
We are asking at least 12 young people to take part.  
 
3 What will happen if I decide not to take part? 
 
It is totally up to you whether or not you take part in this study. It is your right to decide not to take 
part if you wish.  
 
If you decide not to take part this will not stop you from taking part in ODYSSEY or affect your care 
now or in the future in any way.  
 
If you do decide to take part, blood samples will be taken and stored from you so researchers can 
learn more about anti-HIV medicines. If at any point you want to stop being in the study we hope that 
you will still allow us to use these samples. If, however, you do not give your permission then we will 
destroy them. 
 
4 What will happen if I take part? 
 
If you do decide to take part, we will go through this information sheet together.  We will give a copy 
to you to keep. Your parent/carer will then be asked to sign a consent form to show you both 
understand the information and agree to take part. We will also ask you to sign a form giving your 
assent to join the study. 
 
 


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Your wellbeing will be monitored closely during the study. If for any reason your medicine needs to 
be changed this will be done by your doctor in the usual way. 
 
Important to know 
 
If you decide to take part you will need to spend one day in clinic while taking anti-TB 
medicines.  
 
At least a month after you stop taking anti-TB medicines, you will spend a second day at the 
clinic and may need to stay overnight. 
 
At the start of the study you will be taking dolutegravir and anti-TB medicines. At this point we will 
take some blood samples to measure the level of dolutegravir in the blood.  
 
You will be asked to come into hospital for a whole day. You will have up to 7 blood samples taken 
during the day (over a 12 hour period) to test the level of dolutegravir and anti-TB medicine in your 
blood. A cream with local pain-killing effect will be used to make the skin numb and a thin flexible tube 
(called a cannula) will be inserted into a vein for the day to enable the blood samples to be taken. All 
blood samples will be taken from the cannula, so only one needle prick is required. Each blood sample 
will be small (about half a teaspoon), and the amount will be is safe for your age and weight. 
 
At least a month after you have completed your anti-TB treatment you will be asked to spend a second 
day at the clinic and another 7 blood samples will be taken (over a 24 hour period). This may require 
an overnight stay in hospital.  
 
At this point the dolutegravir-anti-TB medicines study will end. However, usual clinic ODYSSEY visits 
will continue for routine monitoring of your health. 
 
5 What are the possible benefits and disadvantages of taking part? 
 
What are the possible benefits of taking part in this study? 
We cannot promise that participating in the study will directly help you but the results of this study 
will give us more information about how dolutegravir and anti-TB medicines work together in children 
and young people. It is very important that we have this information so we can make sure that children 
and young people are given the correct amount of medicine. 
This information will help children and young people across the world with HIV and TB and in the 
future it may mean you have the chance to get the most appropriate amount of medicines. 
  
What are the possible disadvantages and risks of taking part in this study? 
It’s important to think about these before deciding to take part.   
 
This study will not result in any risk to your health. However, you will have to spend two days in the 
clinic and may need to stay overnight on the second day. 
Each day, up to 7 small blood samples will be taken but only one needle prick will be needed each day. 
 
 
6 More information about taking part 
 
Who has checked this study is safe? 
This study has been looked at by an independent group of people (a Research Ethics Committee) to 
make sure that, as far as possible, the safety and wellbeing of anyone taking part in the study is 


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protected.  
 
A second group (the Independent Data Monitoring Committee) will meet regularly during the study 
to review the results as they come out and will recommend if the study is safe to continue. This is 
standard for all studies looking at medicines for adults or children. 
 
What if something goes wrong? 
The PENTA Foundation has made arrangements for compensation should you come to any harm from 
participating in this study. However, if you are harmed due to someone’s negligence then you may 
have reasons for legal action for compensation against the hospital where the negligence occurred. 
 
With your permission your GP will be informed of your participation in the study. Your hospital doctor 
is not receiving any personal payment for carrying out this research. [Country specific, delete if not 
applicable] 
 
What will happen to my information collected during this study? 
All information collected during the ODYSSEY study will be kept completely confidential and names 
will not be used. You will only be identified using a study number, an anonymous code and their date 
of birth. Your clinic notes may be looked at by study staff from the PENTA Foundation, the trials units 
co-ordinating the study or other independent people authorised to ensure that the ODYSSEY study is 
being properly carried out. They may also be seen by the companies who are supplying medicine for 
the study or relevant international regulatory authorities. Confidentiality will be maintained at all 
times. 
 
If the results of this study are reported or published no information will be included that could identify 
you (no name or date of birth). The study will be conducted in agreement with the country specific 
data protection regulations.  
 
7 Contacts for more information 
 
If you would like more information about the study please ask the doctor or nurse at your clinic. If you 
still need more information please call: 
 
Contact: _________________________ 
Tel: _____________________________ 
 
 


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INFORMATION SHEETS FOR QUALITATIVE SUBSTUDY  
 
Information sheets for in-depth interviews (IDIs)- 10-18 year olds 
 Information sheets – IDIs- young people (15- 18 year olds) 
 Information sheets- IDIs – young people (10-14 year olds) 
 Information sheets- IDIs- parents/ guardians 
 Information sheets – IDIs- caregivers 
 Information sheets – IDIs- young people (15- 19 year olds) - DTG alert 
 Information sheets- IDIs – young people (10-14 year olds) - DTG alert 
 Information sheets- IDIs- parents/ guardians - DTG alert 
Information sheets for focus group discussions (FGDs) 10-18 year olds 
 Information sheets- FGDs- young people (15-18 year olds) 
 Information sheets- FGDs- young people (10-14 year olds) 
 Information sheets- FGDs- parents/ guardians 


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ODYSSEY QUALITATIVE STUDY: 
PARTICIPANT INFORMATION SHEET FOR IN-DEPTH INTERVIEWS 15-18 YEAR OLDS  
(Insert version no and date) 
 
We are doing a study to hear from young people (aged 10-18 years) about their experiences 
of growing up with HIV. We would like you to join our study. 
Before you decide if you want to take part please read this information sheet carefully and 
ask any questions you may have.  
 
What is the purpose of the study?  
This is a study to find out about what it is like for young people growing up with HIV and taking 
HIV treatment. In particular, we are looking to better understand what it is like to take second-
line HIV treatment. Second-line means that you were already taking one set of anti-HIV 
medicine that were no longer working well and your doctor decided it was time for you 
change to a new combination.  We are interested in learning from young people what can 
make it difficult to take their treatment and what might help make it easier. We will do this 
by talking with young people, like you, about their experiences. This is because we think that 
the best way to learn about the experiences of young people is to listen carefully to what they 
have to say. This type of research is called a qualitative study.  
 
Why is the study being done?  
Until now there hasn’t been much research done which asks young people themselves about 
their experiences of being on second-line treatment. This is why we are doing the study. By 
listening to what young people tell us we hope to make some suggestions about how to 
improve support for young people to take their treatment.  
 
Who is doing the study?  
This study is being run in two of the sites, one in Uganda and one in Zimbabwe, where the 
ODYSSEY trial is being conducted. This qualitative study is being done by a small team of 
researchers from Uganda, Zimbabwe and the United Kingdom. We have done similar research 
before in these sites and are experienced in talking with young people.  
 
Why are we asking you?  
We are asking whether you would like to take part in this study because you are participating 
in the   ODYSSEY trial and are aged between 10-18 years old.  
 
What would I be asked to do?  
We would like you to meet a researcher for two interviews. The first interview will be close 
to when you begin the ODYSSEY trial and the second interview would take place later on in 
the trial. Each interview will be like a conversation and will last for about an hour. There are 
no wrong or right answers. You do not have to talk about any topics that you do not want to. 
You can stop the interview at any time, without having to explain why.  
We would like to audio record these interviews, if this is OK with you. The interview will take 
place somewhere that you feel comfortable, probably a private place at the clinic.  
  


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What will happen to any information collected about me during this study? 
Any information that you share with us will only be seen by members of the research team. 
This means that whenever we write or talk about anything you have told us we never use 
your real name. All information about you will be stored securely. 
The only exception to this is if you tell us something that makes us worried about you or 
another young person’s safety, such as physical harm or neglect. If we think that we should 
tell someone else, we will talk to you about it first and ask if you would like us to do that.  
 
How will the research be used? 
The findings of this study will be reported to a wide range of people who are involved in 
providing treatment, care and support for children and young people living with HIV. The 
findings will be used to guide the way young people on second-line HIV treatment are 
supported in the future.  
 
What are the benefits and risks of taking part? 
You will be part of a study that aims to help young people live well with HIV and to support 
those taking second-line treatment. Some young people may find the opportunity to talk 
about their experiences of growing up with HIV and taking treatment to be a really good thing.  
Some young people though might find it a difficult subject to talk about. The researcher will 
take care to ask questions sensitively. It is up to you what you want to tell us. Also if you want 
there can be someone available from your clinic to talk to if you feel that you want to at any 
point during the study, including after the interview.   
 
Do I have to take part? 
No, you do not have to take part in the study. Your access to the clinic will not be affected in 
anyway if you decide not to take part. It will not affect any of the services that you currently 
receive.   If you do decide to take part but later change your mind this is OK too.   
 
Will I receive anything for taking part? 
Yes, your travel expenses will be covered for the interviews. If you are accompanied to the 
interview then your escort’s travel expenses will be covered too.  You will also receive 10,000 
Ugandan shillings or local equivalent. [Uganda- delete as appropriate] 
 
Yes, your travel expenses will be covered for the interviews. You will receive US$7 per 
interview or local equivalent. If you are accompanied to the interview then your escort’s 
travel expenses will be covered too.  [Zimbabwe- delete as appropriate] 
 
Can I have some more information before I decide? 
If you would like to find out more before deciding the staff at your clinic can arrange for you 
to speak to one of the researchers more about it.   
 
I’m happy to take part. Now what? 
Once you have signed the assent or consent form and, if you are under 18 years old your carer 
has given their consent, the researcher will contact you and your carer, if necessary, to 
arrange the first interview. 


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What happens if you have questions? 
If you or the person who takes care of you have any questions, you can contact: xxxxxxxx    
If you cannot access a telephone to call, you can ask xxxxxxxx (a person from your 
clinic/village) to telephone for you so you can ask your question. 
 
Thank you for reading this! 


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ODYSSEY QUALITATIVE STUDY: 
PARTICIPANT INFORMATION SHEET FOR IN-DEPTH INTERVIEWS 10-14 YEAR OLDS 
(Insert version no and date) 
 
We are doing a study with young people (aged 10-18 years) about their experiences of 
growing up with HIV. We would like you to join our study. 
Before you decide if you want to take part we would like you to read the information below 
carefully. Someone can help you read it if that is easier. It is important that you understand 
what we are asking you to do and you should feel comfortable to ask any questions, however 
big or small.  
  
What is the purpose of the study?  
This is a study to find out about what it is like for young people when they are growing up 
with HIV. We are really interested to understand more about what it is like for you and other 
young people to take your HIV treatment every day. We especially want to understand what 
it is like when your treatment has been changed to what is called second-line. Second-line 
means that you were already taking one set of anti-HIV medicine that were no longer working 
well and your doctor decided it was time for you change to a new combination.   We want to 
know what can make it difficult to take treatment and what might help make it easier. We 
will do this by talking with young people, like you, about what it is like. This is because we 
think that the best way to learn about this is to listen carefully to what young people have to 
say.  
 
Why is the study being done?  
We don’t at the moment know very much about what it is like for young people to take 
second-line treatment. So we are doing this study so that we can learn more about it. This will 
help us to make suggestions about how to help young people with taking their treatment.  
 
Who is doing the study?  
This study is being run in Uganda and Zimbabwe. The researchers working on this study are 
from Uganda, Zimbabwe as well as the United Kingdom. We have done lots of work like this 
before.  
 
Why are we asking you?  
We are asking whether you would like to take part in this study because you are already 
talking part in the ODYSSEY trial and are aged between 10-18 years old.  
 
What would I be asked to do?  
We would like you to meet a researcher for two interviews. The first interview will happen 
after you have started the ODYSSEY trial and the second interview will take place later on in 
the trial. The interviews will be like a conversation. They will last for about an hour. There are 
no wrong or right answers. You do not have to talk about anything that you don’t want to and 
you will not need to say why.   
As we want to listen very carefully to everything that you tell us we would like to audio record 
the interviews. We will only record them if you are OK with this.  


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The interview will take place somewhere that you feel comfortable. This will probably be at 
the clinic, somewhere private so that no one can overhear what we will be talking about.    
    
What will happen to any information collected about me during this study? 
Anything that you tell us will only be listened to by the research team. This means that 
whenever we write or talk about anything you have told us we never use your real name. We 
will be very careful to keep all the information about you locked away so that no one else can 
see it.  
The only exception to this is if you tell us something that makes us worried about you or 
another young person’s safety. If we are concerned and think that we should tell someone 
else, we will talk to you about it first and ask if you would like us to do that.  
 
How will the research be used? 
We will tell lots of people who look after children and young people living with HIV what we 
have learnt from our study.  What we learn will be used to guide the way young people on 
second-line HIV treatment are supported in the future  
 
What are the benefits and risks of taking part? 
You will be part of a study that aims to help young people live well with HIV and to support 
those taking second-line treatment. Some young people may find the opportunity to talk 
about their experiences of growing up with HIV and taking treatment to be a really good thing.  
Some young people though might find it a difficult subject to talk about. The researcher will 
take care to ask questions thoughtfully. It is up to you what you want to tell us. Also if you 
want there can be someone available from your clinic to talk to if you feel that you want to at 
any point during the study, including after the interview.   
 
Do I have to take part? 
No, you do not have to take part in the study. If you say no, everything that you receive at the 
clinic will be just the same as before.   If you do decide to take part but later change your mind 
this is OK too.   
 
Will I receive anything for taking part? 
Yes, your travel expenses will be covered for the interviews. If you are accompanied to the 
interview then the expenses of the person who comes with you will also be covered.  You will 
also receive 10,000 Ugandan shillings or local equivalent. [Uganda- delete as appropriate] 
 
Yes, your travel expenses will be covered for the interviews. You will receive US$7 per 
interview or local equivalent. If you are accompanied to the interview then the person who 
comes with you will be covered too.  [Zimbabwe- delete as appropriate] 
 
 
 
 
Can I have some more information before I decide? 


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If you would like to find out more before deciding the staff at your clinic can arrange for you 
to speak to one of the researchers more about it.  We will be very happy to answer any of 
your questions.  
 
I’m happy to take part. Now what? 
Once you and your carer have signed the assent or consent form the researcher will contact 
you and your carer to arrange the first interview. 
 
What happens if you have questions? 
If you or the person who takes care of you have any questions you can contact: xxxxxxxx  
 If you cannot access a telephone to call, you can ask xxxxxxxx (a person from your 
clinic/village) to telephone for you so you can ask your question. 
  
 
Thank you for reading this! 


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ODYSSEY QUALITATIVE STUDY: 
PARENT/CARER INFORMATION SHEET FOR IN-DEPTH INTERVIEWS  
(Insert version no and date) 
 
We are doing a study to hear from young people (aged 10-18 years) about their experiences 
of growing up with HIV. We would like your child to join our study. 
Before you decide if you want your child to take part please read this information sheet 
carefully and ask any questions you may have.  
 
What is the purpose of the study?  
This is a study to find out about what it is like for young people growing up with HIV and taking 
HIV treatment. In particular, we are looking to better understand what it is like to be on 
second-line HIV treatment. Second-line means that someone was already taking one set of 
anti-HIV medicine that were no longer working well and their doctor decided it was time for 
them change to a new combination.   We are interested in learning from young people what 
can make it difficult to take treatment and what might help make it easier. This will be done 
by talking with young people, like your child, about their experiences. This is because we think 
that the best way to learn about the experiences of young people is to listen carefully to what 
they have to say. This type of research is called a qualitative study.  
 
Why is the study being done?  
Up until now there hasn’t been much research done which asks young people themselves 
about their experiences of being on second-line treatment. This is why we are doing the study. 
By listening to what young people tell us we hope to make some suggestions about how to 
improve support for young people to take their treatment.  
 
Who is doing the study?  
This study is being run in two sites where the ODYSSEY trial is being conducted. One is at JCRC 
in Uganda and one is at the University of Zimbabwe in Harare, Zimbabwe. This qualitative 
study is being done by a small team of researchers from Uganda, Zimbabwe and the United 
Kingdom. We have done similar research before in these sites and are experienced in talking 
with young people about similar topics.  
 
Why are we asking your child?  
We are asking whether you are happy for your child to take part in this study because your 
child is already participating in the ODYSSEY trial and is aged between 10-18 years old.  
 
What would my child be asked to do?  
We would like your child to meet with a researcher for two interviews. The first interview will 
be close to when they begin the ODYSSEY trial and the second interview would take place 
later on in the trial. Each interview will be like a conversation and will last for about an hour. 
There are no wrong or right answers. Your child does not have to talk about anything that 
they do not want to. Your child can stop the interview at any time, without having to explain 
why.  


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We would like to audio record these interviews, if this is OK with you and your child. The 
interview will take place somewhere that your child feels comfortable, probably at the clinic 
where a private place will be found for them to meet the researcher.    
 
What will happen to any information collected about my child during this study? 
Any information that your child shares with us will only be seen by members of the research 
team. This means that whenever we write or talk about anything your child has told us we 
would never use their real name. All information about your child will be stored securely. 
 
The only exception to this is if your child tells us something that makes us worried about your 
child or another young person’s safety, such as physical harm or neglect. If we think that we 
should tell someone else, we will talk to them about it first and ask if they would like us to do 
that.  
 
How will the research be used? 
The findings of this study will be reported to a wide range of people who are involved in 
providing treatment, care and support for children and young people living with HIV. The 
findings will be used to guide the way young people on second-line HIV treatment are 
supported in the future  
 
What are the benefits and risks of taking part? 
Your child will be part of a study that aims to help young people live well with HIV and to 
support those taking second-line treatment. Some young people may find the opportunity to 
talk about their experiences of growing up with HIV and taking treatment to be a really good 
thing.  Some young people though might find it a difficult subject to talk about. The researcher 
will take care to ask questions sensitively. It is up to your child what they want to tell us. Also 
if your child wants there can be someone available from their clinic to talk to if they feel that 
they want to at any point during the study, including after the interview.   
 
Does my child have to take part? 
No, they do not have to take part in the study. Their access to the clinic will not be affected 
in anyway if you or your child decides that you do not want them to take part. It will not affect 
any of the services that they currently receive.   If your child does decide to take part but later 
changes their mind this is OK too.   
 
Will my child receive anything for taking part? 
Yes, their travel expenses will be covered for the interviews. If they are accompanied to the 
interview then their escort’s travel expenses will be covered too.  They will also receive 10,000 
Ugandan shillings or local equivalent. [Uganda- delete as appropriate] 
Yes, their travel expenses will be covered for the interviews. They will receive US$7 per 
interview or local equivalent. If they are accompanied to the interview then their escort’s 
travel expenses will be covered too.  [Zimbabwe- delete as appropriate] 
 
Can I have some more information before I decide? 
If you would like to find out more before you decide the staff at your clinic can arrange for 
you to speak to one of the researchers more about it.   


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I’m happy for my child to take part. Now what? 
Once you have signed the consent form and, if your child has given their assent, the 
researcher will contact you and your child to arrange the first interview. 
 
What happens if you have questions? 
If you or your child have any questions you can contact: xxxxxxxxx 
 If you cannot access a telephone to call, you can ask xxxxxxxx (a person from your 
clinic/village) to telephone for you so you can ask your question. 
 
Thank you for reading this! 


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Version 6.0 8th November 2019 
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ODYSSEY QUALITATIVE STUDY: 
PARTICIPANT INFORMATION SHEET FOR IN-DEPTH INTERVIEWS - CAREGIVERS 
(Insert version no and date) 
 
As part of the Odyssey trial we are doing a study to hear from young people (aged 10-19 years) 
about their experiences of growing up with HIV and their caregivers. We would like you to 
join our study. 
Before you decide if you want to take part please read this information sheet carefully and 
ask any questions you may have.  
 
What is the purpose of the study?  
This is a study to find out about what it is like for young people growing up with HIV and taking 
HIV treatment. In particular, we are looking to better understand what it is like for young 
people to grow up well with HIV, including being able to take their treatment well and access 
the information that they need.  We are interested in learning from young people and their 
caregivers what can make it difficult for young people to grow up well with HIV and what 
might help make it easier. We will do this by talking with young people and their caregivers, 
like you, about their experiences. This is because we think that the best way to learn about 
the experiences of young people is to listen carefully to what they have to say. This type of 
research is called a qualitative study.  
 
Why is the study being done?  
Until now there hasn’t been much research done which asks young people themselves about 
their experiences of growing up with HIV and also what it is like for their caregivers. This is 
why we are doing the study. By listening to what young people and their caregivers tell us we 
hope to make some suggestions about how to improve support for young people.  
 
Who is doing the study?  
This study is being run in two of the sites, one in Uganda and one in Zimbabwe, where the 
ODYSSEY trial is being conducted. This qualitative study is being done by a small team of 
researchers from Uganda, Zimbabwe and the United Kingdom. We have done similar research 
before in these sites and are experienced in talking with caregivers and young people.  
 
Why are we asking you?  
We are asking whether you would like to take part in this study because a young person that 
you care for is participating in the ODYSSEY trial. They have agreed that it is okay if we ask 
you if you would like to be involved in the caregiver part of our study.  
 
What would I be asked to do?  
We would like you to meet a researcher for an interview. The interview will be like a 
conversation and will last for about an hour. There are no wrong or right answers. You do not 
have to talk about any topics that you do not want to. You can stop the interview at any time, 
without having to explain why.  
We would like to audio record these interviews, if this is OK with you. The interview will take 
place somewhere that you feel comfortable, probably a private place at the clinic.  


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ODYSSEY (PENTA 20)    
 
 
 
 
 
 
 
 
Page 153 of 324 
  
What will happen to any information collected about me during this study? 
Any information that you share with us will only be seen by members of the research team. 
This means that whenever we write or talk about anything you have told us we never use 
your real name. We will not reveal any information that you tell us that can be personally 
linked to you to anyone else, including the young person you care for. Nor shall we share 
anything with you that they have told us.  All information about you will be stored securely. 
The only exception to this is if you tell us something that makes us worried about a young 
person’s safety, such as physical harm or neglect. If we think that we should tell someone 
else, we will talk to you about it first and ask if you would like us to do that.  
 
How will the research be used? 
The findings of this study will be reported to a wide range of people who are involved in 
providing treatment, care and support for children and young people living with HIV. The 
findings will be used to guide the way young people on  HIV treatment are supported in the 
future.  
 
What are the benefits and risks of taking part? 
You will be part of a study that aims to help young people live well with HIV as they grow up. 
Some people may find the opportunity to talk about what it is like to care for someone who 
is growing up with HIV to be a really good thing.  Some though might find it a difficult subject 
to talk about. The researcher will take care to ask questions sensitively. It is up to you what 
you want to tell us. Also if you want there can be someone available from your clinic to talk 
to if you feel that you want to at any point during the study, including after the interview.   
 
Do I have to take part? 
No, you do not have to take part in the study. Your own or the young person’s access to the 
clinic will not be affected in anyway if you decide not to take part. It will not affect any of the 
services that you or they currently receive.   If you do decide to take part but later change 
your mind this is OK too.   
 
Will I receive anything for taking part? 
Yes, your travel expenses will be covered for the interview. You will also receive 10,000 
Ugandan shillings or local equivalent. [Uganda- delete as appropriate] 
 
Yes, your travel expenses will be covered for the interview. You will receive US$7 per 
interview or local equivalent. [Zimbabwe- delete as appropriate] 
 
Can I have some more information before I decide? 
If you would like to find out more before deciding the staff at your clinic can arrange for you 
to speak to one of the researchers more about it.   
 
I’m happy to take part. Now what? 
Once you have signed the consent form the researcher will contact you to arrange the 
interview. 


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What happens if you have questions? 
If you or the person who takes care of you have any questions, you can contact: xxxxxxxx    
If you cannot access a telephone to call, you can ask xxxxxxxx (a person from your 
clinic/village) to telephone for you so you can ask your question. 
 
Thank you for reading this! 


ODYSSEY Protocol  
Version 6.0 8th November 2019 
ODYSSEY (PENTA 20)    
 
 
 
 
 
 
 
 
Page 155 of 324 
ODYSSEY QUALITATIVE STUDY: 
PARTICIPANT INFORMATION SHEET FOR IN-DEPTH INTERVIEW 15-19 YEAR OLDS (DTG alert)  
(Insert version no and date) 
 
We are doing a study to hear from young people (aged 10-19 years) about their experiences 
of growing up with HIV and the discussions they have within the HIV clinic. We would like to 
invite you to take part.  
 
Before you decide if you want to take part please read this information sheet carefully and 
ask any questions you may have.  
 
What is the purpose of the study?  
This is a study to find out about what it is like for young people growing up with HIV, taking 
HIV treatment and being part of ODYSSEY. In particular, we are looking to better understand 
what you discuss about growing up with HIV with healthcare staff and others and what sorts 
of information you would like to have about growing up with HIV. We will do this by talking 
with young people, like you, about their experiences. This is because we think that the best 
way to learn about the experiences and attitudes of young people is to listen carefully to what 
they have to say. This type of research is called a qualitative study.  
 
Why is the study being done?  
Until now there hasn’t been much research done which asks young people themselves about 
their experiences of being in trials and on HIV treatment. This is why we are doing the study. 
By listening to what young people tell us we hope to make some suggestions about how to 
improve support for young people to take their treatment and provide them with information 
that they would find helpful.  
 
Who is doing the study?  
This study is being run in two of the sites, one in Uganda and one in Zimbabwe, where the 
ODYSSEY trial is being conducted. This qualitative study is being done by a small team of 
researchers from Uganda, Zimbabwe and the United Kingdom. We have done similar research 
before in these sites and are experienced in talking with young people.  
 
Why are we asking you?  
We are asking whether you would like to take part in this study because you are participating 
in the ODYSSEY trial and are aged between 10-19 years old.  
 
What would I be asked to do?  
We would like you to meet a researcher for an interview. The interview will be like a 
conversation and will last for about an hour. There are no wrong or right answers. You do not 
have to talk about any topics that you do not want to. You can stop the interview at any time, 
without having to explain why.  
We would like to audio record this interview, if this is OK with you. The interview will take 
place somewhere that you feel comfortable, probably a private place at the clinic.  
  


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What will happen to any information collected about me during this study? 
Any information that you share with us will only be seen by members of the research team. 
This means that whenever we write or talk about anything you have told us we never use 
your real name. All information about you will be stored securely. 
The only exception to this is if you tell us something that makes us worried about you or 
another young person’s safety, such as physical harm or neglect. If we think that we should 
tell someone else, we will talk to you about it first and ask if you would like us to do that.  
 
How will the research be used? 
The findings of this study will be reported to a wide range of people who are involved in 
providing treatment, care and support for children and young people living with HIV. The 
findings will be used to guide the way young people on HIV treatment are supported in the 
future.  
 
What are the benefits and risks of taking part? 
You will be part of a study that aims to help young people live well with HIV and to provide 
them with the information that they need and can understand.  Some young people may find 
the opportunity to talk about their experiences of growing up with HIV to be a really good 
thing.  Some young people though might find it a difficult subject to talk about. The researcher 
will take care to ask questions sensitively. It is up to you what you want to tell us. Also if you 
want there can be someone available from your clinic to talk to if you feel that you want to at 
any point during the study, including after the interview.   
 
Do I have to take part? 
No, you do not have to take part in the study. Your access to the clinic will not be affected in 
anyway if you decide not to take part. It will not affect any of the services that you currently 
receive.   If you do decide to take part but later change your mind this is OK too.   
 
Will I receive anything for taking part? 
Yes, your travel expenses will be covered for the interview. If you are accompanied to the 
interview then your escort’s travel expenses will be covered too.  You will also receive 10,000 
Ugandan shillings or local equivalent. [Uganda- delete as appropriate] 
 
Yes, your travel expenses will be covered for the interview. You will receive US$7 per 
interview or local equivalent. If you are accompanied to the interview then your escort’s 
travel expenses will be covered too.  [Zimbabwe- delete as appropriate] 
 
Can I have some more information before I decide? 
If you would like to find out more before deciding the staff at your clinic can arrange for you 
to speak to one of the researchers more about it.   
 
I’m happy to take part. Now what? 
Once you have signed the assent or consent form and, if you are under 18 years old your carer 
has given their consent, the researcher will contact you and your carer, if necessary, to 
arrange the first interview. 


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Version 6.0 8th November 2019 
ODYSSEY (PENTA 20)    
 
 
 
 
 
 
 
 
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What happens if you have questions? 
If you or the person who takes care of you have any questions, you can contact: xxxxxxxx    
If you cannot access a telephone to call, you can ask xxxxxxxx (a person from your 
clinic/village) to telephone for you so you can ask your question. 
 
Thank you for reading this! 


ODYSSEY Protocol  
Version 6.0 8th November 2019 
ODYSSEY (PENTA 20)    
 
 
 
 
 
 
 
 
Page 158 of 324 
ODYSSEY QUALITATIVE STUDY: 
PARTICIPANT INFORMATION SHEET FOR IN-DEPTH INTERVIEW 10-14 YEAR OLDS (DTG alert) 
(Insert version no and date) 
 
We are doing a study with young people (aged 10-19 years) about their experiences of 
growing up with HIV. We would like you to join our study. 
 
Before you decide if you want to take part we would like you to read the information below 
carefully. Someone can help you read it if that is easier. It is important that you understand 
what we are asking you to do and you should feel comfortable to ask any questions, however 
big or small.  
  
What is the purpose of the study?  
This is a study to find out about what it is like for young people when they are growing up 
with HIV. We are really interested to understand more about what it is like for you and other 
young people to take your HIV treatment every day. We especially want to understand what 
it is like to talk about growing up with HIV and being part of ODYSSEY trial, as well as what 
sorts of information you would like to have about growing up with HIV. We will do this by 
talking with young people. This is because we think that the best way to learn about this is to 
listen carefully to what young people have to say.  
 
Why is the study being done?  
We don’t at the moment know very much about what it is like for young people who are on 
HIV treatment and in a clinical trial.  So we are doing this study so that we can learn more 
about it. This will help us to make suggestions about how to help young people with taking 
their treatment and to have the information that they want to grow up well with HIV.   
 
Who is doing the study?  
This study is being run in Uganda and Zimbabwe. The researchers working on this study are 
from Uganda, Zimbabwe as well as the United Kingdom. We have done lots of work like this 
before.  
 
Why are we asking you?  
We are asking whether you would like to take part in this study because you are already 
talking part in the ODYSSEY trial and are aged between 10-19 years old.  
 
What would I be asked to do?  
We would like you to meet a researcher for an interview.  This will be like a conversation and 
will last for about an hour. There are no wrong or right answers. You do not have to talk about 
anything that you don’t want to and you will not need to say why.   
As we want to listen very carefully to everything that you tell us we would like to audio record 
the interview. We will only record them if you are OK with this.  
The interview will take place somewhere that you feel comfortable. This will probably be at 
the clinic, somewhere private so that no one can overhear what we will be talking about.    
    


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ODYSSEY (PENTA 20)    
 
 
 
 
 
 
 
 
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What will happen to any information collected about me during this study? 
Anything that you tell us will only be listened to by the research team. This means that 
whenever we write or talk about anything you have told us we never use your real name. We 
will be very careful to keep all the information about you locked away so that no one else can 
see it.  
The only exception to this is if you tell us something that makes us worried about you or 
another young person’s safety. If we are concerned and think that we should tell someone 
else, we will talk to you about it first and ask if you would like us to do that.  
 
How will the research be used? 
We will tell lots of people who look after children and young people living with HIV what we 
have learnt from our study.  What we learn will be used to guide the way young people on 
HIV treatment are supported in the future  
 
What are the benefits and risks of taking part? 
You will be part of a study that aims to help young people live well with HIV and to provide 
them with the information that they need and can understand. Some young people may find 
the opportunity to talk about their experiences of growing up with HIV to be a really good 
thing.  Some young people though might find it a difficult subject to talk about. The researcher 
will take care to ask questions thoughtfully. It is up to you what you want to tell us. Also if you 
want there can be someone available from your clinic to talk to if you feel that you want to at 
any point during the study, including after the interview.   
 
Do I have to take part? 
No, you do not have to take part in the study. If you say no, everything that you receive at the 
clinic will be just the same as before.   If you do decide to take part but later change your mind 
this is OK too.   
 
Will I receive anything for taking part? 
Yes, your travel expenses will be covered for the interview. If you are accompanied to the 
interview then the expenses of the person who comes with you will also be covered.  You will 
also receive 10,000 Ugandan shillings or local equivalent. [Uganda- delete as appropriate] 
 
Yes, your travel expenses will be covered for the interview. You will receive US$7 per 
interview or local equivalent. If you are accompanied to the interview then the person who 
comes with you will be covered too.  [Zimbabwe- delete as appropriate] 
 
Can I have some more information before I decide? 
If you would like to find out more before deciding the staff at your clinic can arrange for you 
to speak to one of the researchers more about it.  We will be very happy to answer any of 
your questions.  
 
I’m happy to take part. Now what? 
Once you and your carer have signed the assent or consent form the researcher will contact 
you and your carer to arrange the first interview. 


ODYSSEY Protocol  
Version 6.0 8th November 2019 
ODYSSEY (PENTA 20)    
 
 
 
 
 
 
 
 
Page 160 of 324 
 
What happens if you have questions? 
If you or the person who takes care of you have any questions you can contact: xxxxxxxx  
 If you cannot access a telephone to call, you can ask xxxxxxxx (a person from your 
clinic/village) to telephone for you so you can ask your question. 
  
 
Thank you for reading this! 


ODYSSEY Protocol  
Version 6.0 8th November 2019 
ODYSSEY (PENTA 20)    
 
 
 
 
 
 
 
 
Page 161 of 324 
ODYSSEY QUALITATIVE STUDY: 
PARENT/CARER INFORMATION SHEET FOR IN-DEPTH INTERVIEW (DTG alert) 
(Insert version no and date) 
 
We are doing a study to hear from young people (aged 10-19 years) about their experiences 
of growing up with HIV and being part of a clinical trial. We would like your child to join our 
study. 
Before you decide if you want your child to take part please read this information sheet 
carefully and ask any questions you may have.  
 
What is the purpose of the study?  
This is a study to find out about what it is like for young people growing up with HIV, taking 
HIV treatment and being part of ODYSSEY. In particular, we are looking to better understand 
what information they receive about growing up with HIV, whether they understand the 
information that they are given and their ideas about what forms of information would be 
helpful to them. . This will be done by talking with young people, like your child, about their 
experiences. This is because we think that the best way to learn about the experiences of 
young people is to listen carefully to what they have to say. This type of research is called a 
qualitative study.  
 
Why is the study being done?  
Up until now there hasn’t been much research done which asks young people themselves 
about their experiences of being in a trial, on HIV treatment and what information they want 
about growing up with HIV.  This is why we are doing the study. By listening to what young 
people tell us we hope to make some suggestions about how to improve support for young 
people to take their treatment and to have the information that they want to grow up well 
with HIV.  
 
Who is doing the study?  
This study is being run in two sites where the ODYSSEY trial is being conducted. One is at JCRC 
in Uganda and one is at the University of Zimbabwe in Harare, Zimbabwe. This qualitative 
study is being done by a small team of researchers from Uganda, Zimbabwe and the United 
Kingdom. We have done similar research before in these sites and are experienced in talking 
with young people about similar topics.  
 
Why are we asking your child?  
We are asking whether you are happy for your child to take part in this study because your 
child is already participating in the ODYSSEY trial and is aged between 10-19 years old.  
 
What would my child be asked to do?  
We would like your child to meet with a researcher for an interview. This interview will be like 
a conversation and will last for about an hour. There are no wrong or right answers. Your child 
does not have to talk about anything that they do not want to. Your child can stop the 
interview at any time, without having to explain why.  


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ODYSSEY (PENTA 20)    
 
 
 
 
 
 
 
 
Page 162 of 324 
We would like to audio record this interview, if this is OK with you and your child. The 
interview will take place somewhere that your child feels comfortable, probably at the clinic 
where a private place will be found for them to meet the researcher.    
 
What will happen to any information collected about my child during this study? 
Any information that your child shares with us will only be seen by members of the research 
team. This means that whenever we write or talk about anything your child has told us we 
would never use their real name. All information about your child will be stored securely. 
 
The only exception to this is if your child tells us something that makes us worried about your 
child or another young person’s safety, such as physical harm or neglect. If we think that we 
should tell someone else, we will talk to them about it first and ask if they would like us to do 
that.  
 
How will the research be used? 
The findings of this study will be reported to a wide range of people who are involved in 
providing treatment, care and support for children and young people living with HIV. The 
findings will be used to guide the way young people on HIV treatment are supported in the 
future  
 
What are the benefits and risks of taking part? 
Your child will be part of a study that aims to help young people live well with HIV and to 
provide them with the information that they need and can understand.  . Some young people 
may find the opportunity to talk about their experiences of growing up with HIV to be a really 
good thing.  Some young people though might find it a difficult subject to talk about. The 
researcher will take care to ask questions sensitively. It is up to your child what they want to 
tell us. Also if your child wants there can be someone available from their clinic to talk to if 
they feel that they want to at any point during the study, including after the interview.   
 
Does my child have to take part? 
No, they do not have to take part in the study. Their access to the clinic will not be affected 
in anyway if you or your child decides that you do not want them to take part. It will not affect 
any of the services that they currently receive.   If your child does decide to take part but later 
changes their mind this is OK too.   
 
Will my child receive anything for taking part? 
Yes, their travel expenses will be covered for the interview. If they are accompanied to the 
interview then their escort’s travel expenses will be covered too.  They will also receive 10,000 
Ugandan shillings or local equivalent. [Uganda- delete as appropriate] 
Yes, their travel expenses will be covered for the interview. They will receive US$7 per 
interview or local equivalent. If they are accompanied to the interview then their escort’s 
travel expenses will be covered too.  [Zimbabwe- delete as appropriate] 
 
Can I have some more information before I decide? 
If you would like to find out more before you decide the staff at your clinic can arrange for 
you to speak to one of the researchers more about it.   


ODYSSEY Protocol  
Version 6.0 8th November 2019 
ODYSSEY (PENTA 20)    
 
 
 
 
 
 
 
 
Page 163 of 324 
 
I’m happy for my child to take part. Now what? 
Once you have signed the consent form and, if your child has given their assent, the 
researcher will contact you and your child to arrange the first interview. 
 
What happens if you have questions? 
If you or your child have any questions you can contact: xxxxxxxxx 
If you cannot access a telephone to call, you can ask xxxxxxxx (a person from your 
clinic/village) to telephone for you so you can ask your question. 
 
Thank you for reading this! 
 


ODYSSEY Protocol  
Version 6.0 8th November 2019 
ODYSSEY (PENTA 20)    
 
 
 
 
 
 
 
 
Page 164 of 324 
 
ODYSSEY QUALITATIVE STUDY: 
PARTICIPANT INFORMATION SHEET FOR FOCUS GROUPS 15-19 YEAR OLDS  
(Insert version no and date) 
 
We are doing a study to hear from young people (aged 10-19 years) about their experiences 
of growing up with HIV. We would like you to join our study. 
Before you decide if you want to take part please read this information sheet carefully and 
ask any questions that you may have.  
 
What is the purpose of the study?  
This is a study to find out about what it is like for young people growing up with HIV and taking 
HIV treatment. In particular, we are looking to better understand what it is like to be on HIV 
treatment, what you discuss within the HIV clinic with healthcare staff and others and what 
sorts of information you would like to have about growing up with HIV. This will be done by 
talking with young people, like you, about their experiences. This is because we think that the 
best way to learn about the experiences of young people is to listen carefully to what they 
have to say. This type of research is called a qualitative study.  
 
Why is the study being done?  
Up until now there hasn’t been much research done which asks young people themselves 
about their experiences of being in trials and on HIV treatment. This is why we are doing the 
study. By listening to what young people tell us we hope to make some suggestions about 
how to improve support for young people to take their treatment and in the information that 
they receive.  
 
Who is doing the study?  
This study is being run in two sites in Uganda and Zimbabwe, where the ODYSSEY trial is being 
conducted. This qualitative study is being done by a small team of researchers from Uganda, 
Zimbabwe and the United Kingdom. We have done similar research before in these sites and 
are experienced in talking with young people.  
 
Why are we asking you?  
We are asking whether you would like to take part in this study because you are participating 
in the ODYSSEY trial and are aged between 10-19 years old.  
 
What would I be asked to do?  
We would like to talk to you in a group with other young people who are also on HIV 
treatment and taking part in the ODYSSEY trial. This is called a focus group. We would like you 
to take part in two focus groups.  
 
In each focus group there will be a maximum of 7 other young people present and the 
researcher/s. All the young people will be from the same clinic as you. It will last about an 
hour. We would like to audio record what you say unless you do not want this. You do not 


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have to talk about things that you do not want to talk about, and you can leave the focus 
group at any time and without explaining why. 
 
In the first focus group we will talk as a group about young people’s experience of taking HIV 
treatment, being part of the trial and what it is like to complete some of the trial.   
 
In the second focus group we will talk as a group about what we have learnt so far from our 
research. We are really interested to know what you think about what we have found. We’d 
also like to talk about whether you think that we have correctly understood your situation 
and those of other young people like you. Together we will talk about how we should tell 
other people, such as doctors, the trial teams, and families about what we have learnt and 
the most effective ways to do this.   
 
What will happen to any information collected about me during this study? 
Everyone in the group will be asked to not say anything about what they hear in the focus 
group, except to the researchers or the study counsellors. All the participants are involved in 
the trial and attend the same clinic as you.   
Any information that you share with us will only be seen by members of the research team. 
This means that whenever we write or talk about anything you have told us we never use 
your real name. All information about you will be stored securely. 
The only exception to this is if you tell us something that makes us worried about you or 
another young person’s safety, such as physical harm or neglect. If we have to tell someone 
else, we will talk to you about it first.  
 
How will the research be used? 
The findings of this study will be reported to a wide range of people who are involved in 
providing treatment, care and support for children and young people living with HIV.  The 
findings will be used to guide the way young people on HIV treatment are supported in the 
future. It will also be used to help people who are conducting other HIV treatment trials with 
young people.  
 
What are the benefits and risks of taking part? 
You will be part of a study that aims to help young people to live well with HIV, maintain long 
term adherence and to be given the information that they need and can understand to be 
able to do so. Some young people may find the opportunity to talk about their HIV treatment 
to be a really good thing.  Some young people though might find it difficult to talk about. The 
researchers have done research with young people and will take care to ask questions 
sensitively. It is up to you what you want to tell the group. Also if you want, there can be 
someone available from your clinic to talk to if you feel that you want to at any point during 
the study, including after the focus group.   
 
Do I have to take part? 
No, you do not have to take part in the study. It will not affect any of the services you currently 
receive.   If you do decide to take part but later change your mind this is OK too.   
 
Will I receive anything for taking part? 


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Yes, your travel expenses will be covered for the focus groups. If you are accompanied to the 
focus groups then your escort’s travel expenses will be covered too.  You will also receive 
10,000 Ugandan shillings or local equivalent. [Uganda- delete as appropriate] 
Yes, your travel expenses will be covered for the focus groups. You will receive US$7 per focus 
group or local equivalent. If you are accompanied to the focus group then your escort’s travel 
expenses will be covered too.  [Zimbabwe- delete as appropriate] 
 
Can I have some more information before I decide? 
If you would like to find out more before deciding the staff at your clinic can arrange for you 
to speak to one of the researchers more about it.  We will be very happy to answer any of 
your questions.  
 
I’m happy to take part. Now what? 
Once you have signed the assent or consent form and, if you are under 18 years old your carer 
has given their consent, the researcher will contact you and your carer to arrange the focus 
group. 
 
What happens if you have questions? 
If you or the person who takes care of you have any questions you can contact: xxxxxxx 
 If you cannot access a telephone to call, you can ask xxxxxxxx (a person from your 
clinic/village) to telephone for you so you can ask your question. 
 
Thank you for reading this! If you do decide to take part your help will be very valuable. 
 
 


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ODYSSEY QUALITATIVE STUDY: 
PARTICIPANT INFORMATION SHEET FOR FOCUS GROUPS 10-14 YEAR OLDS  
(Insert version no and date) 
 
We are doing a study to hear from young people (aged 10-19 years) about their experiences 
of growing up with HIV. We would like you to join our study. 
 
Before you decide if you want to take part please read this information sheet carefully. 
Someone can read it to you if that is easier. It is important that you understand what we are 
asking you to do and you should feel comfortable to ask any questions that you have, however 
big or small.  
 
What is the purpose of the study?  
This is a study to find out about what it is like for young people when they are growing up 
with HIV. We are really interested to understand more about what it is like for you and other 
young people to take your HIV treatment every day. We especially want to understand what 
you discuss within the HIV clinic with healthcare staff and others and what sorts of 
information you would like to have about growing up with HIV. We will do this by talking with 
young people, like you, about what it is like. This is because we think that the best way to 
learn about this is to listen carefully to what young people have to say.  
 
Why is the study being done?  
We don’t at the moment know very much about what it is like for young people to take HIV 
treatment well and what kind of information you think that you need to help you. So we are 
doing this study so that we can know more about it. This will help us to make suggestions 
about how to help young people with taking their treatment.  
 
Who is doing the study?  
This study is being run in Uganda and Zimbabwe. The researchers working on this study are 
from Uganda, Zimbabwe as well as the United Kingdom. We have done lots of work like this 
before.  
 
Why are we asking you?  
We are asking whether you would like to take part in this study because you are already 
talking part in the ODYSSEY trial and are aged between 10-19 years old.  
 
What would I be asked to do?  
We would like to talk to you in a group with other young people who are also on HIV 
treatment and taking part in the ODYSSEY trial. This is called a focus group. We would like you 
to take part in two focus groups.  
In each focus group there will be a maximum of 7 other young people present and the 
researcher/s. All the young people will be from the same clinic as you. It will last about an 
hour. We would like to audio record what you say unless you do not want this. You do not 
have to talk about things that you do not want to talk about, and you can leave the focus 
group at any time and without explaining why. 


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In the first focus group we will talk as a group about what it is like to take HIV treatment. We 
will also talk about how everyone in the group has found being part of the ODYSSEY trial, 
including filling in some of the trial’s questionnaires.  
 
In the second focus group we will talk as a group about what we have learnt so far from our 
research. We are really interested to know what you think about what we have found. 
Together we will talk about how we should tell other people, such as doctors, about what we 
have learnt from our study.   
 
What will happen to any information collected about me during this study?  
Everyone in the group will be asked to not say anything about what they hear in the focus 
group, except to the researchers or the study counsellors. All the participants are involved in 
the trial and attend the same clinic as you.   
 
Any information that you share with us will only be seen by members of the research team. 
This means that whenever we write or talk about anything you have told us we never use 
your real name. We will be very careful to keep all the information about you locked away so 
that no one else can see it.  
 
The only exception to this is if you tell us something that makes us worried about you or 
another young person’s safety. If we are concerned and think that we should tell someone 
else, we will talk to you about it first and ask if you would like us to do that.  
 
How will the research be used? 
We will tell lots of people who look after children and young people living with HIV about 
what we have learnt from our study.  This will be used to guide the way young people on 
second-line HIV treatment are supported in the future.  
 
What are the benefits and risks of taking part? 
You will be part of a study that aims to help young people live well with HIV and to be given 
the information that they need and can understand to be able to do so . Some young people 
may find the opportunity to talk about their experiences of growing up with HIV to be a really 
good thing.  Some young people though might find it a difficult subject to talk about. The 
researcher will take care to ask questions thoughtfully. It is up to you what you want to tell 
the group. Also if you want there can be someone available from your clinic to talk to if you 
feel that you want to at any point during the study, including after the interview.   
 
Do I have to take part? 
No, you do not have to take part in the study. If you say no, everything that you receive at the 
clinic will be just the same as before.   If you do decide to take part but later change your mind 
this is OK too.   
 
Will I receive anything for taking part? 
Yes, your travel expenses will be covered for the focus groups. If you are accompanied to the 
focus groups then the expenses of the person who comes with you will also be covered.  You 
will also receive 10,000 Ugandan shillings or local equivalent. [Uganda- delete as appropriate] 


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Yes, your travel expenses will be covered for the focus groups. You will receive US$7 per focus 
group or local equivalent. If you are accompanied to the focus group then the person who 
comes with you will be covered too.  [Zimbabwe- delete as appropriate] 
 
Can I have some more information before I decide? 
If you would like to find out more before deciding the staff at your clinic can arrange for you 
to speak to one of the researchers more about it.  We will be very happy to answer any of 
your questions. 
  
I’m happy to take part. Now what? 
Once you have signed the assent or consent form and, if you are under 18 years old your carer 
has given their consent, the researcher will contact you and your carer to arrange the focus 
group. 
 
What happens if you have questions? 
If you or the person who takes care of you have any questions you can contact: xxxxxx 
 If you cannot access a telephone to call, you can ask xxxxxxxx (a person from your 
clinic/village) to telephone for you so you can ask your question. 
 
 
 
 


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ODYSSEY QUALITATIVE STUDY: 
PARENT/CARER INFORMATION SHEET FOR FOCUS GROUPS  
(Insert version no and date) 
 
We are doing a study to hear from young people (aged 10-19 years) about their experiences 
of growing up with HIV. We would like your child to join our study. 
Before you decide if you want your child to take part please read this information sheet 
carefully and ask any questions you may have.  
 
What is the purpose of the study?  
This is a study to find out about what it is like for young people growing up with HIV and taking 
HIV treatment. In particular, we are looking to better understand what they discuss within 
the HIV clinic with healthcare staff and others and what sorts of information they would like 
to have about growing up with HIV. This will be done by talking with young people, like your 
child, about their experiences. This is because we think that the best way to learn about the 
experiences of young people is to listen carefully to what they have to say. This type of 
research is called a qualitative study.  
 
Why is the study being done?  
Up until now there hasn’t been much research done which asks young people themselves 
about their experiences of growing up with HIV and the information that they think might 
help them. This is why we are doing the study. By listening to what young people tell us we 
hope to make some suggestions about how to improve support for young people.  
 
Who is doing the study?  
This study is being run in two sites where the ODYSSEY trial is being conducted. One is at JCRC 
in Uganda and one is at University of Zimbabwe in Harare, Zimbabwe. This qualitative study 
is being done by a small team of researchers from Uganda, Zimbabwe and the United 
Kingdom. We have done similar research before in these sites and are experienced in talking 
with young people.  
 
Why are we asking your child to take part?  
We are asking whether you would like your child to take part in this study because your child 
is participating in the ODYSSEY trial and are aged between 10-19 years old.  
 
What would my child be asked to do?  
We would like to talk to your child in a group with other young people who are also on HIV 
treatment and taking part in the ODYSSEY trial. This is called a focus group. We would like 
your child to take part in two focus groups.  
In each focus group there will be a maximum of 7 other young people present and the 
researcher/s. All the young people will be from the same clinic as your child. It will last about 
an hour. We would like to audio record what your child and the other young people say unless 
you or your child do not want this. Your child does not have to talk about things that they do 
not want to talk about, and your child can leave the focus group at any time and without 
explaining why. 


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In the first focus group we will talk as a group about young people’s experience of taking HIV 
treatment, being part of the trial and what it is like to complete the some of the trial 
questionnaires.   
In the second focus group we will talk as a group about what we have learnt so far from our 
research. We are really interested to know what your child thinks about what we have found. 
Together we will talk about how we should tell other people, such as doctors, the trial teams, 
and families about what we have learnt and the most effective ways to do this.   
 
What will happen to any information collected about my child during this study?  
Everyone in the group will be asked not to say anything about what they hear in the focus 
group, except to the researchers or the study counsellors. All the participants are involved in 
the trial and attend the same clinic as your child.   
 
Any information that your child shares with us will only be seen by members of the research 
team. This means that whenever we write or talk about anything your child has told us we 
will never use their real name. All information about your child will be stored securely. 
 
The only exception to this is if your child tells us something that makes us worried about them 
or another young person’s safety, such as physical harm or neglect. If we have to tell someone 
else, we will talk to your child about it first.  
 
How will the research be used? 
The findings of this study will be reported to a wide range of people who are involved in 
providing treatment, care and support for children and young people living with HIV.  The 
findings will be used to guide the way young people on HIV treatment are supported in the 
future. It will also be used to help people who are conducting other HIV treatment trials with 
young people.  
 
What are the benefits and risks of taking part? 
Your child will be part of a study that aims to help young people maintain long term adherence 
to second-line treatment. Some young people may find the opportunity to talk about their 
HIV treatment to be a really good thing.  Some young people though might find it difficult to 
talk about. The researchers have done research with young people and will take care to ask 
questions sensitively. It is up to your child what they want to tell us. Also if your child wants, 
there can be someone available from their clinic to talk to if they feel that they want to at any 
point during the study, including after the focus group.   
 
Does my child have to take part? 
No, your child does not have to take part in the study. It will not affect any of the services that 
they currently receive.  If your child does decide to take part but later changes their mind this 
is OK too. 
   
Will my child receive anything for taking part? 
Yes, your child’s travel expenses will be covered for the focus groups. If they are accompanied 
to the focus groups then the expenses of the person who comes with your child will also be 
covered.  They will also receive 10,000 Ugandan shillings or local equivalent. [Uganda- delete 
as appropriate] 


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Yes, their travel expenses will be covered for the focus groups. They will receive US$7 per 
focus group or local equivalent. If your child is accompanied to the focus group then the 
person who comes with them will be covered too.  [Zimbabwe- delete as appropriate] 
 
Can I have some more information before I decide? 
If you would like to find out more before deciding the staff at your clinic can arrange for you 
to speak to one of the researchers more about it.  We will be very happy to answer any of 
your questions.  
 
I’m happy for my child to take part. Now what? 
Once you have signed the assent or consent form and, if you are under 18 years old your carer 
has given their consent, the researcher will contact you and your carer to arrange the focus 
group. 
 
What happens if you have questions? 
If you or your child have any questions you can contact: xxxxxxxx 
If you cannot access a telephone to call, you can ask xxxxxxxx (a person from your 
clinic/village) to telephone for you so you can ask your question. 
 
Thank you for reading this! If you do decide to take part your help will be very valuable. 
 


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INFORMATION SHEETS FOR YOUTH TRIAL BOARD SUBSTUDY  
 
 Information sheets -  young people  
 Information sheets - parents/ guardian 
 Information sheets – YTB facilitators 
 
 
 


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YOUTH TRIAL BOARD  
PARTICIPANT INFORMATION SHEET FOR YOUNG PEOPLE  
(Insert version no and date) 
 
What is a clinical trial? 
Clinical trials see how well new medication works or whether medication can be given in 
different ways. They last for a few years and 100s of patients are involved with scientists 
watching them closely to look at what happens. The aim of most clinical trials is that the 
findings (‘findings’ are all the things the scientists see) may lead to better health care. 
Lots of children and young people living with HIV are part of clinical trials but, until now, they 
have had very few opportunities to say how they think a clinical trial is run, explain its findings 
to other children and young people and how the findings are shown publicly. 
What is a Youth Trial Board (YTB)? 
We are running a project in partnership with ODYSSEY - a new clinical trial - to set up four 
YTBs. A YTB will be a group of up to 8 young people living with HIV who come together 3-4 
times a year and learn about clinical trials, have a say on how they are run and help produce 
information for children, young people and the public about what the trial findings are.  
The aim of each YTB is: 
1) to give a voice to the children and young people involved in the trial, 
2) to improve the experience for those children and young people taking part, so they 
understand what they are taking part in and what the trial finds out. 
 
This is a pilot project, which means no one has tried to do this before. It means that although 
there will be certain things a YTB must do, we will be working out how they run as we go along 
and you will have a say in this. We have different countries involved in this pilot, so we can 
see how YTBs work in different settings. 
Helping design YTBs 
If you become a member of a YTB, we will keep asking you about what it’s like and how you 
think it could be made better. We will do this at each meeting and at the end of the whole 
project. We would also like to have an interview with you to chat about what it is like being a 
YTB member, what works well and what could be done better. We will use the things all the 
YTB members tell us and what we learn from running YTBs for two years to make a toolkit. 
This toolkit will tell others about what we have learnt and how to set up their own YTBs. 
Before you decide whether you want to be involved, it is important that you understand what 
we are doing and what being involved will mean. Please read this information sheet carefully 
and ask any questions you may have.  
Thank you! 


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What are we asking you to do?  
Being a YTB member means you need to come to YTB meetings. These meetings will be with 
up to 7 other young people living with HIV from your country aged 15-19 years old and up to 
3 adult facilitators.  
We would like to have an interview with you about what it is like being part of a YTB. This 
interview will be like a conversation and will last for about an hour. It will be a conversation 
between you and the researcher. There are no wrong or right answers. You do not have to 
talk about any topics that you do not want to. You can stop the interview at any time, without 
having to explain why.  
 
We would like to audio record these interviews, if this is OK with you. The interview will take 
place somewhere that you feel comfortable 
 
What will happen at YTB meetings? 
At a YTB meeting you and the other YTB members will:  
 Learn about trials and how they work 
 Work out ways to ask other children and young people who are on the trial about their 
experiences 
 Learn about how to be an advocate (an advocate is someone that speaks for other 
people) and then do this at meetings with people who run clinical trials 
 Be creative and involved in designing ways to get messages about the trial to the 
children and young people who are part of it 
 Decide what is important and how you are going to tell this to either the people 
running the trial or to children on the trial 
 Help to design how YTBs can work well in the future 
 
Why are we asking you?  
We are asking you to think about whether you would like to be involved because you are aged 
between 15-19 years of age.  
 
Learning from you 
If you decide that you would like to take part in a YTB, it is very important that we learn from 
you and the other YTB members. We will have activities, games and also time to talk in an 
individual interview, where you will be asked about the best and the worst things about being 
a member of a YTB. We want to know your ideas and opinions. We call these ‘reflections’ 
because you will be telling us about what you feel and think. 


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Examples of what we would be writing down include what YTB members think works or 
doesn’t work in a YTB and in a clinical trial and what you would like the people running the 
trial to understand about what it’s like to be a young person living with HIV who is taking part 
in a clinical trial.  
You will be asked at the start of being a YTB member to agree for us to use your reflections, 
we call this ‘giving consent’.  If you change your mind, you can take your consent away. We 
will not be angry with you and want to support you to feel happy and comfortable. You are 
able to stop taking part in the study at any time.  You have control over all of this and it’s fully 
your decision.  
 
What will we do with all the information from the YTB meetings and interviews?  
We would like to use this information to help us design the YTB model. What all YTB members 
say in their reflections and interviews will be written down and what you say will help us build 
a YTB model which can be used in other clinical trials so that young people feel really listened 
to and are able to change things. These reflections will also be used as part of the guidance 
we will write on how to set up YTBs in all countries.  
Will what I say be confidential?  
None of what we see, hear and write down will be linked back to you. Everything will be 
anonymised, which means it won’t have your name so that someone could link it back to you. 
Anything that does have information that we can link back to you will just be seen by members 
of the project team. This means that whenever we write or talk about anything you have told 
us, we never use your real name. All information about you will be stored securely. 
What are the benefits and risks of being involved?  
You will be part of a project that aims to develop a way to meaningfully involve young people 
in how trials are run. The overall goal of YTBs is to improve the experiences of children and 
young people participating in trials and this project is an early step in achieving this goal. There 
are no risks to you in being involved.  
Do I have to take part?  
NO, you do not have to take part. If you prefer to not take part, that is absolutely OK. Saying 
no will also not affect any of the services that you receive. If you decide to take part but later 
change your mind this is OK too. 
    
    


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YOUTH TRIAL BOARD  
PARENT/CARER INFORMATION SHEET   
(Insert version no and date) 
What is a clinical trial? 
Clinical trials see how well new medication works or whether medication can be given in 
different ways. They can last for a few years and often 100s of patients are involved with 
scientists watching them closely to look at what happens. The aim of most clinical trials is that 
the findings (‘findings’ is all the things the scientists see) may lead to better health care. 
Lots of children and young people living with HIV are part of clinical trials but, until now, they 
have had very few opportunities to say how they think a clinical trial is run, explain its findings 
to other children and young people and how the findings are shown publicly. 
What is a Youth Trial Board (YTB)? 
We are running a project in partnership with ODYSSEY - a new clinical trial - to set up four 
YTBs. A YTB will be a group of up to 8 young people living with HIV who come together 3-4 
times a year and learn about clinical trials, have a say on how they are run and help produce 
information for children, young people and the public about what the trial findings are.  
The aim of each YTB is: 
1) to give a voice to the children and young people involved in the trial, 
2) to improve the experience for those children and young people taking part, so they 
understand what they are taking part in and what the trial finds out. 
This is a pilot project, which means no one has tried to do this before. It means that although 
there will be certain things a YTB must do, we will be working out how they run as we go along 
and you will have a say in this. We have different countries involved in this pilot, so we can 
see how this works in different settings. 
 
Helping design YTBs 
If your child becomes a member of a YTB, we will be asking them about what it’s like and how 
they think it could be made better throughout the project. We will do this at each meeting 
and at the end of the project. We would also like to have an interview with your child to speak 
with them about what it is like being a YTB member, what works well and what could be 
improved. We will use the things all the YTB members tell us and what we learn from running 
YTBs for two years to make a toolkit. This toolkit will tell others about what we have learnt 
and how to set up their own YTBs. 
Before you decide whether you want your child to be involved, it is important that you 
understand what we are doing and what being involved will mean. Please read this 
information sheet carefully and ask any questions you may have.  


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Thank you! 
What are we asking your child to do?  
Being a YTB member means your child needs to come to YTB meetings. These meetings will 
be with up to 7 other young people aged 15-19 years old from your country living with HIV 
and up to 3 adult facilitators.  
We would like to have an interview with your child about what it is like for them being part 
of a YTB. This interview will be like a conversation and will last for about an hour. It will be a 
conversation between your child and the researcher. There are no wrong or right answers. 
Your child does not have to talk about any topics that they do not want to. Your child can stop 
the interview at any time, without having to explain why.  
 
We would like to audio record these interviews, if this is OK with you and your child. The 
interview will take place somewhere that your child feels comfortable. 
What will happen at YTB meetings? 
At a YTB meeting your child and the other YTB members will:  
 Learn about trials and how they work 
 Work out ways to ask other children and young people who are on the trial about their 
experiences 
 Learn about how to be an advocate – so someone that speaks for other people – and 
then do this at meetings with people who run clinical trials 
 Be creative and design ways to get messages about the trial to the children and young 
people who are part of it 
 Decide what is important and how you are going to tell this to either the people 
running the trial or to children on the trial 
 Help to design how YTBs can work well in the future 
 
Why are we asking your child?  
We are asking you to think about whether you would like your child to be involved because 
they are aged between 15-19 years of age.  
Learning from your child 
If you and your child decide that you would like them to take part, it is very important that 
we learn from your child and the other YTB members. We will have activities, games and also 
time to talk in an individual interview, where they will be asked about the best and the worst 
things about being a member of a YTB. We want to know their ideas and opinions. We call 
these ‘reflections’ because they will be telling us about what they feel and think. 
Examples of what we would be writing down include what YTB members think works or 
doesn’t work in a YTB and in a clinical trial and what they would like the people running the 
trial to understand about what it’s like to be a young person living with HIV who is taking part 
in a clinical trial.  


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Your child will be asked at the start of being a YTB member to agree for us to use their 
reflections, we call this ‘giving consent’.  If they change their mind, they can take their consent 
away. We will not be angry with them and want to support them to feel happy and 
comfortable.  You and your child have control over all of this and it’s important to us that you 
know that.  
What will we do with all the information from the YTB meetings?  
We would like to use this information to help us design the YTB model. What all YTB members 
say in their reflections and interviews will be written down and what your child says will help 
us build a YTB model where young people feel really listened to and are able to change things. 
These reflections will also be used as part of the guidance we will write on how to set up YTBs 
in all countries.  
Will what my child says be confidential?  
None of what we see, hear and write down will be linked back to your child. Everything will 
be anonymised, which means it won’t have their name so that someone could link it back to 
them. Anything that does have information that we can link back to them will just be seen by 
members of the project team. This means that whenever we write or talk about anything they 
have told us, we never use their real name. All information about them will be stored securely. 
What are the benefits and risks of being involved?  
Your child will be part of a project that aims to develop a way to meaningfully involve young 
people in how trials are run. The overall goal of YTBs is to improve the experiences of children 
and young people participating in trials and this project is an early step in achieving this goal. 
There are no risks to your child in being involved.  
Does my child have to take part?  
NO, your child does not have to take part. If you prefer for your child not to take part, that is 
absolutely OK. Saying no will also not affect any of the services that your child receives. If 
your child decides to take part but later changes their mind this is OK too. 
 
 
 
 


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YOUTH TRIAL BOARD  
YTB FACILITATOR INFORMATION SHEET   
(Insert version no and date) 
What is a Youth Trial Board (YTB)? 
We are running a project in partnership with ODYSSEY - a new clinical trial - to set up four 
YTBs. A YTB will be a group of up to 8 young people living with HIV who come together 3-4 
times a year and learn about clinical trials, have a say on how they are run and help produce 
information for children, young people and the public about what the trial findings are.  
The aim of each YTB is: 
1) to give a voice to the children and young people involved in the trial, 
2) to improve the experience for those children and young people taking part, so they 
understand what they are taking part in and what the trial finds out. 
This is a pilot project, which means no one has tried to do this before. It means that although 
there will be certain things a YTB must do, we will be working out how they run as we go along 
and you will have a say in this. We have different countries involved in this YTB pilot project, 
so we can see how this works in different settings. 
 
Helping design YTBs 
We are in the process of conducting the pilot of the YTBs in four countries and are looking to 
understand the experiences of those who have been taking part and/ or running the YTBs. 
We will be asking YTB participants and facilitators about their experiences of what it has been 
like being involved and how they think the design and delivery of the YTB project would be 
improved. We will do this by conducting individual interviews with participants and 
facilitators to understand their experiences and learn from their ideas and opinions. We will 
use the information that we learn to improve the YTB model and then to make a YTB toolkit. 
This toolkit will tell others about what we have learnt and how to set up their own YTBs. 
Before you decide whether you want to be involved, it is important that you understand what 
we are doing and what being involved will mean. Please read this information sheet carefully 
and ask any questions you may have.  
Thank you! 
What are we asking you to do?  
We would like to have an interview with you about what it is like being part of a YTB as a 
facilitator. This interview will be like a conversation and will last for about an hour. It will be 
a conversation between you and the researcher. There are no wrong or right answers. You do 
not have to talk about any topics that you do not want to. You can stop the interview at any 
time, without having to explain why.  
 


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We would like to audio record these interviews, if this is OK with you. The interview will take 
place somewhere that you feel comfortable. 
Why are we asking you?  
We are asking you to think about whether you would like to be involved because you have 
taken part in the YTB pilot project by being a facilitator. Understanding more about your 
experience of doing so will be valuable to us in designing the YTB toolkit.  
Learning from you 
If you decide that you would like them to take part, we would like to talk to you in an individual 
interview about your experiences of facilitating a YTB, what works well and what could be 
improved, as well as the training needs of facilitators.    
What will we do with all the information?  
We would like to use this information from you, the other facilitators and participants to help 
us design the YTB model and will be used as part of the guidance we will write on how to set 
up YTBs in all countries.  
Will what I say be confidential?  
None of what you tell us in your interview will be linked back to you. This means that 
whenever we write or talk about anything you have told us, we will never use your real name. 
All information about you will be stored securely. 
What are the benefits and risks of being involved?  
You are part of project that aims to develop a way to meaningfully involve young people in 
how trials are run. The overall goal of YTBs is to improve the experiences of children and 
young people participating in trials and this project is an early step in achieving this goal. We 
would like to understand how we can learn from the experiences of those involved in the pilot 
YTBs and how we can improve the YTB model in the future. There are no risks to you in being 
involved.  
Do I have to take part?  
NO, you do not have to take part. If you prefer not to take part, that is absolutely OK.  
 


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20 APPENDIX II TEMPLATE CONSENT AND ASSENT FORMS  
PARENT/CARER – MAIN STUDY CONSENT TO SCREENING  
(To be printed on local-headed paper) 
(Insert version no and date) 
 
ODYSSEY:  A randomised trial of dolutegravir (DTG)-based antiretroviral therapy vs. standard of 
care (SOC) in children with HIV infection starting first-line or switching to second-line antiretroviral 
therapy. 
 
 
 
 
 
 
Please initial (or mark) box if you agree: 
I have read/been read the information sheet (version ____, dated __________) 
for the ODYSSEY study.  
 
I agree to my child being assessed to see whether he/she is eligible to take part 
in this study. 
 
I understand this will involve my child being seen by the doctor who will ask 
questions about my child’s health, and my child having some blood taken for 
testing. 
 
I agree that the results of these tests and an additional blood sample can be 
kept by the ODYSSEY team for further tests if my child starts the study. I 
understand that these results and samples will not be identified by either my or 
my child’s name. 
 
I understand that if my child cannot participate in the study, the stored blood 
sample will be discarded and not used for further tests.   
 
 
Parent/carer’s signature 
(or thumbprint) 
Print name 
Date  
 
 
 
Witness’ signature 
(if thumbprint above) 
Print name 
Date 
 
 
 
 
I have provided the ODYSSEY study information to the potential participant’s parent/legal guardian 
in full and answered all his/her questions. To the best of my knowledge, he/she understands the 
purpose, interventions, risks and benefits of this study and willingly agrees for his/her child to be 
screened for the ODYSSEY study.  
Signature of person 
conducting the informed 
consent process 
Print name 
Date 
 
 
IMPORTANT:  one signed original to be kept in ODYSSEY trial file by the researcher 
 
 
 
one signed copy to be given to the parent/carer 
 
 
 
one signed copy to be kept in the clinic file 
Study number: 
Anonymous code: 


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Page 183 of 324 
PARENT/CARER – MAIN STUDY CONSENT TO RANDOMISATION 
 (To be printed on local-headed paper) 
(Insert version no and date) 
 
ODYSSEY: A randomised trial of dolutegravir (DTG)-based antiretroviral therapy vs. standard of 
care (SOC) in children with HIV infection starting first-line or switching to second-line antiretroviral 
therapy. 
 
 
 
 
 
 
 
 
Please initial (or mark) box if you agree: 
I have read/been read the information sheet (version ____, dated __________) for 
the ODYSSEY study and I understand what will be required if my child participates in 
the study.  
 
 
The study has been explained to me and all my questions have been answered. 
 
 
I understand that my child’s participation is voluntary and that I am free to withdraw 
him or her at any time, without giving any reason, without my medical care or legal 
rights or my child’s medical care or legal rights being affected. 
 
 
I agree to inform the study doctor if my child starts any other new medicine during 
the period of the study. 
 
 
I understand that clinical information may be reviewed by properly authorised 
individuals as part of the study and that such information will be treated as strictly 
confidential. 
 
I agree to allow blood samples to be taken from my child and for my child’s samples 
to be stored for later testing. I understand that these results and samples will not be 
identified by either my or my child’s name and that I may not be given the results of 
tests performed on stored samples. 
 
 
I agree to routine blood results and clinical information being included anonymously 
in continued follow-up after the study has ended (identified only by study number 
and date of birth). 
 
I agree to UCL collecting information about my child from my child’s clinic for this 
research study. This data may be used by UCL and other authorised research 
collaborators to conduct the trial and associated sub-studies 
 
I agree to anonymised study data being transferred to ViiV Healthcare, and to drug 
agencies in other countries. 
 
I agree for my child to participate in the ODYSSEY study  
 
 
 
 
Parent/carer’s signature 
(or thumbprint) 
Print name 
Date 
 
 
 
Witness’ signature  
(if thumbprint above) 
Print name 
Date 
 
 
 
Please turn over the page 
 
Study number: 
Anonymous code: 


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Page 184 of 324 
I have provided the ODYSSEY study information to the participant’s parent/legal guardian in full and 
answered all his/her questions. To the best of my knowledge, he/she understands the purpose, 
interventions, risks and benefits of this study and willingly agrees for his/her child to be enrolled 
into the ODYSSEY study.  
Signature of person 
conducting the informed 
consent process 
Print name 
Date  
 
 
 
I would/would not (please circle) like my child’s GP to be notified about participation in this study. 
 
Signature of Parent/Guardian:______________________________Date:____________ 
 
Name of GP: 
 
 
 
 
 
Contact address of GP: __________________________________________________ 
 
IMPORTANT:  one signed original to be kept in ODYSSEY trial file by the researcher 
 
 
 
one signed copy to be given to the parent/carer 
 
 
 
one signed copy to be kept in the clinic file 
 
 
 
 


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Page 185 of 324 
PARTICIPANT –MAIN STUDY ASSENT TO SCREENING  
(To be printed on local-headed paper)  
 
 
Please tick yes or no to the questions below 
1. Have you read (or had read to you) the information about this study? 
YES   NO  
2. Do you understand that your doctor will check how you are and do some tests on your 
blood to see if you can join the study? 
YES   NO  
 
3. Do you agree that if you start the study your blood samples (without your name on) can 
be used during the study and stored for studies which will help us understand more about 
the virus? (If you don’t start the study, we won’t use your blood samples) 
YES   NO  
 
4. Are you happy to be assessed to see whether you can take part in this study?  
 
YES   NO  
 
 
If any answers are ‘no’ or you don’t want to take part, don’t sign your name. 
If you do want to take part, please sign your name below. 
 
Participant’s signature 
(or thumbprint) 
Print name 
Date 
 
 
 
Witness’ signature 
(if thumbprint used above) 
Print name 
Date 
 
 
 
The person who explained the study to you needs to sign too: 
 
I have provided the ODYSSEY study information to the potential participant in full and answered all 
his/her questions. To the best of my knowledge, he/she understands the purpose, interventions, 
risks and benefits of this study and willingly agrees to be screened for the ODYSSEY study.  
Signature of person 
conducting the informed 
consent process 
Print name 
Date  
 
 
 
IMPORTANT:  one signed original to be kept in ODYSSEY trial file by the researcher 
 
 
 
one signed copy to be given to the participant  
 
 
one signed copy to be kept in the clinic file 
 
 
ODYSSEY –  A randomised trial of dolutegravir (DTG)-based antiretroviral therapy vs. standard of care 
(SOC) in children with HIV infection starting first-line or switching to second-line ART. 
 
Study number: 
Anonymous code: 


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Version 6.0 8th November 2019 
ODYSSEY (PENTA 20)    
 
 
 
 
 
 
 
 
Page 186 of 324 
PARTICIPANT- MAIN STUDY ASSENT TO RANDOMISATION 
(To be printed on local-headed paper) 
(Insert version no and date) 
 
ODYSSEY: A randomised trial of dolutegravir (DTG)-based antiretroviral therapy vs. standard of 
care (SOC) in children with HIV infection starting first-line or switching to second-line ART. 
 
Please tick yes or no to the questions below 
1. Have you read (or had read to you) the information about this study? 
YES   NO  
 
2. Has somebody explained the study to you?  
YES   NO  
 
3. Do you understand what the study is about? 
YES   NO  
 
4. Have you asked all the questions you want? 
YES   NO  
 
5. Have your questions been answered in a way you understand? 
 
YES   NO  
 
6. Do you understand how the study might help you? 
 
 
YES   NO  
 
7. Do you understand the risks of taking part? 
 
 
 
YES   NO  
 
8. Do you understand it’s OK to stop taking part in the study at any time? 
 
YES   NO  
 
9. Do you understand that you cannot choose the group you will be in? 
 
YES   NO  
 
10. Are you happy to take part?  
 
YES   NO  
 
 
If any answers are ‘no’ or you don’t want to take part, don’t sign your name. 
If you do want to take part, you can sign your name below. 
 
Participant’s signature 
(or thumbprint) 
Print name 
Date 
 
 
 
Witness’ signature 
(if thumbprint used above) 
Print name 
Date 
 
 
Please turn over the page 
The person who explained the study to you needs to sign too: 
 
Study number: 
Anonymous code: 


ODYSSEY Protocol  
Version 6.0 8th November 2019 
ODYSSEY (PENTA 20)    
 
 
 
 
 
 
 
 
Page 187 of 324 
I have provided the ODYSSEY study information to the participant in full and answered all his/her 
questions. To the best of my knowledge, he/she understands the purpose, interventions, risks and 
benefits of this study and willingly agrees to be enrolled into the ODYSSEY study.  
Signature of person 
conducting the informed 
consent process 
Print name 
Date  
 
 
 
IMPORTANT:  one signed original to be kept in ODYSSEY trial file by the researcher 
 
 
 
one signed copy to be given to the participant  
 
 
one signed copy to be kept in the clinic file 
 


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Version 6.0 8th November 2019 
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Page 188 of 324 
PARTICIPANT – MAIN STUDY CONSENT TO CONTINUED PARTICIPATION FOR YOUNG 
PEOPLE WHO REACH THE AGE OF CONSENT WHILST IN THE TRIAL 
(To be printed on local-headed paper) 
(Insert version no and date) 
 
ODYSSEY: A randomised trial of dolutegravir (DTG)-based antiretroviral therapy vs. standard of 
care (SOC) in children with HIV infection starting first-line or switching to second-line ART. 
 
 
 
 
 
 
 
 
Please initial (or mark) box if you agree: 
I have read/been read the information sheet (version ____, dated __________) for the 
ODYSSEY study and I understand what will be required if I continue to participate in the 
study.  
 
 
The study has been explained to me and my questions have been answered. 
 
 
 
I understand that my participation is voluntary and that I am free to withdraw at any 
time, without giving any reason, and without my medical care or legal rights being 
affected. 
 
I agree to inform the study doctor if I start any other new medicines during the period 
of the study. 
 
 
I understand that clinical information may be reviewed by properly authorised 
individuals as part of the study and that such information will be treated as strictly 
confidential. 
 
I agree to allow blood samples to be taken and stored for later testing. I understand 
that these results and samples will not be identified by my name and that I may not be 
given the results of tests performed on stored samples.  
 
I agree to routine blood results and clinical information being included anonymously in 
continued follow-up after the study has ended (identified only by study number and 
date of birth). 
 
I agree to UCL collecting information about me from my clinic for this research study. 
This data may be used by UCL and other authorised research collaborators to conduct 
the trial and associated sub-studies. 
 
I agree to anonymised study data being transferred to ViiV Healthcare, and to drug 
agencies in other countries. 
 
 
I agree to take part in the ODYSSEY study  
 
 
 
 
Participant’s signature 
(or thumbprint) 
Print name 
Date 
 
 
 
Witness’ signature  
(if thumbprint above) 
Print name 
Date 
 
 
Please turn over the page 
Study number: 
Anonymous code: 
Study number: 
Anonymous code: 


ODYSSEY Protocol  
Version 6.0 8th November 2019 
ODYSSEY (PENTA 20)    
 
 
 
 
 
 
 
 
Page 189 of 324 
 
I have provided the ODYSSEY study information to the participant in full and answered all his/her 
questions. To the best of my knowledge, he/she understands the purpose, interventions, risks and 
benefits of this study and willingly agrees to continue to participate in the ODYSSEY study. 
Signature of person 
conducting the informed 
consent process 
Print name 
Date 
 
 
 
 
IMPORTANT:  one signed original to be kept in ODYSSEY trial file by the researcher 
 
 
 
one signed copy to be given to the participant  
 
 
one signed copy to be kept in the clinic file 
 
 


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Version 6.0 8th November 2019 
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Page 190 of 324 
PARENT/CARER – RE-CONSENT TO THE ODYSSEY TRIAL 
 (To be printed on local-headed paper) 
(Insert version no and date) 
 
 
ODYSSEY: A randomised trial of dolutegravir (DTG)-based antiretroviral therapy vs. standard of 
care (SOC) in children with HIV infection starting first-line or switching to second-line antiretroviral 
therapy. 
 
 
 
 
 
 
 
 
Please initial (or mark) box if you agree: 
I have read/been read the information sheet (version ____, dated __________) for 
the ODYSSEY study and I understand what will be required if my child participates in 
the study.  
 
 
The study has been explained to me and all my questions have been answered. 
 
 
I understand that my child’s participation is voluntary and that I am free to withdraw 
him or her at any time, without giving any reason, without my medical care or legal 
rights or my child’s medical care or legal rights being affected. 
 
 
I agree to inform the study doctor if my child starts any other new medicine during 
the period of the study. 
 
 
I understand that clinical information may be reviewed by properly authorised 
individuals as part of the study and that such information will be treated as strictly 
confidential. 
 
I agree to allow blood samples to be taken from my child and for my child’s samples 
to be stored for later testing. I understand that these results and samples will not be 
identified by either my or my child’s name and that I may not be given the results of 
tests performed on stored samples. 
 
I agree to routine blood results and clinical information being included anonymously 
in continued follow-up after the study has ended (identified only by study number 
and date of birth). 
 
I agree to UCL collecting information about my child from my child’s clinic for this 
research study. This data may be used by UCL and other authorised research 
collaborators to conduct the trial and associated sub-studies  
 
I agree to anonymised study data being transferred to ViiV Healthcare, and to drug 
agencies in other countries. 
 
I agree for my child to continue to participate in the ODYSSEY study  
 
 
Parent/carer’s signature 
(or thumbprint) 
Print name 
Date 
 
 
 
Witness’ signature  
(if thumbprint above) 
Print name 
Date 
 
 
 
Please turn over the page 
Study number: 
Anonymous code: 


ODYSSEY Protocol  
Version 6.0 8th November 2019 
ODYSSEY (PENTA 20)    
 
 
 
 
 
 
 
 
Page 191 of 324 
 
I have provided the ODYSSEY study information to the participant’s parent/legal guardian in full and 
answered all his/her questions. To the best of my knowledge, he/she understands the purpose, 
interventions, risks and benefits of this study and willingly agrees for his/her child to be enrolled 
into the ODYSSEY study.  
Signature of person 
conducting the informed 
consent process 
Print name 
Date  
 
 
 
I would/would not (please circle) like my child’s GP to be notified about participation in this study. 
 
Signature of Parent/Guardian:______________________________Date:____________ 
 
Name of GP: 
 
 
 
 
 
Contact address of GP: __________________________________________________ 
 
IMPORTANT:  one signed original to be kept in ODYSSEY trial file by the researcher 
 
 
 
one signed copy to be given to the parent/carer 
 
 
 
one signed copy to be kept in the clinic file 
 
 
 
 


ODYSSEY Protocol  
Version 6.0 8th November 2019 
ODYSSEY (PENTA 20)    
 
 
 
 
 
 
 
 
Page 192 of 324 
PARTICIPANT – RE-CONSENT TO THE ODYSSEY TRIAL 
 (To be printed on local-headed paper) 
(Insert version no and date) 
 
 
ODYSSEY: A randomised trial of dolutegravir (DTG)-based antiretroviral therapy vs. standard of 
care (SOC) in children with HIV infection starting first-line or switching to second-line antiretroviral 
therapy. 
 
 
 
 
 
 
 
 
Please initial (or mark) box if you agree: 
I have read/been read the information sheet (version ____, dated __________) for 
the ODYSSEY study and I understand what will be required if I participate in the 
study.  
 
 
The study has been explained to me and all my questions have been answered. 
 
 
I understand that my participation is voluntary and that I am free to withdraw at any 
time, without giving any reason, without my medical care or legal rights being 
affected. 
 
 
I agree to inform the study doctor if I start any other new medicine during the period 
of the study. 
 
 
I understand that clinical information may be reviewed by properly authorised 
individuals as part of the study and that such information will be treated as strictly 
confidential. 
 
I agree to allow blood samples to be taken and stored for later testing. I understand 
that these results and samples will not be identified by my name and that I may not 
be given the results of tests performed on stored samples. 
 
I agree to routine blood results and clinical information being included anonymously 
in continued follow-up after the study has ended (identified only by study number 
and date of birth). 
 
I agree to UCL collecting information about me from my clinic for this research 
study. This data may be used by UCL and other authorised research collaborators to 
conduct the trial and associated sub-studies. 
 
I agree to anonymised study data being transferred to ViiV Healthcare, and to drug 
agencies in other countries. 
 
I agree to continue to participate in the ODYSSEY study  
 
 
Participant signature 
(or thumbprint) 
Print name 
Date 
 
 
 
Witness’ signature  
(if thumbprint above) 
Print name 
Date 
 
 
 
Please turn over the page 
 
Study number: 
Anonymous code: 


ODYSSEY Protocol  
Version 6.0 8th November 2019 
ODYSSEY (PENTA 20)    
 
 
 
 
 
 
 
 
Page 193 of 324 
I have provided the ODYSSEY study information to the participant in full and answered all his/her 
questions. To the best of my knowledge, he/she understands the purpose, interventions, risks and 
benefits of this study and willingly agrees to continue participation in the ODYSSEY study.  
Signature of person 
conducting the informed 
consent process 
Print name 
Date  
 
 
 
_ 
IMPORTANT:  one signed original to be kept in ODYSSEY trial file by the researcher 
 
 
 
one signed copy to be given to the parent/carer 
 
 
 
one signed copy to be kept in the clinic file 
 
 
 


ODYSSEY Protocol  
Version 6.0 8th November 2019 
ODYSSEY (PENTA 20)    
 
 
 
 
 
 
 
 
Page 194 of 324 
PARTICIPANT- MAIN STUDY RE-ASSENT TO THE ODYSSEY TRIAL 
(To be printed on local-headed paper) 
(Insert version no and date) 
 
ODYSSEY: A randomised trial of dolutegravir (DTG)-based antiretroviral therapy vs. standard of 
care (SOC) in children with HIV infection starting first-line or switching to second-line ART. 
 
Please tick yes or no to the questions below 
1. Have you read (or had read to you) the information about this study? 
YES   NO  
 
2. Has somebody explained the study to you?  
YES   NO  
 
3. Do you understand what the study is about? 
YES   NO  
 
4. Have you asked all the questions you want? 
YES   NO  
 
5. Have your questions been answered in a way you understand? 
 
YES   NO  
 
6. Do you understand how the study might help you? 
 
 
YES   NO  
 
7. Do you understand the risks of taking part? 
 
 
 
YES   NO  
 
8. Do you understand it’s OK to stop taking part in the study at any time? 
 
YES   NO  
 
9. Do you understand that you cannot choose the group you will be in? 
 
YES   NO  
 
10. Are you happy to continue to take part? 
 
 
YES   NO  
 
 
If any answers are ‘no’ or you don’t want to take part, don’t sign your name. 
If you do want to take part, you can sign your name below. 
 
Participant’s signature 
(or thumbprint) 
Print name 
Date 
 
 
 
Witness’ signature 
(if thumbprint used above) 
Print name 
Date 
 
 
Please turn over the page 
The person who explained the study to you needs to sign too: 
 
Study number: 
Anonymous code: 


ODYSSEY Protocol  
Version 6.0 8th November 2019 
ODYSSEY (PENTA 20)    
 
 
 
 
 
 
 
 
Page 195 of 324 
I have provided the ODYSSEY study information to the participant in full and answered all his/her 
questions. To the best of my knowledge, he/she understands the purpose, interventions, risks and 
benefits of this study and willingly agrees to be enrolled into the ODYSSEY study.  
Signature of person 
conducting the informed 
consent process 
Print name 
Date  
 
 
 
IMPORTANT:  one signed original to be kept in ODYSSEY trial file by the researcher 
 
 
 
one signed copy to be given to the participant  
 
 
one signed copy to be kept in the clinic file 
 
 
 


ODYSSEY Protocol  
Version 6.0 8th November 2019 
ODYSSEY (PENTA 20)    
 
 
 
 
 
 
 
 
Page 196 of 324 
PARENT/CARER – CONSENT TO EXTENDED FOLLOW-UP 
 (To be printed on local-headed paper) 
(Insert version no and date) 
 
ODYSSEY: A randomised trial of dolutegravir (DTG)-based antiretroviral therapy vs. standard of 
care (SOC) in children with HIV infection starting first-line or switching to second-line antiretroviral 
therapy. 
 
 
 
 
 
 
 
 
Please initial (or mark) box if you agree: 
I have read/been read the information sheet (version ____, dated __________) for 
extended follow-up within the ODYSSEY study and I understand what will be 
required if my child participates.  
 
 
The reason for extended follow-up has been explained to me and all my questions 
have been answered. 
 
 
I understand that my child’s participation is voluntary and that I am free to withdraw 
him or her at any time, without giving any reason, without my medical care or legal 
rights or my child’s medical care or legal rights being affected. 
 
 
I agree to inform the study doctor if my child starts any other new medicine during 
the extended follow-up period. 
 
 
I understand that clinical information may be reviewed by properly authorised 
individuals as part of the study and that such information will be treated as strictly 
confidential. 
 
I agree to UCL collecting information on routine blood results and clinical 
information on my child from my child’s clinic for the extended follow-up period. 
This data may be used by UCL and other authorised research collaborators to 
conduct the trial 
 
I agree to anonymised study data being transferred to ViiV Healthcare, and to drug 
agencies in other countries. 
 
I agree for my child to participate in the extended follow-up period for ODYSSEY 
study  
 
 
 
 
Parent/carer’s signature 
(or thumbprint) 
Print name 
Date 
 
 
 
Witness’ signature  
(if thumbprint above) 
Print name 
Date 
 
 
 
Please turn over the page 
 
 
 
 
 
Study number: 
Anonymous code: 


ODYSSEY Protocol  
Version 6.0 8th November 2019 
ODYSSEY (PENTA 20)    
 
 
 
 
 
 
 
 
Page 197 of 324 
The person who explained the study to you needs to sign too: 
 
I have provided the ODYSSEY extended follow-up information to the participant’s parent/legal 
guardian in full and answered all his/her questions. To the best of my knowledge, he/she 
understands the purpose, interventions, risks and benefits and willingly agrees for his/her child to 
participate in the extended follow-up period for the ODYSSEY study.  
Signature of person 
conducting the informed 
consent process 
Print name 
Date  
 
 
 
IMPORTANT:  one signed original to be kept in ODYSSEY trial file by the researcher 
 
 
 
one signed copy to be given to the participant  
 
 
one signed copy to be kept in the clinic file 
 
 


ODYSSEY Protocol  
Version 6.0 8th November 2019 
ODYSSEY (PENTA 20)    
 
 
 
 
 
 
 
 
Page 198 of 324 
PARTICIPANT – CONSENT TO EXTENDED FOLLOW-UP 
 (To be printed on local-headed paper) 
(Insert version no and date) 
 
ODYSSEY: A randomised trial of dolutegravir (DTG)-based antiretroviral therapy vs. standard of 
care (SOC) in children with HIV infection starting first-line or switching to second-line antiretroviral 
therapy. 
 
 
 
 
 
 
 
 
Please initial (or mark) box if you agree: 
I have read/been read the information sheet (version ____, dated __________) for 
extended follow-up within the ODYSSEY study and I understand what will be 
required if I participate.  
 
 
The reason for extended follow-up has been explained to me and all my questions 
have been answered. 
 
 
I understand that my participation is voluntary and that I am free to withdraw at any 
time, without giving any reason, without my medical care or legal rights being 
affected. 
 
 
I agree to inform the study doctor if I start any other new medicine during the 
extended follow-up period. 
 
 
I understand that clinical information may be reviewed by properly authorised 
individuals as part of the study and that such information will be treated as strictly 
confidential. 
 
I agree to UCL collecting information on my routine blood results and clinical 
information from my clinic for the extended follow-up period. This data may be used 
by UCL and other authorised research collaborators to conduct the trial. 
 
I agree to anonymised study data being transferred to ViiV Healthcare, and to drug 
agencies in other countries. 
 
I agree to participate in the extended follow-up period for ODYSSEY study  
 
 
 
 
 
Participant’s signature 
(or thumbprint) 
Print name 
Date 
 
 
 
Witness’ signature  
(if thumbprint above) 
Print name 
Date 
 
 
 
 
Please turn over the page 
 
 
 
 
 
Study number: 
Anonymous code: 


ODYSSEY Protocol  
Version 6.0 8th November 2019 
ODYSSEY (PENTA 20)    
 
 
 
 
 
 
 
 
Page 199 of 324 
The person who explained the study to you needs to sign too: 
 
I have provided the ODYSSEY extended follow-up information to the participant in full and 
answered all his/her questions. To the best of my knowledge, he/she understands the purpose, 
interventions, risks and benefits and willingly agrees to participate in the extended follow-up period 
for the ODYSSEY study.  
Signature of person 
conducting the informed 
consent process 
Print name 
Date  
 
 
 
IMPORTANT:  one signed original to be kept in ODYSSEY trial file by the researcher 
 
 
 
one signed copy to be given to the participant  
 
 
one signed copy to be kept in the clinic file 
 
 
 


ODYSSEY Protocol  
Version 6.0 8th November 2019 
ODYSSEY (PENTA 20)    
 
 
 
 
 
 
 
 
Page 200 of 324 
PARTICIPANT – ASSENT TO EXTENDED FOLLOW-UP 
(To be printed on local-headed paper) 
(Insert version no and date) 
 
ODYSSEY: A randomised trial of dolutegravir (DTG)-based antiretroviral therapy vs. standard of 
care (SOC) in children with HIV infection starting first-line or switching to second-line ART. 
 
Please tick yes or no to the questions below 
1. Have you read (or had read to you) the information about extended follow-up 
for this study? 
YES   NO  
 
2. Has somebody explained extended follow-up for this study to you?  
YES   NO  
 
3. Do you understand what follow-up for the study is about? 
YES   NO  
 
4. Have you asked all the questions you want? 
YES   NO  
 
5. Have your questions been answered in a way you understand? 
 
YES   NO  
 
6. Do you understand how extended follow-up might help you?  
 
YES   NO  
 
7. Do you understand the risks of taking part? 
 
 
 
YES   NO  
 
8. Do you understand that it’s OK to stop taking part in extended follow-up at any 
time? 
 
YES   NO  
 
9. Are you happy to take part?  
 
YES   NO  
 
 
If any answers are ‘no’ or you don’t want to take part, don’t sign your name. 
If you do want to take part, you can sign your name below. 
 
Participant’s signature 
(or thumbprint) 
Print name 
Date 
 
 
 
Witness’ signature 
(if thumbprint used above) 
Print name 
Date 
 
 
Please turn over the page 
 
 
 
 
 
Study number: 
Anonymous code: 


ODYSSEY Protocol  
Version 6.0 8th November 2019 
ODYSSEY (PENTA 20)    
 
 
 
 
 
 
 
 
Page 201 of 324 
The person who explained the study to you needs to sign too: 
 
I have provided the ODYSSEY study information to the participant in full and answered all his/her 
questions. To the best of my knowledge, he/she understands the purpose, interventions, risks and 
benefits of this study and willingly agrees to be enrolled into the ODYSSEY study.  
Signature of person 
conducting the informed 
consent process 
Print name 
Date  
 
 
 
IMPORTANT:  one signed original to be kept in ODYSSEY trial file by the researcher 
 
 
 
one signed copy to be given to the participant  
 
 
one signed copy to be kept in the clinic file 


ODYSSEY Protocol  
Version 6.0 8th November 2019 
ODYSSEY (PENTA 20)    
 
 
 
 
 
 
 
 
Page 202 of 324 
PARENT/CARER – CONSENT TO STORAGE OF BLOOD SAMPLES FOR FUTURE TESTING 
 
(To be printed on local-headed paper) 
(Insert version no and date)  
 
Please initial (or mark) box if you agree: 
I agree to allow blood samples to be taken from my child and for my child’s samples 
to be stored for later testing. I understand that these results and samples will not be 
identified by either my or my child’s name and that I may not be given the results of 
tests performed on stored samples. 
 
 
 
Parent/carer’s signature 
(or thumbprint) 
Print name 
Date  
 
 
 
Witness’ signature 
(if thumbprint above) 
Print name 
Date 
 
 
 
 
I have provided the ODYSSEY study information to the participant’s parent/legal guardian in full and 
answered all his/her questions. To the best of my knowledge, he/she understands the purpose, risks 
and benefits of blood sample storage and willingly agrees for his/her child to have their blood 
samples stored for future testing.  
Signature of person 
conducting the informed 
consent process 
Print name 
Date  
 
 
 
IMPORTANT:  one signed original to be kept in ODYSSEY trial file by the researcher 
 
 
 
one signed copy to be given to the parent/carer 
 
 
 
one signed copy to be kept in the clinic file 
 
ODYSSEY:  A randomised trial of dolutegravir (DTG)-based antiretroviral therapy vs. standard of care 
(SOC) in children with HIV infection starting first-line or switching to second-line ART. 
 
Study number: 
Anonymous code: 


ODYSSEY Protocol  
Version 6.0 8th November 2019 
ODYSSEY (PENTA 20)    
 
 
 
 
 
 
 
 
Page 203 of 324 
PARTICIPANT - CONSENT TO STORAGE OF BLOOD SAMPLES FOR FUTURE TESTING 
 
(To be printed on local-headed paper)  
(Insert version no and date) 
 
Please initial (or mark) box if you agree: 
I agree to allow blood samples to be taken and stored for later testing. I understand 
that these results and samples will not be identified by my name and that I may not 
be given the results of tests performed on stored samples. 
 
 
 
Participant’s signature 
(or thumbprint) 
Print name 
Date  
 
 
 
Witness’ signature 
(if thumbprint above) 
Print name 
Date 
 
 
 
 
I have provided the ODYSSEY study information to the participant in full and answered all his/her 
questions. To the best of my knowledge, he/she understands the purpose, risks and benefits of 
blood sample storage and willingly agrees to have their blood samples stored for future testing.  
Signature of person 
conducting the informed 
consent process 
Print name 
Date  
 
 
 
IMPORTANT:  one signed original to be kept in ODYSSEY trial file by the researcher 
 
 
 
one signed copy to be given to the parent/carer 
 
 
 
one signed copy to be kept in the clinic file 
 
 
ODYSSEY:  A randomised trial of dolutegravir (DTG)-based antiretroviral therapy vs. standard of care 
(SOC) in children with HIV infection starting first-line or switching to second-line ART. 
 
Study number: 
Anonymous code: 


ODYSSEY Protocol  
Version 6.0 8th November 2019 
ODYSSEY (PENTA 20)    
 
 
 
 
 
 
 
 
Page 204 of 324 
PARTICIPANT – ASSENT TO STORAGE OF BLOOD SAMPLES FOR FUTURE TESTING 
 
(To be printed on local-headed paper) 
(Insert version no and date) 
 
 
ODYSSEY: A randomised trial of dolutegravir (DTG)-based antiretroviral therapy vs. standard of 
care (SOC) in children with HIV infection starting first-line or switching to second-line ART. 
 
Please tick yes or no to the questions below 
1. Do you understand that we would like to keep some of your blood samples to 
test in the future? 
YES   NO  
 
2. Do you understand that we will not put your name on the samples so that 
other people will not know that they belong to you?  
YES   NO  
 
3. Do you understand that you may not be given the results from these tests? 
YES   NO  
 
4. Are you happy for us to keep your blood samples to test in the future? 
 
 
YES   NO  
 
 
If any answers are ‘no’, don’t sign your name. 
 
If you are happy for us to store your blood samples to test in the future, you can sign your name 
below. 
 
Participant’s signature 
(or thumbprint) 
Print name 
Date 
 
 
 
Witness’ signature 
(if thumbprint used above) 
Print name 
Date 
 
 
The person who explained the study to you needs to sign too: 
 
I have provided the ODYSSEY study information to the participant in full and answered all his/her 
questions. To the best of my knowledge, he/she understands the purpose, interventions, risks and 
benefits of blood sample storage and willingly agrees to have their blood samples stored for future 
testing.  
Signature of person 
conducting the informed 
consent process 
Print name 
Date  
 
 
 
IMPORTANT:  one signed original to be kept in ODYSSEY trial file by the researcher 
 
 
 
one signed copy to be given to the participant  
 
 
one signed copy to be kept in the clinic file 
Study number: 
Anonymous code:  


ODYSSEY Protocol  
Version 6.0 8th November 2019 
ODYSSEY (PENTA 20)    
 
 
 
 
 
 
 
 
Page 205 of 324 
PARENT/CARER – MAIN STUDY & WB PK 1 CONSENT TO SCREENING (3 TO <14KG) 
(To be printed on local-headed paper) 
(Insert version no and date) 
 
ODYSSEY:  A randomised trial of dolutegravir (DTG)-based antiretroviral therapy vs. standard of 
care (SOC) in children with HIV infection starting first-line or switching to second-line antiretroviral 
therapy. 
 
 
 
 
 
 
 
Please initial (or mark) box if you agree: 
I have read/been read the information sheet (version ____, dated __________) 
about the ODYSSEY study and the PK (blood levels) study.  
 
I agree to my child being assessed to see whether he/she is eligible to take part 
in this study. 
 
I understand this will involve my child being seen by the doctor who will ask 
questions about my child’s health, and my child having some blood taken for 
testing. 
 
I agree that the results of these tests and an additional blood sample can be 
kept by the ODYSSEY team for further tests if my child starts the study. I 
understand that these results and samples will not be identified by either my or 
my child’s name. 
 
I understand that if my child cannot participate in the study, the stored blood 
sample will be discarded and not used for further tests.   
 
I agree to my child taking part in the PK (blood levels) study if they enter 
ODYSSEY and are allocated dolutegravir. 
 
 
Parent/carer’s signature 
(or thumbprint) 
Print name 
Date  
 
 
 
Witness’ signature 
(if thumbprint above) 
Print name 
Date 
 
 
 
 
I have provided the ODYSSEY study information to the potential participant’s parent/legal guardian 
in full and answered all his/her questions. To the best of my knowledge, he/she understands the 
purpose, interventions, risks and benefits of this study and willingly agrees for his/her child to be 
screened for the ODYSSEY study.  
Signature of person 
conducting the informed 
consent process 
Print name 
Date 
 
 
IMPORTANT:  one signed original to be kept in odyssey trial file by the researcher 
 
 
one signed copy to be given to the parent/carer 
 
 
one signed copy to be kept in the clinic file 
 
Study number: 
Anonymous code: 


ODYSSEY Protocol  
Version 6.0 8th November 2019 
ODYSSEY (PENTA 20)    
 
 
 
 
 
 
 
 
Page 206 of 324 
PARENT/CARER – MAIN STUDY & WB PK 1 CONSENT TO RANDOMISATION (3 TO <14KG) 
(To be printed on local-headed paper) 
(Insert version no and date) 
 
ODYSSEY: A randomised trial of dolutegravir (DTG)-based antiretroviral therapy vs. standard of 
care (SOC) in children with HIV infection starting first-line or switching to second-line antiretroviral 
therapy. 
 
 
 
 
 
 
 
Please initial (or mark) box if you agree: 
I have read/been read the information sheet (version ____, dated __________) 
about the ODYSSEY study and the PK (blood levels) study and I understand what will 
be required if my child participates in the study.  
 
 
The study has been explained to me and all my questions have been answered. 
 
 
I understand that my child’s participation is voluntary and that I am free to withdraw 
him or her at any time, without giving any reason, without my medical care or legal 
rights or my child’s medical care or legal rights being affected. 
 
 
I agree to inform the study doctor if my child starts any other new medicine during 
the period of the study. 
 
 
I understand that clinical information may be reviewed by properly authorised 
individuals as part of the study and that such information will be treated as strictly 
confidential. 
 
I agree to allow blood samples to be taken from my child and for my child’s samples 
to be stored for later testing. I understand that these results and samples will not be 
identified by either my or my child’s name and that I may not be given the results of 
tests performed on stored samples. 
 
 
I agree to routine blood results and clinical information being included anonymously 
in continued follow-up after the study has ended (identified only by study number 
and date of birth). 
 
I agree to UCL collecting information about me from my clinic for this research 
study. This data may be used by UCL and other authorised research collaborators to 
conduct the trial and associated sub-studies. 
 
I agree to anonymised study data being transferred to ViiV Healthcare, and to drug 
agencies in other countries. 
 
I agree for my child to participate in the ODYSSEY study.  
 
 
 
I agree to my child taking part in the PK (blood levels) study if they are allocated 
dolutegravir. 
 
 
Parent/carer’s signature 
(or thumbprint) 
Print name 
Date 
 
 
 
Witness’ signature  
(if thumbprint above) 
Print name 
Date 
 
 
 
Study number: 
Anonymous code: 


ODYSSEY Protocol  
Version 6.0 8th November 2019 
ODYSSEY (PENTA 20)    
 
 
 
 
 
 
 
 
Page 207 of 324 
 
I have provided the ODYSSEY study information to the participant’s parent/legal guardian in full and 
answered all his/her questions. To the best of my knowledge, he/she understands the purpose, 
interventions, risks and benefits of this study and willingly agrees for his/her child to be enrolled 
into the ODYSSEY study.  
Signature of person 
conducting the informed 
consent process 
Print name 
Date  
 
 
 
I would/would not (please circle) like my child’s GP to be notified about participation in this study. 
[Country specific, delete if not applicable] 
 
Signature of Parent/Guardian:______________________________Date:____________ 
 
Name of GP: 
 
 
 
 
 
Contact address of GP: __________________________________________________ 
 
 
IMPORTANT:  one signed original to be kept in odyssey trial file by the researcher 
 
 
 
one signed copy to be given to the parent/carer 
 
 
 
one signed copy to be kept in the clinic file 
 


ODYSSEY Protocol  
Version 6.0 8th November 2019 
ODYSSEY (PENTA 20)    
 
 
 
 
 
 
 
 
Page 208 of 324 
PARTICIPANT – MAIN STUDY & WB PK 1  ASSENT TO SCREENING (3 TO <14KG) 
(To be printed on local-headed paper)  
(Insert version no and date) 
 
 
Please tick yes or no to the questions below 
1. Have you read (or had read to you) the information about this study and the PK (blood 
levels) study? 
YES   NO  
2. Do you understand that your doctor will check how you are and do some tests on your 
blood to see if you can join the study? 
YES   NO  
3. Do you agree that if you start the study your blood samples (without your name on) can 
be used during the study and stored for studies which will help us understand more about 
the virus? (If you don’t start the study, we won’t use your blood samples) 
YES   NO  
4. Are you happy to be assessed to see whether you can take part in this study?  
YES   NO  
5. Do you agree to taking part in the PK (blood levels) study? 
YES   NO  
 
If any answers are ‘no’ or you don’t want to take part, don’t sign your name. 
If you do want to take part, you can sign your name below. 
 
Participant’s signature 
(or thumbprint) 
Print name 
Date 
 
 
 
Witness’ signature 
(if thumbprint used above) 
Print name 
Date 
 
 
 
The person who explained the study to you needs to sign too: 
 
I have provided the ODYSSEY study information to the potential participant in full and answered all 
his/her questions. To the best of my knowledge, he/she understands the purpose, interventions, 
risks and benefits of this study and willingly agrees to be screened for the ODYSSEY study.  
Signature of person 
conducting the informed 
consent process 
Print name 
Date  
 
 
 
IMPORTANT:  one signed original to be kept in odyssey trial file by the researcher 
 
 
 
one signed copy to be given to the participant  
 
 
one signed copy to be kept in the clinic file 
 
ODYSSEY –  A randomised trial of dolutegravir (DTG)-based antiretroviral therapy vs. standard of care 
(SOC) in children with HIV infection starting first-line or switching to second-line ART. 
Study number: 
Anonymous code: 


ODYSSEY Protocol  
Version 6.0 8th November 2019 
ODYSSEY (PENTA 20)    
 
 
 
 
 
 
 
 
Page 209 of 324 
PARTICIPANT- MAIN STUDY & WB PK 1 ASSENT TO RANDOMISATION (3 TO <14KG) 
(To be printed on local-headed paper) 
(Insert version no and date) 
 
ODYSSEY: A randomised trial of dolutegravir (DTG)-based antiretroviral therapy vs. standard of 
care (SOC) in children with HIV infection starting first-line or switching to second-line ART. 
 
Please tick yes or no to the questions below 
1. Have you read (or had read to you) the information about this study and the 
PK (blood levels) study? 
YES   NO  
2. Has somebody explained the study to you?  
YES   NO  
3. Do you understand what the study is about? 
YES   NO  
4. Have you asked all the questions you want? 
YES   NO  
5. Have your questions been answered in a way you understand? 
 
YES   NO  
6. Do you understand how the study might help you? 
 
 
YES   NO  
7. Do you understand the risks of taking part? 
 
 
 
YES   NO  
8. Do you understand it’s OK to stop taking part in the study at any time? 
 
YES   NO  
9. Do you understand that you cannot choose the group you will be in? 
 
YES   NO  
10. Are you happy to take part?  
 
YES   NO  
11. Do you agree to taking part in the PK (blood levels) study? 
YES   NO  
 
If any answers are ‘no’ or you don’t want to take part, don’t sign your name. 
If you do want to take part, you can sign your name below. 
 
Participant’s signature 
(or thumbprint) 
Print name 
Date 
 
 
 
Witness’ signature 
(if thumbprint used above) 
Print name 
Date 
 
 
Study number: 
Anonymous code: 


ODYSSEY Protocol  
Version 6.0 8th November 2019 
ODYSSEY (PENTA 20)    
 
 
 
 
 
 
 
 
Page 210 of 324 
 
The person who explained the study to you needs to sign too: 
 
I have provided the ODYSSEY study information to the participant in full and answered all his/her 
questions. To the best of my knowledge, he/she understands the purpose, interventions, risks and 
benefits of this study and willingly agrees to be enrolled into the ODYSSEY study.  
Signature of person 
conducting the informed 
consent process 
Print name 
Date  
 
 
 
IMPORTANT:  one signed original to be kept in ODYSSEY trial file by the researcher 
 
 
 
one signed copy to be given to the participant  
 
 
one signed copy to be kept in the clinic file 
 


ODYSSEY Protocol  
Version 6.0 8th November 2019 
ODYSSEY (PENTA 20)    
 
 
 
 
 
 
 
 
Page 211 of 324 
PARENT/CARER - CONSENT TO PHARMACOKINETIC (WB PK 1) STUDY (3 TO <25KG)  
 
(To be printed on local-headed paper) 
(Insert version no and date) 
 
Please initial (or mark) box if you agree: 
I have read/been read the information sheet (version ____, dated __________) for 
the ODYSSEY weight band PK 1 (blood levels) study and I understand what will be 
required if my child participates in the study.  
 
 
The weight band PK 1 study has been explained to me and my questions have been 
answered. 
 
I understand that my child’s participation in this study is voluntary and that I am free 
to withdraw him or her at any time, without giving any reason, without my medical 
care or legal rights or my child’s medical care or legal rights being affected. 
 
 
I agree for small quantities of blood to be stored with anonymised labelling so that 
further work can be done to help understand more about HIV treatment. [Country 
specific, delete if not applicable] 
 
 
I agree to UCL collecting information about me from my clinic for this research 
study. This data may be used by UCL and other authorised research collaborators to 
conduct the trial and associated sub-studies. 
 
I agree to anonymised study data being transferred to ViiV Healthcare, and to drug 
agencies in other countries. 
 
I agree for my child to participate in the ODYSSEY weight band PK 1 (blood levels) 
study if they are eligible. 
 
 
 
Parent/carer’s signature 
(or thumbprint) 
Print name 
Date  
 
 
 
Witness’ signature 
(if thumbprint above) 
Print name 
Date 
 
 
 
 
I have provided the ODYSSEY WB PK 1 study information to the participant’s parent/legal guardian 
in full and answered all his/her questions. To the best of my knowledge, he/she understands the 
purpose, interventions, risks and benefits of this study and willingly agrees for his/her child to 
participate in the ODYSSEY WB PK 1 study.  
Signature of person 
conducting the informed 
consent process 
Print name 
Date  
 
 
 
ODYSSEY: A randomised trial of dolutegravir (DTG)-based antiretroviral therapy vs. standard of care 
(SOC) in children with HIV infection starting first-line or switching to second-line ART. 
 
Study number: 
Anonymous code: 


ODYSSEY Protocol  
Version 6.0 8th November 2019 
ODYSSEY (PENTA 20)    
 
 
 
 
 
 
 
 
Page 212 of 324 
IMPORTANT:  one signed original to be kept in ODYSSEY trial file by the researcher 
 
 
 
one signed copy to be given to the parent/carer 
 
 
 
one signed copy to be kept in the clinic file 


ODYSSEY Protocol  
Version 6.0 8th November 2019 
ODYSSEY (PENTA 20)    
 
 
 
 
 
 
 
 
Page 213 of 324 
PARTICIPANT - ASSENT TO PHARMACOKINETIC (WB PK 1) SUBSTUDY (3 TO <25KG) 
(To be printed on local-headed paper) 
(Insert version no and date) 
 
ODYSSEY: A randomised trial of dolutegravir (DTG)-based antiretroviral therapy vs. standard of 
care (SOC) in children with HIV infection starting first-line or switching to second-line ART. 
 
Please tick yes or no to the questions below 
1. Have you read (or had read to you) the information about the blood levels 
study? 
YES   NO  
2. Has somebody explained this study to you?  
YES   NO  
3. Do you understand what this study is about? 
YES   NO  
4. Have you asked all the questions you want? 
YES   NO  
5. Have your questions been answered in a way you understand? 
 
 
YES   NO  
6. Do you understand how this study might help you? 
 
YES   NO  
7. Do you understand the disadvantages of taking part?  
 
YES   NO  
8. Do you understand it’s OK to stop taking part in the study at any time? 
YES   NO  
9. Do you understand that if you take part in the blood levels study you will need 
to come to the clinic for a whole day (over a 24 hour period) to check the level of 
medicine in your blood and maybe sleep there? 
YES   NO  
10. Are you happy to take part?  
YES   NO  
 
If any answers are ‘no’ or you don’t want to take part, don’t sign your name. 
If you do want to take part, you can sign your name below. 
 
Participant’s signature 
(or thumbprint) 
Print name 
Date 
 
 
 
Witness’ signature 
(if thumbprint used above) 
Print name 
Date 
 
 
 
 
The person who explained the study to you needs to sign too: 
 
Study number: 
Anonymous code: 


ODYSSEY Protocol  
Version 6.0 8th November 2019 
ODYSSEY (PENTA 20)    
 
 
 
 
 
 
 
 
Page 214 of 324 
I have provided the ODYSSEY WB PK 1 study information to the participant in full and answered all 
his/her questions. To the best of my knowledge, he/she understands the purpose, interventions, 
risks and benefits of this study and willingly agrees to participate in the ODYSSEY WB PK 1 study.  
Signature of person 
conducting the informed 
consent process 
Print name 
Date  
 
 
 
IMPORTANT:  one signed original to be kept in ODYSSEY trial file by the researcher 
 
 
 
one signed copy to be given to the participant  
 
 
one signed copy to be kept in the clinic file 
 


ODYSSEY Protocol  
Version 6.0 8th November 2019 
ODYSSEY (PENTA 20)    
 
 
 
 
 
 
 
 
Page 215 of 324 
PARENT/CARER - CONSENT TO PHARMACOKINETIC (WB PK 2) STUDY (≥25KG) 
 
(To be printed on local-headed paper) 
(Insert version no and date) 
 
Please initial (or mark) box if you agree: 
I have read/been read the information sheet (version ____, dated __________) for 
the ODYSSEY weight band PK 2 (blood level)s study and I understand what will be 
required if my child participates in the study.  
 
 
The weight band PK study has been explained to me and my questions have been 
answered. 
 
I understand that my child’s participation in this study is voluntary and that I am free 
to withdraw him or her at any time, without giving any reason, without my medical 
care or legal rights or my child’s medical care or legal rights being affected. 
 
 
I agree for small quantities of blood to be stored with anonymised labelling so that 
further work can be done to help understand more about HIV treatment. [Country 
specific, delete if not applicable] 
 
 
I agree to study data including my child’s study number and age being transferred to 
ViiV Healthcare, and to drug agencies in other countries. 
 
I agree for my child to participate in the ODYSSEY weight band PK 2 (blood levels) 
study if they are eligible.  
 
 
 
 
Parent/carer’s signature 
(or thumbprint) 
Print name 
Date  
 
 
 
Witness’ signature 
(if thumbprint above) 
Print name 
Date 
 
 
 
 
I have provided the ODYSSEY WB PK 2 study information to the participant’s parent/legal guardian 
in full and answered all his/her questions. To the best of my knowledge, he/she understands the 
purpose, interventions, risks and benefits of this study and willingly agrees for his/her child to 
participate in the ODYSSEY WB PK 2 study.  
Signature of person 
conducting the informed 
consent process 
Print name 
Date  
 
 
 
IMPORTANT:  one signed original to be kept in ODYSSEY trial file by the researcher 
 
 
 
one signed copy to be given to the parent/carer 
 
 
 
one signed copy to be kept in the clinic file 
ODYSSEY: A randomised trial of dolutegravir (DTG)-based antiretroviral therapy vs. standard of care 
(SOC) in children with HIV infection starting first-line or switching to second-line ART. 
 
Study number: 
Anonymous code: 


ODYSSEY Protocol  
Version 6.0 8th November 2019 
ODYSSEY (PENTA 20)    
 
 
 
 
 
 
 
 
Page 216 of 324 
PARTICIPANT - ASSENT TO PHARMACOKINETIC (WB PK 2) STUDY (≥25KG) 
 
(To be printed on local-headed paper) 
(Insert version no and date) 
 
ODYSSEY: A randomised trial of dolutegravir (DTG)-based antiretroviral therapy vs. standard of 
care (SOC) in children with HIV infection starting first-line or switching to second-line ART. 
 
Please tick yes or no to the questions below 
1. Have you read (or had read to you) the information about the blood levels study? 
YES   NO  
2. Has somebody explained this study to you?  
YES   NO  
3. Do you understand what this study is about? 
YES   NO  
4. Have you asked all the questions you want? 
YES   NO  
5. Have your questions been answered in a way you understand? 
 
 
YES   NO  
6. Do you understand how this study might help you? 
 
YES   NO  
7. Do you understand the disadvantages of taking part? 
 
 
YES   NO  
8. Do you understand it’s OK to stop taking part in the study at any time? 
YES   NO  
9. Do you understand that if you do take part in the PK (blood levels) study you will need 
to come to the clinic for a whole day to check the level of medicine in your blood and 
maybe sleep there? 
YES   NO  
10. Do you understand that if you do take part in the PK (blood levels) study your dose of 
medicine will be changed after the first blood sampling day? 
YES   NO  
11. Do you understand that if you do take part in the PK (blood levels) study you will need 
to come back to the clinic for a second full day to check the level of medicine in your 
blood and maybe sleep there? 
YES   NO  
12. Are you happy to take part? 
 
YES   NO  
 
If any answers are ‘no’ or you don’t want to take part, don’t sign your name. 
If you do want to take part, you can sign your name below. 
 
Participant’s signature 
(or thumbprint) 
Print name 
Date 
 
 
 
Witness’ signature 
(if thumbprint used above) 
Print name 
Date 
 
 
 
The person who explained the study to you needs to sign too: 
 
Study number: 
Anonymous code: 


ODYSSEY Protocol  
Version 6.0 8th November 2019 
ODYSSEY (PENTA 20)    
 
 
 
 
 
 
 
 
Page 217 of 324 
I have provided the ODYSSEY WB PK 2 study information to the participant in full and answered all 
his/her questions. To the best of my knowledge, he/she understands the purpose, interventions, 
risks and benefits of this study and willingly agrees to participate in the ODYSSEY WB PK 2 study.  
Signature of person 
conducting the informed 
consent process 
Print name 
Date  
 
 
 
IMPORTANT:  one signed original to be kept in ODYSSEY trial file by the researcher 
 
 
 
one signed copy to be given to the participant  
 
 
one signed copy to be kept in the clinic file 
 


ODYSSEY Protocol  
Version 6.0 8th November 2019 
ODYSSEY (PENTA 20)    
 
 
 
 
 
 
 
 
Page 218 of 324 
PARENT/CARER - CONSENT TO PHARMACOKINETIC (TB PK) STUDY 
 
(To be printed on local-headed paper)  
(Insert version no and date) 
 
Please initial (or mark) box if you agree: 
I have read/been read the information sheet (version ____, dated __________) for 
the ODYSSEY TB PK (blood levels) study and I understand what will be required if my 
child participates in the study.  
 
 
The TB PK study has been explained to me and my questions have been answered. 
 
I understand that my child’s participation in this study is voluntary and that I am free 
to withdraw him or her at any time, without giving any reason, without my medical 
care or legal rights or my child’s medical care or legal rights being affected. 
 
 
I agree for small quantities of blood to be stored with anonymised labelling so that 
further work can be done to help understand more about HIV and TB effective 
treatment. [Country specific, delete if not applicable] 
 
 
I agree to UCL collecting information about me from my clinic for this research 
study. This data may be used by UCL and other authorised research collaborators to 
conduct the trial and associated sub-studies. 
 
I agree to anonymised study data being transferred to ViiV Healthcare, and to drug 
agencies in other countries. 
 
I agree for my child to participate in the ODYSSEY TB PK (blood levels) study  
 
 
 
 
Parent/carer’s signature 
(or thumbprint) 
Print name 
Date  
 
 
 
Witness’ signature 
(if thumbprint above) 
Print name 
Date 
 
 
 
 
I have provided the ODYSSEY TB PK study information to the participant’s parent/legal guardian in 
full and answered all his/her questions. To the best of my knowledge, he/she understands the 
purpose, interventions, risks and benefits of this study and willingly agrees for his/her child to 
participate in the ODYSSEY TB PK study.  
Signature of person 
conducting the informed 
consent process 
Print name 
Date  
 
 
 
IMPORTANT:  one signed original to be kept in ODYSSEY trial file by the researcher 
 
 
 
one signed copy to be given to the parent/carer 
 
 
 
one signed copy to be kept in the clinic file 
ODYSSEY: A randomised trial of dolutegravir (DTG)-based antiretroviral therapy vs. standard of care 
(SOC) in children with HIV infection starting first-line or switching to second-line ART. 
 
Study number: 
Anonymous code: 


ODYSSEY Protocol  
Version 6.0 8th November 2019 
ODYSSEY (PENTA 20)    
 
 
 
 
 
 
 
 
Page 219 of 324 
PARTICIPANT - ASSENT TO PHARMACOKINETIC (TB PK) STUDY 
 
(To be printed on local-headed paper) 
(Insert version no and date) 
 
ODYSSEY: A randomised trial of dolutegravir (DTG)-based antiretroviral therapy vs. standard of 
care (SOC) in children with HIV infection starting first-line or switching to second-line ART. 
 
Please tick yes or no to the questions below 
1. Have you read (or had read to you) the information about the blood levels study? 
YES   NO  
2. Has somebody explained this study to you?  
YES   NO  
3. Do you understand what this study is about? 
YES   NO  
4. Have you asked all the questions you want? 
 
YES   NO  
5. Have your questions been answered in a way you understand? 
 
 
YES   NO  
6. Do you understand how this study might help you? 
 
 
YES   NO  
7. Do you understand the disadvantages of taking part?  
 
 
YES   NO  
8. Do you understand it’s OK to stop taking part in the study at any time? 
YES   NO  
9. Do you understand that you will need to come to the clinic for a whole day to 
check the level of medicine in your blood? 
YES   NO  
10. Do you understand that you will need to come back to the clinic for a second 
full day to check the level of drugs in your blood and maybe sleep there? 
YES   NO  
11. Are you happy to take part?  
 
YES   NO  
 
If any answers are ‘no’ or you don’t want to take part, don’t sign your name. 
If you do want to take part, you can sign your name below. 
 
Participant’s signature 
(or thumbprint) 
Print name 
Date 
 
 
 
Witness’ signature 
(if thumbprint used above) 
Print name 
Date 
 
 
Study number: 
Anonymous code: 


ODYSSEY Protocol  
Version 6.0 8th November 2019 
ODYSSEY (PENTA 20)    
 
 
 
 
 
 
 
 
Page 220 of 324 
 
The person who explained the study to you needs to sign too: 
 
I have provided the ODYSSEY TB PK study information to the participant in full and answered all 
his/her questions. To the best of my knowledge, he/she understands the purpose, interventions, 
risks and benefits of this study and willingly agrees to participate in the ODYSSEY TB PK study.  
Signature of person 
conducting the informed 
consent process 
Print name 
Date  
 
 
 
IMPORTANT:  one signed original to be kept in ODYSSEY trial file by the researcher 
 
 
 
one signed copy to be given to the participant  
 
 
one signed copy to be kept in the clinic file 


ODYSSEY Protocol  
Version 6.0 8th November 2019 
ODYSSEY (PENTA 20)    
 
 
 
 
 
 
 
 
Page 221 of 324 
CONSENT AND ASSENT FORMS FOR QUALITATIVE SUBSTUDY  
Consent/ assent forms for in-depth interviews - IDIs (10-18 year olds) 
 
Assent form- IDIs- 10-17 years olds 
 
Consent form- IDIs- 18 year olds 
 
Consent form- IDIs- parents/ carers 
 
Consent form- IDIs- caregivers 
Consent/ assent forms for in-depth interviews (DTG) - IDIs (10-19 year olds) 
 
Assent form- IDIs- 10-17 years olds (DTG) 
 
Consent form- IDIs- 18-19 year olds (DTG) 
 
Consent form- IDIs- parents/ carers (DTG) 
Consent / assent forms for focus group discussions - FGDs (10-19 year olds) 
 
Assent form- FGDs- 10-17 years olds 
 
Consent form- FGDs- 18-19 year olds 
 
Consent form- FGDs- parents/ carers 
 


ODYSSEY Protocol  
Version 6.0 8th November 2019 
ODYSSEY (PENTA 20)    
 
 
 
 
 
 
 
 
Page 222 of 324 
ODYSSEY QUALITATIVE STUDY: 
ASSENT FORM FOR IN-DEPTH INTERVIEWS 10-17 YEAR OLDS  
(To be printed on local-headed paper) 
(Insert version no and date) 
Please tick yes or no to answer the questions below.   
1. Have you read (or had read to you) the information about this study? 
 
YES   NO  
2. Has somebody explained the study to you? 
YES   NO  
3. Do you understand what the study is about? 
YES   NO  
4. Have you asked all the questions you want? 
YES   NO  
5. Have your questions been answered in a way you understand? 
YES   NO  
6. Do you understand it’s OK to stop taking part at any time? 
YES   NO  
7. Do you understand that you don’t have to answer any questions that you do 
not want to? 
YES   NO  
8. Is it OK if we audio record our discussions? 
YES   NO  
9. Do you understand that we will speak with you on two separate occasions?    
YES   NO  
10. Are you happy to take part? 
YES   NO  
If any answers are ‘no’ or you don’t want to take part, don’t sign your name. 
If you do want to take part, you can sign your name below. 
 
Participant’s signature 
(or thumbprint) 
Print name 
Date 
 
 
 
Witness’ signature 
(if thumbprint used above) 
Print name 
Date 
 
 
The person who explained the study to you needs to sign too: 
I have provided the Qualitative study information to the potential participant in full and answered 
all his/her questions. To the best of my knowledge, he/she understands the purpose, interventions, 
risks and benefits of this study and willingly agrees to participate in the Qualitative study.  
Signature of person 
conducting the informed 
consent process 
Print name 
Date  
 
 
IMPORTANT:  one signed original to be kept in ODYSSEY trial file by the researcher 
 
 
 
one signed copy to be given to the participant  
 
 
one signed copy to be kept in the clinic file 


ODYSSEY Protocol  
Version 6.0 8th November 2019 
ODYSSEY (PENTA 20)    
 
 
 
 
 
 
 
 
Page 223 of 324 
ODYSSEY QUALITATIVE STUDY: 
CONSENT FORM FOR IN-DEPTH INTERVIEWS YOUNG PEOPLE (18 YEARS OLD)  
(To be printed on local-headed paper) 
(Insert version no and date) 
 
I _____________________________________________ agree to take part in this study.  
 
I have read and understood the information sheet on the study, version X 
YES   NO  
I have been given the opportunity to ask questions and I am satisfied with 
the answers that you have given me. 
YES   NO  
I agree to my contact details being given to the study team so that they can 
contact me to arrange the interview and about other study arrangement 
matters.  
 
 
 
 
YES   NO  
I understand that the researcher will interview me on two separate 
occasions.  
This will involve them talking to them for about an hour each time about my  
experience of being on second-line HIV treatment. 
 
YES   NO  
I agree to this interview being audio-recorded.   
YES   NO  
I know that I do not have to talk about things that I do not want to talk about.  
I can stop talking to the researchers at any time and without giving a reason  
for this.  
 
YES   NO  
I understand that everything that I talk to the researchers about is 
confidential. However if the researchers are told that myself or another child 
is at serious risk of harm, they may have to pass this information on to 
someone else. 
YES   NO  
I agree that anonymised direct quotes from the interview may be used in the 
public reporting of this study.   
YES   NO  
 
 
 
 
My questions have been answered by …………………………………………………………… 
 
Participant’s signature 
(or thumbprint) 
Print name 
Date 
 
 
 
Witness’ signature 
(if thumbprint used above) 
Print name 
Date 
 
 
 
The person who explained the study to you needs to sign too: 
 


ODYSSEY Protocol  
Version 6.0 8th November 2019 
ODYSSEY (PENTA 20)    
 
 
 
 
 
 
 
 
Page 224 of 324 
I have provided the Qualitative study information to the potential participant in full and answered 
all his/her questions. To the best of my knowledge, he/she understands the purpose, interventions, 
risks and benefits of this study and willingly agrees to participate in the Qualitative study.  
Signature of person 
conducting the informed 
consent process 
Print name 
Date  
 
 
 
IMPORTANT:  one signed original to be kept in ODYSSEY trial file by the researcher 
 
 
 
one signed copy to be given to the participant  
 
 
one signed copy to be kept in the clinic file 
 
 


ODYSSEY Protocol  
Version 6.0 8th November 2019 
ODYSSEY (PENTA 20)    
 
 
 
 
 
 
 
 
Page 225 of 324 
ODYSSEY QUALITATIVE STUDY: 
CONSENT FORM FOR IN-DEPTH INTERVIEWS PARENT/CARERS  
 (To be printed on local-headed paper) 
(Insert version no and date) 
 
I _____________________________________________ agree to my child taking part in this study.  
 
I have read and understood the information sheet on the study, version X 
 
YES   NO  
I have been given the opportunity to ask questions and I am satisfied with the 
answers that you have given me. 
 
YES   NO  
I agree to my contact details being given to the study team so that they can 
contact me to arrange the interview and about other study arrangement 
matters. 
YES   NO  
I understand that the researcher will interview my child on two separate 
occasions. This will involve them talking with my child for about an hour about 
my child’s experience of being on second-line treatment. 
 
YES   NO  
I agree to this interview being audio-recorded.   
YES   NO  
I know that my child does not have to talk about things that he/she does not 
want to talk about. My child can stop talking to the researchers at any time and 
without giving a reason for this.  
YES   NO  
I understand that everything that my child talks to the researchers about is 
confidential. However if the researchers are told that a child is at serious risk of 
harm, they may have to pass this information on to someone else.  
 
YES   NO  
I agree that anonymised direct quotes from the interview may be used in the 
public reporting of this study.   
YES   NO  
 
 
 
 
 
 
 
 
 
My questions have been answered by …………………………………………………………… 
 
 
Parent/carer’s signature 
(or thumbprint) 
Print name 
Date 
 
 
 
Witness’ signature 
(if thumbprint used above) 
Print name 
Date 
 
 
 
The person who explained the study to you needs to sign too: 
 
I have provided the Qualitative study information to the potential participant’s parent/legal 
guardian in full and answered all his/her questions. To the best of my knowledge, he/she 
understands the purpose, interventions, risks and benefits of this study and willingly agrees to 
participate in the Qualitative study.  
Signature of person 
conducting the informed 
consent process 
Print name 
Date  


ODYSSEY Protocol  
Version 6.0 8th November 2019 
ODYSSEY (PENTA 20)    
 
 
 
 
 
 
 
 
Page 226 of 324 
 
 
 
IMPORTANT:  one signed original to be kept in ODYSSEY trial file by the researcher 
 
 
 
one signed copy to be given to the participant  
 
 
one signed copy to be kept in the clinic file 


ODYSSEY Protocol  
Version 6.0 8th November 2019 
ODYSSEY (PENTA 20)    
 
 
 
 
 
 
 
 
Page 227 of 324 
ODYSSEY QUALITATIVE STUDY: 
CONSENT FORM FOR IN-DEPTH INTERVIEWS WITH CAREGIVERS  
 (To be printed on local-headed paper) 
(Insert version no and date) 
 
I _____________________________________________ agree to taking part in this study.  
 
I have read and understood the information sheet on the study, version X 
 
YES   NO  
I have been given the opportunity to ask questions and I am satisfied with the 
answers that you have given me. 
 
YES   NO  
I agree to my contact details being given to the study team so that they can 
contact me to arrange the interview and about other study arrangement 
matters. 
YES   NO  
I understand that the researcher will conduct an interview with me. This will 
involve us talking for about an hour about what it is like caring for my child and 
my child’s experience of growing up with HIV. 
 
YES   NO  
I agree to this interview being audio-recorded.   
YES   NO  
I know that I do not have to talk about things that I not want to talk about. I can 
stop talking to the researchers at any time and without giving a reason for this.  
YES   NO  
I understand that everything that I talk to the researchers about is confidential. 
However if I tell the researchers that a child is at serious risk of harm, they may 
have to pass this information on to someone else.  
 
YES   NO  
I agree that anonymised direct quotes from the interview may be used in the 
public reporting of this study.   
YES   NO  
 
 
 
 
 
 
 
 
 
My questions have been answered by …………………………………………………………… 
 
 
Caregiver’s signature 
(or thumbprint) 
Print name 
Date 
 
 
 
Witness’ signature 
(if thumbprint used above) 
Print name 
Date 
 
 
 
The person who explained the study to you needs to sign too: 
 
I have provided the Qualitative study information to the potential participant’s parent/legal 
guardian in full and answered all his/her questions. To the best of my knowledge, he/she 
understands the purpose, interventions, risks and benefits of this study and willingly agrees to 
participate in the Qualitative study.  
Signature of person 
conducting the informed 
consent process 
Print name 
Date  


ODYSSEY Protocol  
Version 6.0 8th November 2019 
ODYSSEY (PENTA 20)    
 
 
 
 
 
 
 
 
Page 228 of 324 
 
 
 
IMPORTANT:  one signed original to be kept in ODYSSEY trial file by the researcher 
 
 
 
one signed copy to be given to the participant  
 
 
one signed copy to be kept in the clinic file 


ODYSSEY Protocol  
Version 6.0 8th November 2019 
ODYSSEY (PENTA 20)    
 
 
 
 
 
 
 
 
Page 229 of 324 
ODYSSEY QUALITATIVE STUDY: 
ASSENT FORM FOR IN-DEPTH INTERVIEWS 10-17 YEAR OLDS (DTG)  
(To be printed on local-headed paper) 
(Insert version no and date) 
Please tick yes or no to answer the questions below.   
1. Have you read (or had read to you) the information about this study? 
 
YES   NO  
2. Has somebody explained the study to you? 
YES   NO  
3. Do you understand what the study is about? 
YES   NO  
4. Have you asked all the questions you want? 
YES   NO  
5. Have your questions been answered in a way you understand? 
YES   NO  
6. Do you understand it’s OK to stop taking part at any time? 
YES   NO  
7. Do you understand that you don’t have to answer any questions that you do 
not want to? 
YES   NO  
8. Is it OK if we audio record our discussions? 
YES   NO  
9. Are you happy to take part? 
YES   NO  
If any answers are ‘no’ or you don’t want to take part, don’t sign your name. 
If you do want to take part, you can sign your name below. 
 
Participant’s signature 
(or thumbprint) 
Print name 
Date 
 
 
 
Witness’ signature 
(if thumbprint used above) 
Print name 
Date 
 
 
The person who explained the study to you needs to sign too: 
I have provided the Qualitative study information to the potential participant in full and answered 
all his/her questions. To the best of my knowledge, he/she understands the purpose, interventions, 
risks and benefits of this study and willingly agrees to participate in the Qualitative study.  
Signature of person 
conducting the informed 
consent process 
Print name 
Date  
 
 
IMPORTANT:  one signed original to be kept in ODYSSEY trial file by the researcher 
 
 
 
one signed copy to be given to the participant  
 
 
one signed copy to be kept in the clinic file 


ODYSSEY Protocol  
Version 6.0 8th November 2019 
ODYSSEY (PENTA 20)    
 
 
 
 
 
 
 
 
Page 230 of 324 
ODYSSEY QUALITATIVE STUDY: 
CONSENT FORM FOR IN-DEPTH INTERVIEWS YOUNG PEOPLE (18-19 YEARS OLD) (DTG) 
(To be printed on local-headed paper) 
(Insert version no and date) 
 
I _____________________________________________ agree to take part in this study.  
 
I have read and understood the information sheet on the study, version X 
YES   NO  
I have been given the opportunity to ask questions and I am satisfied with 
the answers that you have given me. 
YES   NO  
I agree to my contact details being given to the study team so that they can 
contact me to arrange the interview and about other study arrangement 
matters.  
 
 
 
 
YES   NO  
I understand that the researcher will interview me that will last for about an 
hour about my experience of growing up with HIV and being on HIV 
treatment. 
YES   NO  
I agree to this interview being audio-recorded.   
YES   NO  
I know that I do not have to talk about things that I do not want to talk about.  
I can stop talking to the researchers at any time and without giving a reason  
for this.  
 
YES   NO  
I understand that everything that I talk to the researchers about is 
confidential. However if the researchers are told that myself or another child 
is at serious risk of harm, they may have to pass this information on to 
someone else. 
YES   NO  
I agree that anonymised direct quotes from the interview may be used in the 
public reporting of this study.   
YES   NO  
 
 
 
 
My questions have been answered by …………………………………………………………… 
 
Participant’s signature 
(or thumbprint) 
Print name 
Date 
 
 
 
Witness’ signature 
(if thumbprint used above) 
Print name 
Date 
 
 
 
The person who explained the study to you needs to sign too: 
 


ODYSSEY Protocol  
Version 6.0 8th November 2019 
ODYSSEY (PENTA 20)    
 
 
 
 
 
 
 
 
Page 231 of 324 
I have provided the Qualitative study information to the potential participant in full and answered 
all his/her questions. To the best of my knowledge, he/she understands the purpose, interventions, 
risks and benefits of this study and willingly agrees to participate in the Qualitative study.  
Signature of person 
conducting the informed 
consent process 
Print name 
Date  
 
 
 
IMPORTANT:  one signed original to be kept in ODYSSEY trial file by the researcher 
 
 
 
one signed copy to be given to the participant  
 
 
one signed copy to be kept in the clinic file 
 
 


ODYSSEY Protocol  
Version 6.0 8th November 2019 
ODYSSEY (PENTA 20)    
 
 
 
 
 
 
 
 
Page 232 of 324 
ODYSSEY QUALITATIVE STUDY: 
CONSENT FORM FOR IN-DEPTH INTERVIEWS PARENT/CARERS (DTG)  
 (To be printed on local-headed paper) 
(Insert version no and date) 
 
I _____________________________________________ agree to my child taking part in this study.  
 
I have read and understood the information sheet on the study, version X 
 
YES   NO  
I have been given the opportunity to ask questions and I am satisfied with the 
answers that you have given me. 
 
YES   NO  
I agree to my contact details being given to the study team so that they can 
contact me to arrange the interview and about other study arrangement 
matters. 
YES   NO  
I understand that the researcher will interview my child for about an hour about 
my child’s experience of growing up with HIV and being on HIV treatment. 
 
YES   NO  
I agree to this interview being audio-recorded.   
YES   NO  
I know that my child does not have to talk about things that he/she does not 
want to talk about. My child can stop talking to the researchers at any time and 
without giving a reason for this.  
YES   NO  
I understand that everything that my child talks to the researchers about is 
confidential. However if the researchers are told that a child is at serious risk of 
harm, they may have to pass this information on to someone else.  
 
YES   NO  
I agree that anonymised direct quotes from the interview may be used in the 
public reporting of this study.   
YES   NO  
 
 
 
 
 
 
 
 
 
My questions have been answered by …………………………………………………………… 
 
 
Parent/carer’s signature 
(or thumbprint) 
Print name 
Date 
 
 
 
Witness’ signature 
(if thumbprint used above) 
Print name 
Date 
 
 
 
The person who explained the study to you needs to sign too: 
 
I have provided the Qualitative study information to the potential participant’s parent/legal 
guardian in full and answered all his/her questions. To the best of my knowledge, he/she 
understands the purpose, interventions, risks and benefits of this study and willingly agrees to 
participate in the Qualitative study.  
Signature of person 
conducting the informed 
consent process 
Print name 
Date  


ODYSSEY Protocol  
Version 6.0 8th November 2019 
ODYSSEY (PENTA 20)    
 
 
 
 
 
 
 
 
Page 233 of 324 
 
 
 
IMPORTANT:  one signed original to be kept in ODYSSEY trial file by the researcher 
 
 
 
one signed copy to be given to the participant  
 
 
one signed copy to be kept in the clinic file 
 
 


ODYSSEY Protocol  
Version 6.0 8th November 2019 
ODYSSEY (PENTA 20)    
 
 
 
 
 
 
 
 
Page 234 of 324 
ODYSSEY QUALITATIVE STUDY: 
ASSENT FORM FOR FOCUS GROUP DISCUSSIONS (10-17 YEAR OLDS)  
 (To be printed on local-headed paper) 
(Insert version no and date) 
Please tick yes or no to answer the questions below.   
 
1. Have you read (or had read to you) the information about this study? 
 
YES   NO  
2. Has somebody explained the study to you? 
YES   NO  
3. Do you understand what the study is about? 
YES   NO  
4. Have you asked all the questions you want?   
YES   NO  
5. Have your questions been answered in a way you understand? 
YES   NO  
6. Do you understand it’s OK to stop taking part at any time? 
YES   NO  
7. Do you understand that you don’t have to answer any questions that you do 
not want to? 
YES   NO  
8. Do you understand that there will be two focus groups that we would like 
you to take part in? 
YES   NO  
9. Do you understand that you should not tell anyone what you hear about 
other people in the focus groups, but that you can talk about it with the 
researchers and clinic counsellors?     
YES   NO  
10. Is it OK if we audio record our discussions? 
YES   NO  
11. Are you happy to take part? 
YES   NO  
 
If you do want to take part, you can sign your name below. 
 
If any answers are ‘no’ or you don’t want to take part, don’t sign your name. 
If you do want to take part, you can sign your name below. 
 
Participant’s signature 
(or thumbprint) 
Print name 
Date 
 
 
 
Witness’ signature 
(if thumbprint used above) 
Print name 
Date 
 
 
 
The person who explained the study to you needs to sign too: 
 


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I have provided the Qualitative study information to the potential participant in full and answered 
all his/her questions. To the best of my knowledge, he/she understands the purpose, interventions, 
risks and benefits of this study and willingly agrees to participate in the Qualitative study.  
Signature of person 
conducting the informed 
consent process 
Print name 
Date  
 
 
 
IMPORTANT:  one signed original to be kept in ODYSSEY trial file by the researcher 
 
 
 
one signed copy to be given to the participant  
 
 
one signed copy to be kept in the clinic file 
 
 
Thank you for your help! 
 
 


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ODYSSEY QUALITATIVE STUDY: 
CONSENT FORM FOR FOCUS GROUP DISCUSSIONS (YOUNG PEOPLE OVER 18-19 YEARS)  
 
(To be printed on local-headed paper) 
(Insert version no and date) 
 
I _____________________________________________ agree to taking part in this study.  
I have read and understood the information sheet on the ODYSSEY 
qualitative study, version……..  
 
YES   NO  
I have been given the opportunity to ask questions and I am satisfied with 
the answers that you have given me. 
 
 
YES   NO  
I agree to my contact details being given to the qualitative study team and 
understand that they will contact me. 
YES   NO  
I understand that I am being asked to participate in two focus groups.  For 
each focus group this will involve the researcher talking with me and up to 
seven other young people for about an hour about their experiences of being 
on second-line HIV treatment.  
YES   NO  
I agree to the focus groups being audio-recorded. 
YES   NO  
I know that I do not have to talk about things that I do not want to talk about.  
I understand that I can stop talking to the researchers at any time and 
without  
giving a reason for this.  
YES   NO  
I understand that everything that I to the group about is confidential. I 
understand that I and the other participants will agree to not talk about what 
anyone else says in the focus groups, except for with the researchers and 
counsellors.  
 
YES   NO  
I agree that anonymised direct quotes from the focus groups may be used. 
YES   NO  
 
My questions have been answered by …………………………………………………………… 
 
 
Participant’s signature 
(or thumbprint) 
Print name 
Date 
 
 
 
Witness’ signature 
(if thumbprint used above) 
Print name 
Date 
 
 
 
The person who explained the study to you needs to sign too: 
 
I have provided the Qualitative study information to the potential participant in full and answered 
all his/her questions. To the best of my knowledge, he/she understands the purpose, interventions, 
risks and benefits of this study and willingly agrees to participate in the Qualitative study.  


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Signature of person 
conducting the informed 
consent process 
Print name 
Date  
 
 
 
IMPORTANT:  one signed original to be kept in ODYSSEY trial file by the researcher 
 
 
 
one signed copy to be given to the participant  
 
 
one signed copy to be kept in the clinic file 
 
 
 
 
 


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ODYSSEY QUALITATIVE STUDY: 
CONSENT FORM FOR FOCUS GROUP DISCUSSIONS (PARENT/CARERS)  
(To be printed on local-headed paper) 
(Insert version no and date) 
 
I _____________________________________________ agree to my child taking part in this study.  
 
I have read and understood the information sheet on the ODYSSEY 
qualitative study, version……..  
 
 
 
 
 
 
YES   NO  
I have been given the opportunity to ask questions and I am satisfied with 
the answers that you have given me. 
YES   NO  
I agree to my contact details being given to the qualitative study team and 
understand that they will contact me should my child be selected to take part 
in the study.  
 
YES   NO  
I understand that my child will participate in two focus groups. For each focus 
group this will involve them talking with my child and up to seven other 
young people for about an hour about their experiences of being on second-
line HIV treatment. 
YES   NO  
I agree to the focus groups being audio-recorded. 
YES   NO  
I know that my child does not have to talk about things that he/she does not 
want to talk about. My child can stop talking to the researchers at any time 
and without giving a reason for this. 
 
YES   NO  
I understand that everything that my child talks to the researchers about is 
confidential and that my child and other participants will agree to not talking 
about what anyone else says in the focus group, except for with the 
researchers and counsellors.  
 
 
 
 
 
YES   NO  
I understand that  if the researchers are told that a child is at serious risk of 
harm, they may have to pass this information on to someone else. 
 
YES   NO  
I agree that anonymised direct quotes from the focus group may be used.  
 
YES   NO  
 
My questions have been answered by …………………………………………………………… 
 
 
Parent/carer’s signature 
(or thumbprint) 
Print name 
Date 
 
 
 
Witness’ signature 
(if thumbprint used above) 
Print name 
Date 
 
 
 
The person who explained the study to you needs to sign too: 
 


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I have provided the Qualitative study information to the potential participant’s parent/legal 
guardian in full and answered all his/her questions. To the best of my knowledge, he/she 
understands the purpose, interventions, risks and benefits of this study and willingly agrees to 
participate in the Qualitative study.  
Signature of person 
conducting the informed 
consent process 
Print name 
Date  
 
 
 
IMPORTANT:  one signed original to be kept in ODYSSEY trial file by the researcher 
 
 
 
one signed copy to be given to the participant  
 
 
one signed copy to be kept in the clinic file 
 
 
 
 
 


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CONSENT FORMS AND ASSENT FORMS FOR YOUTH TRIAL BOARD PROJECT  
Consent/ assent forms for in-depth interviews - IDIs (10-18 year olds) 
 
Assent form - 10-17 years olds 
 
Consent form - 18 year olds 
 
Consent form - parents/ carers 
 
Consent form – YTB facilitators  


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YOUTH TRIAL BOARD PROJECT  
ASSENT FORM FOR YOUTH TRIAL BOARD PROJECT FOR YOUNG PEOPLE   
(To be printed on local-headed paper) 
(Insert version no and date) 
 
I _____________________________________________ agree to taking part in this project.  
 
I have read and understood the information sheet on the Youth Trial Board 
project, version…….. 
 
YES   NO  
I have been given the chance to ask questions and I am happy with the answers 
that you have given me. 
YES   NO  
I understand that being a Youth Trial Board member means that what we say 
and discuss in our meetings over the course of the project may be observed and 
notes taken.  
 
YES   NO  
I understand that I am being asked to take part in an individual interview about 
my experiences participating in the Youth Trials Board project. 
YES   NO  
I understand that everything that is said in the meetings is confidential and that 
the notes will be anonymised.   
YES   NO  
I understand that at any time I can withdraw my consent for the observations 
about what I say in the meetings and the interview to be used.   
YES   NO  
I agree that anonymised direct quotes from the meetings and interview can be 
used. 
 
 
YES   NO  
 
My questions have been answered by …………………………………………………………… 
 
If any answers are ‘no’ or you don’t want to take part, don’t sign your name. 
If you do want to take part, you can sign your name below. 
 
Participant’s signature 
(or thumbprint) 
Print name 
Date 
 
 
 
Witness’ signature 
(if thumbprint used above) 
Print name 
Date 
 
 
 
The person who explained the project to you needs to sign too: 
 
I have provided the Youth Trial Board project information to the potential participant in full and 
answered all his/her questions. To the best of my knowledge, he/she understands the purpose, 
interventions, risks and benefits of this study and willingly agrees to participate in the Youth Trial 
Board project.  
Signature of person 
conducting the informed 
consent process 
Print name 
Date  
 
 


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IMPORTANT:  one signed original to be kept in ODYSSEY trial file by the researcher 
 
 
 
one signed copy to be given to the participant  
 
 
one signed copy to be kept in the clinic file 
 


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YOUTH TRIAL BOARD PROJECT  
CONSENT FORM FOR YOUTH TRIAL BOARD PROJECT FOR YOUNG ADULT PARTICIPANTS 
(To be printed on local-headed paper) 
(Insert version no and date) 
 
I _____________________________________________ agree to taking part in this project.  
 
I have read and understood the information sheet on the Youth Trial Board 
project, version…….. 
 
YES   NO  
I have been given the chance to ask questions and I am happy with the 
answers that you have given me. 
YES   NO  
I understand that being a Youth Trial Board member means that what we 
say and discuss in our meetings over the course of the project may be 
observed and notes taken. 
YES   NO  
I understand that I am taking part in an individual interview about my experiences 
participating in the Youth Trials Board project.  
YES   NO  
I understand that everything that is said in the meetings and interview is 
confidential and that the notes will be anonymised. 
YES   NO  
I understand that at any time I can withdraw my consent for the 
observations about what I say in the meetings and the interview to be used. 
YES   NO  
I agree that anonymised direct quotes from the meetings and interview can 
be used. 
 
YES   NO  
 
My questions have been answered by …………………………………………………………… 
 
Participant’s signature 
(or thumbprint) 
Print name 
Date 
 
 
 
Witness’ signature 
(if thumbprint used above) 
Print name 
Date 
 
 
 
The person who explained the study to you needs to sign too: 
I have provided the Youth Trial Board project information to the potential participant in full and 
answered all his/her questions. To the best of my knowledge, he/she understands the purpose, 
interventions, risks and benefits of this study and willingly agrees to participate in the Youth Trial 
Board project.  


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Signature of person 
conducting the informed 
consent process 
Print name 
Date  
 
 
 
IMPORTANT:  one signed original to be kept in ODYSSEY trial file by the researcher 
 
 
 
one signed copy to be given to the participant  
 
 
one signed copy to be kept in the clinic file 
 
 
 
 


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YOUTH TRIAL BOARD PROJECT  
CONSENT FORM FOR YOUTH TRIAL BOARD PROJECT FOR PARENTS/ GUARDIANS 
(To be printed on local-headed paper) 
(Insert version no and date) 
 
I _____________________________________________ agree to taking part in this project.  
 
I have read and understood the information sheet on the Youth Trial Board 
project, version…….. 
 
YES   NO  
I have been given the chance to ask questions and I am happy with the 
answers that you have given me. 
YES   NO  
I understand that my child being a Youth Trial Board member means that 
what they say and discuss in the meetings over the course of the project 
may be observed and notes taken. 
YES   NO  
I understand that my child will take part in an individual interview about their 
experiences participating in the Youth Trials Board project.  
YES   NO  
I understand that everything that is said in the meetings and interview is 
confidential and that the notes will be anonymised.  
 
YES   NO  
I agree that anonymised direct quotes from the meetings and interview can 
be used. 
 
YES   NO  
 
My questions have been answered by …………………………………………………………… 
 
Parent/carer’s signature 
(or thumbprint) 
Print name 
Date 
 
 
 
Witness’ signature 
(if thumbprint used above) 
Print name 
Date 
 
 
 
The person who explained the study to you needs to sign too: 
 
I have provided the Youth Trial Board project information to the potential participant’s parent/legal 
guardian in full and answered all his/her questions. To the best of my knowledge, he/she 
understands the purpose, interventions, risks and benefits of this study and willingly agrees to 
participate in the Youth Trial Board project.  
Signature of person 
conducting the informed 
consent process 
Print name 
Date  


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IMPORTANT:  one signed original to be kept in ODYSSEY trial file by the researcher 
 
 
 
one signed copy to be given to the participant  
 
 
one signed copy to be kept in the clinic file 
 
 


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YOUTH TRIAL BOARD PROJECT  
CONSENT FORM FOR YOUTH TRIAL BOARD PROJECT FOR FACILITATORS 
(To be printed on local-headed paper) 
(Insert version no and date) 
 
I _____________________________________________ agree to taking part in this project.  
 
I have read and understood the information sheet on the Youth Trial Board project, 
version…….. 
 
YES   NO  
I have been given the chance to ask questions and I am happy with the answers 
that you have given me. 
YES   NO  
I understand that I am taking part in an individual interview about my experiences 
participating in the Youth Trials Board project.  
YES   NO  
I understand that everything that is said in the interview is confidential and that the 
notes will be anonymised. 
YES   NO  
I understand that at any time I can withdraw my consent for what I say in the 
interview to be used. 
YES   NO  
I agree that anonymised direct quotes from interview can be used. 
 
YES   NO  
 
My questions have been answered by …………………………………………………………… 
 
Participant’s signature 
(or thumbprint) 
Print name 
Date 
 
 
 
Witness’ signature 
(if thumbprint used above) 
Print name 
Date 
 
 
 
The person who explained the study to you needs to sign too: 
I have provided the Youth Trial Board project information to the potential participant in full and 
answered all his/her questions. To the best of my knowledge, he/she understands the purpose, 
interventions, risks and benefits of this study and willingly agrees to participate in an interview 
about the the Youth Trial Board project.  
Signature of person 
conducting the informed 
consent process 
Print name 
Date  
 
 


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IMPORTANT:  one signed original to be kept in ODYSSEY trial file by the researcher 
 
 
 
one signed copy to be given to the participant  
 
 
one signed copy to be kept in the clinic file 
 
 


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21 APPENDIX III  TEMPLATE GP LETTER  
(To be printed on local headed paper).  
(Insert version no and date) 
 
Dear Dr ________________________________  
 
 
 
The parents of________________________and him/herself, have agreed to participate in the 
ODYSSEY study.  This is a randomised multicentre international trial co-ordinated by PENTA, which is 
funded by the European Commission (see www.PENTA-ID.org). 
 
ODYSSEY aims to compare the efficacy and toxicity of antiretroviral regimens containing two NRTIs 
and the new integrase inhibitor dolutegravir versus standard combination regimens containing 
two/three NRTIs and either an NNRTI, a protease inhibitor or a first generation integrase inhibitor, 
raltegravir. Adherence to and acceptability of the different regimens will also be compared.  
 
The trial will enrol 700 children under 18 years of age from clinical centres in Europe, Africa, Asia, 
North and South America and will include 2 groups of children: those initiating antiretroviral therapy 
and those switching to a second-line regimen. All children will be followed until the last patient 
recruited has completed 96 weeks of follow-up.  
 
 
Your patient has been randomised to: 
 dolutegravir containing regimen  
 standard combination therapy. 
 
 
I would be very grateful if you could inform me of any concomitant medication that you prescribe to 
this child during the study. 
 
I enclose a summary of the trial and a copy of the Patient Information Sheet. If you would like a copy 
of the full protocol or have any comments or problem, please contact: 
 
Dr _____________________ 
 
Enc.  
Trial Summary 
Patient Information Sheet 


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22 APPENDIX IV  TEMPLATE ADHERENCE QUESTIONNAIRES 
 
 
 


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23 APPENDIX V  TEMPLATE ACCEPTABILITY QUESTIONNAIRES 


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24 APPENDIX VI  ADAPTED WHO CLINICAL STAGING OF HIV/AIDS FOR PATIENTS WITH 
CONFIRMED HIV INFECTION  
The table below summarising WHO clinical staging for children and adolescents (1); Diagnostic 
criteria for these conditions, are described in Appendix VII 
 
 
Children (<15 years of age)  
 
Adolescents (≥15 years of age)  
Clinical Stage 1 
 
Clinical Stage 1 
 
 
Asymptomatic 
 
Persistent generalized lymphadenopathy 
 
 
 
Asymptomatic 
 
Persistent generalized lymphadenopathy 
Clinical stage 2 
 
Clinical stage 2 
 
 
Unexplained persistent 
hepatosplenomegaly 
 
Papular pruritic eruptions 
 
Fungal nail infection 
 
Angular cheilitis 
 
Lineal gingival erythema 
 
Extensive wart virus infection 
 
Extensive molluscum contagiosum 
 
Recurrent oral ulcerations 
 
Unexplained persistent parotid 
enlargement 
 
Herpes zoster 
 
Recurrent or chronic upper respiratory 
tract infections (otitis media, otorrhoea, 
sinusitis or tonsillitis) 
 
 
 
Moderate unexplained weight loss 
(<10% of presumed or measured body 
weight) 
 
Recurrent respiratory tract infections 
(sinusitis, tonsillitis, otitis media and 
pharyngitis) 
 
Herpes zoster 
 
Angular cheilitis 
 
Recurrent oral ulceration 
 
Papular pruritic eruptions 
 
Seborrhoeic dermatitis 
 
Fungal nail infections 
Clinical Stage 3  ( *= severe WHO clinical stage 3 for the ODYSSEY trial) 
 
 
 
Unexplained moderate malnutrition or 
wasting not adequately responding to 
standard therapy* 
 
Unexplained persistent diarrhoea (14 
days or more) 
 
Unexplained persistent fever (above 
37.5°C intermittent or constant, 
for longer than one month) 
 
Persistent oral candidiasis (after first 6–8 
weeks of life)* 
 
Oral hairy leukoplakia 
 
Acute necrotizing ulcerative gingivitis or 
periodontitis 
 
Lymph node tuberculosis 
 
 
Unexplained severe weight loss (>10% of 
presumed or measured body weight)* 
 
Unexplained chronic diarrhoea for 
longer than one month 
 
Unexplained persistent fever (above 
37.6°C intermittent or constant, 
for longer than one month) 
 
Persistent oral candidiasis* 
 
Oral hairy leukoplakia 
 
Pulmonary tuberculosis (current) 
 
Severe bacterial infections (such as 
pneumonia, empyema, pyomyositis, 
bone or joint infection, meningitis or 
bacteraemia) 


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 
Pulmonary tuberculosis 
 
Severe recurrent bacterial pneumonia 
 
Symptomatic lymphoid interstitial 
pneumonitis* 
 
Chronic HIV-associated lung disease 
including bronchiectasis* 
 
Unexplained anaemia (<8 g/dl), 
neutropaenia (<0.5 × 109 per litre)and or 
chronic thrombocytopaenia (<50 × 109 
per litre) 
 
Acute necrotizing ulcerative stomatitis, 
gingivitis or periodontitis 
 
Unexplained anaemia (<8 g/dl), 
neutropaenia (<0.5 × 109 per litre) or 
chronic thrombocytopaenia (<50 × 109 
per litre) 
Clinical Stage 4 
 
 
 
Unexplained severe wasting, stunting or 
severe malnutrition not responding to 
standard therapy 
 
Pneumocystis pneumonia 
 
Recurrent severe bacterial infections 
(such as empyema, pyomyositis, bone or 
joint infection or meningitis but 
excluding pneumonia) 
 
Chronic herpes simplex infection 
(orolabial or cutaneous of more than 
one month’s duration or visceral at any 
site) 
 
Oesophageal candidiasis (or candidiasis 
of trachea, bronchi or lungs) 
 
Extrapulmonary tuberculosis 
 
Kaposi’s sarcoma 
 
Cytomegalovirus infection: retinitis or 
cytomegalovirus infection affecting 
another organ, with onset at age older 
than one month 
 
Central nervous system toxoplasmosis 
(after one month of life) 
 
Extrapulmonary cryptococcosis 
(including meningitis) 
 
HIV encephalopathy 
 
Disseminated endemic mycosis 
(coccidiomycosis or histoplasmosis) 
 
Disseminated non-tuberculous 
mycobacterial infection 
 
Chronic cryptosporidiosis (with 
diarrhoea) 
 
Chronic isosporiasis 
 
Cerebral or B-cell non-Hodgkin 
lymphoma 
 
Progressive multifocal 
leukoencephalopathy 
 
Symptomatic HIV-associated 
nephropathy or HIV-associated 
cardiomyopathy 
 
 
HIV wasting syndrome 
 
Pneumocystis pneumonia 
 
Recurrent severe bacterial pneumonia 
 
Chronic herpes simplex infection 
(orolabial, genital or anorectal 
of more than one month’s duration or 
visceral at any site) 
 
Oesophageal candidiasis (or candidiasis 
of trachea, bronchi or lungs) 
 
Extrapulmonary tuberculosis 
 
Kaposi’s sarcoma 
 
Cytomegalovirus infection (retinitis or 
infection of other organs) 
 
Central nervous system toxoplasmosis 
 
HIV encephalopathy 
 
Extrapulmonary cryptococcosis including 
meningitis 
 
Disseminated non-tuberculous 
mycobacterial infection 
 
Progressive multifocal 
leukoencephalopathy 
 
Chronic cryptosporidiosis (with 
diarrhoea) 
 
Chronic isosporiasis 
 
Disseminated mycosis (coccidiomycosis 
or histoplasmosis) 
 
Recurrent non-typhoidal Salmonella 
bacteraemia 
 
Lymphoma (cerebral or B-cell non-
Hodgkin) or other solid HIV-associated 
tumours 
 
Invasive cervical carcinoma 
 
Atypical disseminated leishmaniasis 
 
Symptomatic HIV-associated 
nephropathy or symptomatic HIV-
associated cardiomyopathy 


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References: 
1.   World Health Organization. WHO case definitions of HIV for surveillance, and revised clinical 
staging and immunological classification of HIV related disease in adults and children. Geneva: 
World Health Organization; 2007. 
 


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25 APPENDIX VII  ADAPTED DIAGNOSTIC CRITERIA FOR WHO CLINICAL STAGING EVENTS IN 
CHILDREN YOUNGER THAN 15 YEARS  
The table is reproduced from WHO case definitions of HIV for surveillance and revised clinical staging 
and immunological classification of HIV-related disease in adults and children (1). Definitions for 
moderate (grade 3) and severe (grade 4) malnutrition are modified using definitions from WHO (1) 
and CDC (2,3). 
CLINICAL EVENT 
CLINICAL DIAGNOSIS 
DEFINITIVE DIAGNOSIS  
Clinical Stage 1 
Asymptomatic 
No HIV related symptoms reported and no clinical 
signs on examination. 
Not applicable. 
 
Persistent 
generalized 
lymphadenopathy  
Persistent swollen or enlarged lymph nodes >1 cm 
at two or more non-contiguous sites (excluding 
inguinal) without known cause. 
Clinical diagnosis 
Clinical Stage 2 
Unexplained 
persistent 
hepatosplenomeg
aly  
Enlarged liver and spleen without obvious cause. 
Clinical diagnosis 
 
Papular pruritic 
eruptions 
Papular pruritic vesicular lesions. Also common in 
uninfected children: scabies and insect bites should 
be excluded.  
Clinical diagnosis 
Extensive wart 
virus infection 
Characteristic warty skin lesions; small fleshy grainy 
bumps, often rough, flat on sole of feet (plantar 
warts); facial, more than 5% of body area or 
disfiguring. 
Clinical diagnosis 
Extensive 
molluscum 
contagiosum 
infection 
 
Characteristic skin lesions: small flesh-coloured, 
pearly or pink, dome-shaped or umbilicated growths 
may be inflamed or red; facial, more than 5% of 
body area or disfiguring. Giant molloscum may 
indicate more advanced immunodeficiency 
Clinical diagnosis 
Fungal nail 
infections 
Fungal paronychia (painful, red and swollen nail 
bed) or onycholysis (painless separation of the nail 
from the nail bed.) Proximal white subungual 
onchomycosis is uncommon without 
immunodeficiency 
Clinical diagnosis 
Recurrent oral 
ulcerations  
 
Current event plus at least one previous episode in 
past six months. Aphthous ulceration, typically with 
a halo of inflammation & yellow-grey 
pseudomembrane.  
Clinical diagnosis 
Unexplained 
persistent parotid 
enlargement  
 
Asymptomatic bilateral swelling that may 
spontaneously resolve and recur, in absence of 
other known cause, usually painless 
Clinical diagnosis 
Lineal gingival 
erythema  
Erythematous band that follows the contour of the 
free gingival line; may be associated with 
spontaneous bleeding 
Clinical diagnosis 
Herpes zoster  
 
Painful rash with fluid-filled blisters, dermatomal 
distribution, can be haemorrhagic on erythematous 
background, and can become large and confluent. 
Does not cross the midline 
Clinical diagnosis 


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CLINICAL EVENT 
CLINICAL DIAGNOSIS 
DEFINITIVE DIAGNOSIS  
Recurrent upper 
respiratory tract 
infection  
 
Current event with at least one episode in past 6 
months. Symptom complex; fever with unilateral 
face pain and nasal discharge (sinusitis) or painful 
swollen eardrum (otitis media), sore throat with 
productive cough (bronchitis), sore throat 
(pharyngitis) and barking croup-like cough (LTB). 
Persistent or recurrent ear discharge.  
Clinical diagnosis 
Clinical Stage 3 
Unexplained 
moderate 
malnutrition* 
Weight loss: low weight-for-age or weight-for-height 
up to −2 standard deviations from the mean OR clear 
deviation from a previous growth trajectory or 
documented crossing of percentile lines, not explained 
by poor or inadequate feeding and or other 
infections, and not adequately responding to 
standard management. 
Documented loss of body 
weight of -2 standard 
deviations from the mean 
OR or documented 
crossing of percentile 
lines, 
failure to gain weight on 
standard management and 
no other cause identified 
during investigation. 
Unexplained 
persistent 
diarrhoea  
 
Unexplained persistent (14 days or more) diarrhoea 
(loose or watery stool, three or more times daily), 
not responding to standard treatment.  
Confirmed by stools 
observed and documented 
as unformed. Culture and 
microscopy reveal no 
pathogens. 
Unexplained 
persistent fever 
(>37.5oC 
intermittent or 
constant for 
longer than one 
month) 
Reports of fever or night sweat for longer than one 
month, either intermittent or constant, with 
reported lack of response to antibiotics or 
antimalarial agents. No other obvious foci of disease 
reported or found on examination. Malaria must be 
excluded in malaria areas. 
Confirmed by documented 
fever of >37.50 ◦C with 
negative blood culture, 
negative malaria slide and 
normal or unchanged 
chest X-ray, and no other 
obvious foci of disease.  
Oral candidiasis 
(after first 6-8 
weeks of life) 
Persistent or recurring creamy white to yellow soft 
small plaques which can be scraped off 
(pseudomembranous), or red patches on tongue, 
palate or lining of mouth, usually painful or tender 
(erythematous form).  
Confirmed by microscopy 
or culture.  
Oral hairy 
leukoplakia 
Fine small linear patches on lateral borders of 
tongue, generally bilaterally, which do not scrape 
off.  
Clinical diagnosis 
Lymph node 
tuberculosis 
Non acute, painless "cold" enlargement of 
peripheral lymph nodes, localized to one region. 
May have draining sinuses. Response to standard 
anti- tuberculosis treatment in one month. 
Confirmed by histology or 
fine needle aspirate for 
Ziehl-Nielsen stain or 
culture.  
Pulmonary 
tuberculosis 
  
Nonspecific symptoms, e.g. chronic cough, fever, 
night sweats, anorexia and weight loss. In the older 
child also productive cough and haemoptysis. 
History of contact with adults with smear-positive 
pulmonary tuberculosis. No response to standard 
broad-spectrum antibiotic treatment. 
Confirmed by one or more 
sputum positive smear for 
acid-fast bacilli and/or 
radiographic abnormalities 
consistent with active 
tuberculosis and/or 
culture-positive for 
Mycobacterium.  


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CLINICAL EVENT 
CLINICAL DIAGNOSIS 
DEFINITIVE DIAGNOSIS  
Severe recurrent 
bacterial 
pneumonia  
Cough with fast breathing, chest indrawing, nasal 
flaring, wheezing, and grunting. Crackles or 
consolidation on auscultation. Responds to course 
of antibiotics. Current episode plus one or more in 
previous 6 months. 
Confirmed by isolation of 
bacteria from appropriate 
clinical specimens 
(induced sputum, BAL, 
lung aspirate).  
Acute necrotizing 
ulcerative 
gingivitis or 
stomatitis, or 
acute necrotizing 
ulcerative 
periodontitis  
Severe pain, ulcerated gingival papillae, loosening of 
teeth, spontaneous bleeding, bad odour, and rapid 
loss of bone and/or soft tissue. 
Clinical diagnosis 
Symptomatic 
lymphocytic 
interstitial 
pneumonitis 
No presumptive clinical diagnosis. 
Diagnosed by chest X-ray: 
bilateral reticulonodular 
interstitial pulmonary 
infiltrates present for 
more than two months 
with no response to 
antibiotic treatment and 
no other pathogen found. 
Oxygen saturation 
persistently <90%. May 
present with cor 
pulmonale and increased 
exercise-induced fatigue. 
Characteristic histology. 
Chronic HIV-
associated lung 
disease (including 
bronchiectasis) 
History of cough productive of copious amounts of 
purulent sputum (bronchiectasis only), with or 
without clubbing, halitosis, and crepitations and/or 
wheezes on auscultation 
Confirmed by chest X-ray: 
may show honeycomb 
appearance (small cysts) 
and/or persistent areas of 
opacification and/or 
widespread lung 
destruction, with fibrosis 
and loss of volume.  
Unexplained 
anaemia (<8g/dl), 
or neutropaenia 
(<0.5 x 109 per 
litre) and/or 
chronic 
thrombocytopaeni
a (<50 x 109 per 
litre)  
No presumptive clinical diagnosis. 
Diagnosed on laboratory 
testing, not explained by 
other non-HIV conditions, 
not responding to 
standard therapy with 
haematinics, antimalarial 
agents or anthelmintic 
agents as outlined in WHO 
Integrated Management of 
Childhood Illness (IMCI) 
guidelines.  
Clinical Stage 4 
Unexplained 
severe wasting, 
stunting or severe 
malnutrition not 
adequately 
Persistent weight loss, stunting, wasting or 
malnutrition not explained by poor or inadequate 
feeding, other infections and not adequately 
responding in two weeks to standard therapy. 
Visible severe wasting of muscles, with or without 
Documented weight for 
height or weight for age of 
more than –3 standard 
deviations from the mean 


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CLINICAL EVENT 
CLINICAL DIAGNOSIS 
DEFINITIVE DIAGNOSIS  
responding to 
standard therapy*  
 
oedema of both feet, and/or weight-for-height of –3 
standard deviations from the mean or downward 
crossing of at least two weight percentile lines. 
or documented downward 
crossing of at least two 
complete weight 
percentile lines with or 
without oedema  
Pneumocystis 
pneumonia  
Dry cough, progressive difficulty in breathing, 
cyanosis, tachypnoea and fever; chest indrawing or 
stridor. (Severe or very severe pneumonia as in 
WHO IMCI guidelines). Usually rapid onset especially 
in infants under six months of age. Response to 
high-dose co-trimoxazole with or without 
prednisolone. Chest X-ray shows typical bilateral 
perihilar diffuse infiltrates 
Confirmed by: cytology or 
immunofluorescent 
microscopy of induced 
sputum or BAL or histology 
of lung tissue.  
 
Recurrent severe 
bacterial 
infection, e.g. 
empyema, 
pyomyositis, bone 
or joint infection 
or meningitis but 
excluding 
pneumonia 
Fever accompanied by specific symptoms or signs 
that localize infection. Responds to antibiotics. 
Current episode plus one or more in previous 6 
months 
Confirmed by culture of 
appropriate clinical 
specimen.  
Chronic herpes 
simplex infection; 
(orolabial or 
cutaneous of 
more than 
one month's 
duration or 
visceral at any 
site)  
Severe and progressive painful orolabial, genital, or 
anorectal lesions caused by HSV infection present 
for more than one month.  
 
Confirmed by culture 
and/or histology 
Oesophageal 
candidiasis 
(or candidiasis of 
trachea, bronchi 
or lungs). 
Difficulty in swallowing or pain on swallowing (food 
and fluids). In young children, suspect particularly if 
oral Candida observed and food refusal occurs 
and/or difficulties or crying when feeding.  
Confirmed by macroscopic 
appearance at endoscopy, 
microscopy of specimen 
from tissue or macroscopic 
appearance at 
bronchoscopy or histology.  
Extrapulmonary or 
disseminated 
tuberculosis 
Systemic illness usually with prolonged fever, night 
sweats, and weight loss. Clinical features of organs 
involved, e.g. sterile pyuria, pericarditis, ascites, 
pleural effusion, meningitis, arthritis or orchiti, 
pericardial or abdominal  
Confirmed by positive 
microscopy showing acid-
fast bacilli or culture of 
Mycobacterium TB from 
blood or other relevant 
specimen except sputum 
or BAL. Biopsy and 
histology.  
Kaposi sarcoma  
 
 
Typical appearance in skin or oropharynx of 
persistent, initially flat, patches with a pink or blood-
bruise colour, skin lesions that usually develop into 
nodules.  
Not required but may be 
confirmed by: 
- typical red-purple lesions 
seen on bronchoscopy or 
endoscopy;  


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CLINICAL EVENT 
CLINICAL DIAGNOSIS 
DEFINITIVE DIAGNOSIS  
- dense masses in lymph 
nodes, viscera or lungs by 
palpation or radiology; and 
- histology. 
CMV retinitis or 
CMV infection 
affecting another 
organ, with onset 
at age over 1 
month. 
 
Retinitis only.  
CMV retinitis may be diagnosed by experienced 
clinicians: typical eye lesions on serial fundoscopic 
examination; discrete patches of retinal whitening 
with distinct borders, spreading centrifugally, often 
following blood vessels, associated with retinal 
vasculitis, haemorrhage and necrosis.  
Definitive diagnosis 
required for other sites. 
Histology. Cerebrospinal 
fluid polymerase chain 
reaction  
CNS 
toxoplasmosis 
with onset at age 
over 1 month. 
 
Fever, headache, focal neurological signs, 
convulsions. Usually responds within 10 days to 
specific therapy.  
 
Not required but 
confirmed by computed 
tomography (CT) scan (or 
other neuroimaging) 
showing single or multiple 
lesions with mass effect or 
enhancing with contrast.  
Extrapulmonary 
cryptococcosis 
(including 
meningitis) 
Meningitis: usually subacute, fever with increasing 
severe headache, meningism, confusion and 
behavioural changes that respond to cryptococcal 
therapy. 
Confirmed by CSF 
microscopy (India ink or 
Gram stain), serum or CSF 
CRAG test or culture. 
HIV 
encephalopathy  
At least one of the following, progressing over at 
least two months in the absence of another illness:  
- failure to attain, or loss of, developmental 
milestones, loss of intellectual ability; OR 
- progressive impaired brain growth demonstrated 
by stagnation of head circumference; OR 
- acquired symmetric motor deficit accompanied by 
two or more of the following: paresis, pathological 
reflexes, ataxia, gait disturbances.  
Confirmed by 
neuroimaging (brain CT 
scan or MRI) 
demonstrating atrophy 
and basal ganglia 
calcification and excluding 
other causes.  
Disseminated 
mycosis 
(coccidiomycosis, 
histoplasmosis, 
penicilliosis)  
 
 
No presumptive clinical diagnosis. 
Diagnosed by: 
Histology: usually 
granuloma formation.  
Isolation: antigen 
detection from affected 
tissue; culture or 
microscopy from clinical 
specimen or blood culture. 
Disseminated 
mycobacteriosis,  
other than TB  
No presumptive clinical diagnosis. 
Nonspecific clinical 
symptoms including 
progressive weight loss, 
fever, anaemia, night 
sweats, fatigue or 
diarrhoea; plus culture of 
atypical mycobacterial 
species from stool, blood, 
body fluid or other body 
tissue, excluding lung. 


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CLINICAL EVENT 
CLINICAL DIAGNOSIS 
DEFINITIVE DIAGNOSIS  
Chronic 
cryptosporidiosis  
 
No presumptive clinical diagnosis. 
Confirmed by cysts 
identified on modified 
Ziehl-Nielsen microscopic 
examination of unformed 
stool 
Chronic Isospora 
 No presumptive clinical diagnosis. 
Confirmed in children with 
chronic diarrhoea by 
microscopic examination.  
 
Cerebral or B-cell 
non-Hodgkin 
lymphoma 
No presumptive clinical diagnosis. 
 
Diagnosed by CNS 
neuroimaging: at least one 
lesion with mass effect on 
brain scan; histology of 
relevant specimen  
Progressive multi 
focal 
leukoencephalopa
thy  
 
No presumptive clinical diagnosis. 
Diagnosed by progressive 
nervous system disorder 
(cognitive dysfunction, gait 
or speech disorder, visual 
loss, limb weakness and 
cranial nerve palsies) 
together with hypodense 
white matter lesions on 
neuroimaging or positive 
polyomavirus Jacob 
Creutzfeldt PCR on 
cerebrospinal fluid 
Symptomatic HIV-
associated 
nephropathy 
No presumptive clinical diagnosis. 
Renal biopsy 
Symptomatic HIV-
associated 
cardiomyopathy 
No presumptive clinical diagnosis. 
Cardiomegaly and 
evidence of poor left 
ventricular function 
confirmed by 
echocardiography 
* Modified definitions for moderate (grade 3) and severe (grade 4) malnutrition from WHO and CDC clinical stage classifications (1,2,3)  
 
References: 
1. World Health Organization. WHO case definitions of HIV for surveillance, and revised clinical 
staging and immunological classification of HIV related disease in adults and children. Geneva: 
World Health Organization; 2007. 
2. Centers for Disease Control and Prevention. 1994 revised classification system for human 
immunodeficiency virus infection in children less than 13 years of age. MMWR. 1994;43(RR-
12):1-10. 
3. 1993 revised classification system for HIV infection and expanded surveillance case definition for 
AIDS among adolescents and adults. MMWR Recommendations and reports : Morbidity and 
mortality weekly report Recommendations and reports / Centers for Disease Control. 
1992;41(RR-17):1-19. 
 


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26 APPENDIX VIII  CRITERIA FOR WHO CLINICAL STAGING EVENTS FOR YOUNG PEOPLE 15 YEARS 
AND OLDER  
Criteria for WHO clinical staging events (1). 
 
CLINICAL EVENT  
CLINICAL DIAGNOSIS  
DEFINITIVE DIAGNOSIS 
Clinical stage 1 
Asymptomatic.  
No HIV-related symptoms reported 
and no signs on examination. 
Not applicable. 
Persistent generalized 
lymphadenopathy. 
Painless enlarged lymph nodes >1 
cm in two or more non-contiguous 
sites 
(excluding inguinal) in the absence 
of known cause and persisting for 
three months or more. 
Histology. 
Clinical stage 2 
Unexplained moderate 
weight loss (<10% of 
body 
weight). 
Reported unexplained 
involuntary weight loss in 
pregnancy failure to gain 
weight. 
Documented weight loss 
<10% of body weight. 
Recurrent upper 
respiratory 
tract infections (current 
event plus one or more 
in 
last six-month period). 
Symptom complex, such as 
unilateral face pain with nasal 
discharge (sinusitis), 
painful inflamed eardrum (otitis 
media) or 
tonsillopharyngitis without features 
of viral infection  (such as coryza or 
cough). 
Laboratory studies where  
available, such as culture of 
suitable body fluid. 
Herpes zoster. 
Painful vesicular rash in dermatomal 
distribution of a nerve supply, does 
not 
cross the midline. 
Clinical diagnosis. 
Angular cheilitis. 
Splits or cracks at the angle of the 
mouth not due to iron or vitamin 
deficiency, usually respond to 
antifungal treatment. 
Clinical diagnosis. 
Recurrent oral 
ulceration 
(two or more episodes 
in 
last six months). 
Aphthous ulceration, typically 
painful with a halo of inflammation 
and a yellow grey 
pseudomembrane. 
Clinical diagnosis. 
Papular pruritic 
eruption. 
Papular pruritic lesions, often with 
marked postinflammatory 
pigmentation. 
Clinical diagnosis. 
Seborrhoeic dermatitis. 
Itchy scaly skin condition, 
particularly affecting hairy areas 
(scalp, axillae, upper 
trunk and groin). 
Clinical diagnosis. 
Fungal nail infection. 
Paronychia (painful red and swollen 
nail bed) or onycholysis (separation 
of 
Fungal culture of the nail or nail 
plate material. 


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CLINICAL EVENT  
CLINICAL DIAGNOSIS  
DEFINITIVE DIAGNOSIS 
the nail from the nail bed) of the 
fingernails (white discoloration – 
especially involving proximal part of 
nail plate – with thickening and 
separation of the nail from the nail 
bed). 
Clinical stage 3 
Unexplained severe 
weight loss (more than 
10% of body weight). 
Reported unexplained involuntary 
weight loss (>10% of body weight) 
and visible thinning of face, waist 
and extremities with obvious 
wasting or body mass index <18.5 
kg/m2; in pregnancy, the weight 
loss may be masked. 
Documented loss of more than 
10% of body weight. 
Unexplained chronic 
diarrhoea for longer 
than one month. 
Chronic diarrhoea (loose or watery 
stools three or more times daily) 
reported for longer than one month. 
Three or more stools observed 
and documented as unformed, 
and two or more stool tests 
reveal no pathogens. 
Unexplained persistent 
fever 
(intermittent or 
constant and lasting for 
longer than one month). 
Fever or night sweats for more than 
one month, either intermittent or 
constant with reported lack of 
response to antibiotics or 
antimalarial agents, without other 
obvious foci of disease reported or 
found on examination; malaria must 
be excluded in malarious areas. 
Documented fever >37.5°C with 
negative blood culture, 
negative Ziehl-Nielsen stain, 
negative malaria slide, normal 
or unchanged chest X-ray and 
no other obvious focus of 
infection. 
Persistant oral 
candidiasis. 
Persistent or recurring creamy white 
curd-like plaques that can be 
scraped off (pseudomembranous) or 
red patches on tongue, palate or 
lining of mouth, usually painful or 
tender (erythematous form). 
Clinical diagnosis. 
Oral hairy leukoplakia. 
Fine white small linear or 
corrugated lesions on lateral 
borders of the tongue that do not 
scrape off. 
Clinical diagnosis. 
Pulmonary tuberculosis 
(current). 
Chronic symptoms: (lasting at least 
2–3 weeks) cough, haemoptysis, 
shortness of breath, chest pain, 
weight loss, fever, night sweats; 
PLUS EITHER 
positive sputum smear; 
OR 
negative sputum smear; 
AND 
compatible chest radiograph 
(including but not restricted to 
upper lobe infiltrates, caritation, 
pulmonary fibrosist shrinkage. No 
evidence of extrapulmonary 
disease. 
Isolation of M. tuberculosis on 
sputum culture or histology of 
lung biopsy (with compatible 
symptoms). 


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CLINICAL EVENT  
CLINICAL DIAGNOSIS  
DEFINITIVE DIAGNOSIS 
Acute necrotizing 
ulcerative gingivitis or 
necrotizing ulcerative 
periodontitis. 
Severe pain, ulcerated gingival 
papillae, loosening of teeth, 
spontaneous bleeding, bad odour 
and rapid loss of bone and/or soft 
tissue. 
Clinical diagnosis. 
Severe bacterial 
infection 
(such as pneumonia, 
meningitis, empyema, 
pyomyositis, bone or 
joint infection, 
bacteraemia and severe 
pelvic inflammatory 
disease). 
Fever accompanied by specific 
symptoms or signs that localize 
infection and response to 
appropriate antibiotic. 
Isolation of bacteria from 
appropriate clinical specimens 
(usually sterile sites). 
Unexplained anaemia 
(<8 g/dl), neutropaenia 
(<0.5 × 109 per litre) or 
chronic (more than one 
month) 
thrombocytopaenia 
(<50 × 109 per litre). 
Not presumptive clinical diagnosis. 
Diagnosed on laboratory testing 
and not explained by other non-
HIV conditions; 
not responding to standard 
therapy with haematinics, 
antimalarial agents or 
anthelmintic agents as outlined 
in relevant national treatment 
guidelines, WHO Integrated 
Management of Childhood 
Illness guidelines or other 
relevant guidelines. 
Clinical stage 4 
HIV wasting syndrome 
Unexplained involuntary weight loss 
(>10% baseline body weight), with 
obvious wasting or body mass index 
<18.5; 
PLUS EITHER 
unexplained chronic diarrhoea 
(loose or watery stools three or 
more times daily) reported for 
longer than one month; 
OR 
reports of fever or night sweats for 
more than one month without other 
cause and lack of response to 
antibiotics or antimalarial agents; 
malaria must be excluded in 
malarious areas. 
Documented weight loss (>10% 
of body weight); 
PLUS EITHER 
two or more unformed stools 
negative for pathogens; 
OR 
documented temperature of 
>37.5°C with no other cause of 
disease, negative blood culture, 
negative malaria slide and 
normal or unchanged chest X-
ray. 
Pneumocystis 
pneumonia 
Dyspnoea on exertion or 
nonproductive cough of recent 
onset (within the past three 
months), tachypnoea and fever; 
AND 
Chest X-ray evidence of diffuse 
bilateral interstitial infiltrates; 
AND 
Cytology or immunofluorescent 
microscopy of induced sputum 
or bronchoalveolar lavage or 
histology of lung tissue. 


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CLINICAL EVENT  
CLINICAL DIAGNOSIS  
DEFINITIVE DIAGNOSIS 
No evidence of bacterial 
pneumonia; bilateral crepitations on 
auscultation with or without 
reduced air entry. 
Recurrent bacterial 
pneumonia 
(this episode plus one or 
more episodes in last six 
months) 
Current episode plus one or more 
previous episodes in the past six 
months; acute onset (<2 weeks) of 
severe symptoms (such as fever, 
cough, dyspnoea, and chest pain) 
PLUS new consolidation on clinical 
examination or chest X-ray; 
response to antibiotics. 
Positive culture or antigen test 
of a compatible organism. 
Chronic herpes simplex 
virus infection  
 
(orolabial, genital or 
anorectal) of more than 
one month or visceral 
infection of any 
duration. 
Painful, progressive anogenital or 
orolabial ulceration; lesions caused 
by recurrence of herpes simplex 
virus infection and reported for 
more than one month. History of 
previous episodes. Visceral herpes 
simplex virus requires definitive 
diagnosis.  
Positive culture or DNA (by 
polymerase chain reaction) of 
herpes simplex virus or 
compatible cytology or 
histology. 
Oesophageal candidiasis 
Recent onset of retrosternal pain or 
difficulty on swallowing (food and 
fluids) together with oral candidasis. 
Macroscopic appearance at 
endoscopy or bronchoscopy, or 
by microscopy or histology. 
Extrapulmonary 
tuberculosis 
Systemic illness (such as fever, night 
sweats, weakness and weight loss). 
Other evidence for extrapulmonary 
or disseminated tuberculosis varies 
by site: Pleural, pericardia, 
peritoneal involvement, meningitis, 
mediastinal or abdominal 
lymphadenopathy or ostetis. 
Discrete peripheral lymph node 
Mycobacterium tuberculosis 
infection (especially cervical) is 
considered a less severe form of 
extrapulmonary tuberculosis. 
M. tuberculosis isolation or 
compatible histology from 
appropriate site or radiological 
evidence of miliary 
tuberculosis; (diffuse uniformly 
distributed small miliary 
shadows or micronodules on 
chest X-ray). 
Kaposi sarcoma 
Typical gross appearance in skin or 
oropharynx of persistent, initially 
flat, patches with a pink or 
violaceous colour, skin lesions that 
usually develop into plaques or 
nodules. 
Macroscopic appearance at 
endoscopy or bronchoscopy, or 
by histology. 
Cytomegalovirus 
disease 
(other than liver, spleen 
or lymph node) 
Retinitis only: may be diagnosed by 
experienced clinicians. Typical eye 
lesions on fundoscopic examination: 
discrete patches of retinal hitening 
with distinct borders, spreading 
centrifugally, often following blood 
vessels, associated with retinal 
vasculitis, haemorrhage and 
necrosis. 
Compatible histology or 
cytomegalovirus demonstrated 
in cerebrospinal fluid by culture 
or DNA (by polymerase chain 
reaction). 


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CLINICAL EVENT  
CLINICAL DIAGNOSIS  
DEFINITIVE DIAGNOSIS 
Central nervous system 
toxoplasmosis 
Recent onset of a focal nervous 
system abnormality consistent with 
intracranial disease or reduced level 
of consciousness  
AND 
response within 10 days to specific 
therapy. 
Positive serum toxoplasma 
antibody AND (if available) 
single or multiple intracranial 
mass lesion on neuroimaging 
(computed tomography or 
magnetic resonance imaging). 
HIV encephalopathy 
Disabling cognitive and/or motor 
dysfunction interfering with 
activities of daily living, progressing 
over weeks or months in the 
absence of a concurrent illness or 
condition other than HIV infection 
that might explain the findings. 
Diagnosis of exclusion: and (if 
available) neuroimaging 
(computed tomography or 
magnetic resonance imaging). 
Extrapulmonary 
cryptococcosis  
(including meningitis) 
Meningitis: usually subacute, fever 
with increasing severe headache, 
meningism, confusion, behavioural 
changes that respond to 
cryptococcal therapy. 
Isolation of Cryptococcus 
neoformans from 
extrapulmonary site or positive 
cryptococcal antigen test on 
cerebrospinal fluid or blood. 
Disseminated 
nontuberculous 
mycobacteria infection 
No presumptive clinical diagnosis. 
Diagnosed by finding atypical 
mycobacterial species from 
stool, blood, body fluid or other 
body tissue, excluding the 
lungs. 
Progressive multifocal 
leukoencephalopathy 
No presumptive clinical diagnosis. 
Progressive nervous system 
disorder (cognitive dysfunction, 
gait/speech disorder, visual 
loss, limb weakness and cranial 
nerve palsies) together with 
hypodense white matter lesions 
on neuro-imaging or positive 
polyomavirus JC polymerase 
chain reaction on cerebrospinal 
fluid. 
Chronic 
cryptosporidiosis 
(with diarrhoea lasting 
more than one month) 
No presumptive clinical diagnosis. 
Cysts identified on modified 
Ziehl-Nielsen stain microscopic 
examination of unformed stool. 
Chronic isosporiasis  
No presumptive clinical diagnosis. 
Identification of Isospora. 
Disseminated mycosis 
(coccidiomycosis or 
histoplasmosis)  
No presumptive clinical diagnosis. 
Histology, antigen detection or 
culture from clinical specimen 
or blood culture. 
Recurrent non-typhoid 
Salmonella bacteraemia 
 
No presumptive clinical diagnosis. 
Blood culture. 
Lymphoma (cerebral or 
B-cell non-Hodgkin) 
No presumptive clinical diagnosis. 
Histology of relevant specimen 
or, for central nervous system 
tumours, neuroimaging 
techniques. 
Invasive cervical 
carcinoma 
No presumptive clinical diagnosis. 
Histology or cytology. 


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CLINICAL EVENT  
CLINICAL DIAGNOSIS  
DEFINITIVE DIAGNOSIS 
Atypical disseminated 
leishmaniasis 
No presumptive clinical diagnosis. 
Diagnosed by histology 
(amastigotes visualized) or 
culture from any appropriate 
clinical specimen. 
Symptomatic HIV-
associated nephropathy 
No presumptive clinical diagnosis. 
Renal biopsy. 
Symptomatic HIV-
associated 
cardiomyopathy 
No presumptive clinical diagnosis. 
Cardiomegaly and evidence of 
poor left ventricular function 
confirmed by 
echocardiography. 
 
 
References: 
1. World Health Organization. WHO case definitions of HIV for surveillance, and revised clinical 
staging and immunological classification of HIV related disease in adults and children. Geneva: 
World Health Organization; 2007. 


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27 APPENDIX IX  ADAPTED DAIDS TOXICITY GRADINGS 
The toxicity grading table is adapted from the Division of AIDS (DAIDS) Table for Grading the Severity 
of Adult and Pediatric Adverse Events, Version 2.0. [November 2014]. Available from: 
http://rsc.tech-res.com/docs/default-source/safety/daids_ae_grading_table_v2_nov2014.pdf (1). 
The changes from the previous version of the DAIDS Table are highlighted in yellow. 
 
Neutrophil grading for children aged >7 days, are based on WHO 2010 guidelines (2) recognising the 
lower normal levels in African populations. These are highlighted in grey. 
 
General Instructions: 
If the need arises to grade a clinical adverse event (AE) that is not identified in the DAIDS AE Grading 
Table, use the category “Estimating Severity Grade” located at the top of the table.  
 
If the severity of an AE could fall under either one of two grades (e.g. the severity of an AE could be 
either Grade 2 or Grade 3) select the higher of the two grades for the AE. 
 
Definitions: 
Basic self-care functions 
Adults: Activities such as bathing, dressing, toileting, transfer or 
movement, continence, and feeding.  
Young children: Activities that are age and culturally appropriate, 
such as feeding one’s self with culturally appropriate eating 
implements. 
Chemical pregnancy 
A pregnancy in which a positive pregnancy test is followed by a 
negative pregnancy test without evidence of a clinical pregnancy 
loss. 
Disability 
A substantial disruption of a person’s ability to conduct normal life 
functions. 
Intervention 
Medical, surgical, or other procedures recommended or provided 
by a healthcare professional for the treatment of an adverse event. 
Hospitalisation 
Does not include the following hospital admissions: under 24 
hours, unrelated to an adverse event (e.g., for labour and delivery, 
cosmetic surgery, social or administrative for temporary placement 
[for lack of a place to sleep]), protocol-specified, and for diagnosis 
or therapy of a condition that existed before the receipt of a study 
agent and which has not increased in severity or frequency. 
LLN 
Lower limit of normal 
Medical intervention 
Use of pharmacologic or biologic agent(s) for treatment of an AE 
NA 
Not applicable 
Operative intervention 
Surgical OR other invasive mechanical procedures. 
ULN 
Upper limit of normal 
Usual social & functional activities 
Activities which adults and children perform on a routine basis and 
those which are part of regular activities of daily living, for 
example:  
Adults: Adaptive tasks and desirable activities, such as going to 
work, shopping, cooking, use of transportation, or pursuing a 
hobby.  
Young children: Activities that are age and culturally appropriate, 
such as social interactions, play activities, or learning tasks. 
 


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PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-THREATENING 
CLINICAL CONDITIONS: ESTIMATING SEVERITY GRADE FOR PARAMETERS NOT IDENTIFIED IN THE GRADING TABLE 
Clinical adverse event 
NOT identified 
elsewhere in this DAIDS 
AE grading table  
Symptoms causing no 
or minimal 
interference with 
usual social & 
functional activities 
Symptoms causing 
greater than minimal 
interference with usual 
social & functional 
activities 
Symptoms causing 
inability to perform 
usual social & functional 
activities 
Symptoms causing 
inability to perform basic 
self-care functions OR 
Medical or operative 
intervention indicated to 
prevent permanent 
impairment, persistent 
disability, or death  
MAJOR CLINICAL CONDITIONS 
CARDIOVASCULAR 
Arrhythmia  
(by ECG or physical 
examination)     
Specify type, if 
applicable  
No symptoms AND No 
intervention indicated  
No symptoms AND 
Non-urgent 
intervention indicated  
Non-life-threatening 
symptoms AND Non-
urgent intervention 
indicated  
Life-threatening 
arrhythmia OR Urgent 
intervention indicated  
Blood Pressure 
Abnormalities1  
Hypertension (with 
the lowest reading 
taken after repeat 
testing during a visit)  
≥ 18 years of age  
140 to < 160 mmHg 
systolic OR 90 to < 100 
mmHg diastolic  
≥ 160 to < 180 mmHg 
systolic OR ≥ 100 to < 
110 mmHg diastolic  
≥ 180 mmHg systolic OR 
≥ 110 mmHg diastolic  
Life-threatening 
consequences in a 
participant not 
previously diagnosed 
with hypertension (e.g., 
malignant hypertension) 
OR Hospitalization 
indicated  
< 18 years of age  
> 120/80 mmHg  
≥ 95th to < 99th 
percentile + 5 mmHg 
adjusted for age, 
height, and gender 
(systolic and/or 
diastolic)  
≥ 99th percentile + 5 
mmHg adjusted for age, 
height, and gender 
(systolic and/or diastolic)  
Life-threatening 
consequences in a 
participant not 
previously diagnosed 
with hypertension (e.g., 
malignant hypertension) 
OR Hospitalization 
indicated  
Hypotension  
No symptoms  
Symptoms corrected 
with oral fluid 
replacement  
Symptoms AND IV fluids 
indicated  
Shock requiring use of 
vasopressors or 
mechanical assistance to 
maintain blood pressure  
Cardiac Ischemia or 
Infarction  
Report only one  
NA  
NA  
New symptoms with 
ischemia (stable angina) 
OR New testing 
consistent with ischemia  
Unstable angina OR 
Acute myocardial 
infarction  
Heart Failure  
No symptoms AND 
Laboratory or cardiac 
imaging abnormalities  
Symptoms with mild to 
moderate activity or 
exertion  
Symptoms at rest or 
with minimal activity or 
exertion (e.g., 
hypoxemia) OR 
Intervention indicated 
(e.g., oxygen)  
Life-threatening 
consequences OR Urgent 
intervention indicated 
(e.g., vasoactive 
medications, ventricular 
assist device, heart 
transplant)  
Hemorrhage  
(with significant acute 
blood loss)  
NA  
Symptoms AND No 
transfusion indicated  
Symptoms AND 
Transfusion of ≤ 2 units 
packed RBCs indicated  
Life-threatening 
hypotension OR 
Transfusion of > 2 units 
packed RBCs (for 
children, packed RBCs > 
10 cc/kg) indicated  


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PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-THREATENING 
Prolonged PR Interval 
or AV Block  
Report only one  
> 16 years of age  
 
 
PR interval 0.21 to < 
0.25 seconds  
 
 
PR interval ≥ 0.25 
seconds OR Type I 2nd 
degree AV block  
 
 
Type II 2nd degree AV 
block OR Ventricular 
pause ≥ 3.0 seconds  
 
 
Complete AV block  
≤ 16 years of age  
1st degree AV block 
(PR interval > normal 
for age and rate)  
Type I 2nd degree AV 
block  
Type II 2nd degree AV 
block OR Ventricular 
pause ≥ 3.0 seconds  
Complete AV block  
Prolonged QTc 
Interval2  
0.45 to 0.47 seconds  
> 0.47 to 0.50 seconds  > 0.50 seconds OR ≥ 0.06 
seconds above baseline  
Life-threatening 
consequences (e.g., 
Torsade de pointes, 
other associated serious 
ventricular dysrhythmia)  
Thrombosis or 
Embolism  
Report only one  
NA  
Symptoms AND No 
intervention indicated  
Symptoms AND 
Intervention indicated  
Life-threatening embolic 
event (e.g., pulmonary 
embolism, thrombus)  
DERMATOLOGICAL 
Alopecia 
Thinning detectable by 
study participant (or 
by caregiver for young 
children and disabled 
adults) 
Thinning or patchy hair 
loss detectable by 
health care provider 
Complete hair loss 
NA 
Bruising  
Localized to one area  
Localized to more than 
one area  
Generalized  
NA  
Cellulitis  
NA  
Non-parenteral 
treatment indicated 
(e.g., oral antibiotics, 
antifungals, antivirals)  
IV treatment indicated 
(e.g., IV antibiotics, 
antifungals, antivirals)  
Life-threatening 
consequences (e.g., 
sepsis, tissue necrosis)  
Hyperpigmentation 
Slight or localized 
causing no or minimal 
interference with 
usual social & 
functional activities  
Marked or generalized 
causing greater than 
minimal interference 
with usual social & 
functional activities  
NA 
NA 
Hypopigmentation 
Slight or localized 
causing no or minimal 
interference with 
usual social & 
functional activities  
Marked or generalized 
causing greater than 
minimal interference 
with usual social & 
functional activities  
NA 
NA 
Petechiae  
Localized to one area  
Localized to more than 
one area  
Generalized  
NA  
Pruritus3  
(without skin lesions)  
Itching causing no or 
minimal interference 
with usual social & 
functional activities  
Itching causing greater 
than minimal 
interference with usual 
social & functional 
activities  
Itching causing inability 
to perform usual social & 
functional activities  
NA  


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PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-THREATENING 
Rash  
Specify type, if 
applicable  
Localized rash  
Diffuse rash OR Target 
lesions  
Diffuse rash AND 
Vesicles or limited 
number of bullae or 
superficial ulcerations of 
mucous membrane 
limited to one site  
Extensive or generalized 
bullous lesions OR 
Ulceration of mucous 
membrane involving two 
or more distinct mucosal 
sites OR Stevens-Johnson 
syndrome OR Toxic 
epidermal necrolysis  
ENDOCRINE and METABOLIC 
Diabetes Mellitus  
Controlled without 
medication  
Controlled with 
medication OR 
Modification of current 
medication regimen  
Uncontrolled despite 
treatment modification 
OR Hospitalization for 
immediate glucose 
control indicated  
Life-threatening 
consequences (e.g., 
ketoacidosis, 
hyperosmolar non-
ketotic coma, end organ 
failure)  
Gynecomastia  
Detectable by study 
participant, caregiver, 
or physician AND 
Causing no or minimal 
interference with 
usual social & 
functional activities  
Obvious on visual 
inspection AND 
Causing pain with 
greater than minimal 
interference with usual 
social & functional 
activities  
Disfiguring changes AND 
Symptoms requiring 
intervention or causing 
inability to perform 
usual social & functional 
activities  
NA  
Hyperthyroidism  
No symptoms AND 
Abnormal laboratory 
value  
Symptoms causing 
greater than minimal 
interference with usual 
social & functional 
activities OR Thyroid 
suppression therapy 
indicated  
Symptoms causing 
inability to perform 
usual social & functional 
activities OR 
Uncontrolled despite 
treatment modification  
Life-threatening 
consequences (e.g., 
thyroid storm)  
Hypothyroidism  
No symptoms AND 
Abnormal laboratory 
value  
Symptoms causing 
greater than minimal 
interference with usual 
social & functional 
activities OR Thyroid 
replacement therapy 
indicated  
Symptoms causing 
inability to perform 
usual social & functional 
activities OR 
Uncontrolled despite 
treatment modification  
Life-threatening 
consequences (e.g., 
myxedema coma)  
Lipoatrophy4  
Detectable by study 
participant, caregiver, 
or physician AND 
Causing no or minimal 
interference with 
usual social & 
functional activities  
Obvious on visual 
inspection AND 
Causing greater than 
minimal interference 
with usual social & 
functional activities  
Disfiguring changes  
NA  
Lipohypertrophy5  
Detectable by study 
participant, caregiver, 
or physician AND 
Causing no or minimal 
interference with 
usual social & 
functional activities  
Obvious on visual 
inspection AND 
Causing greater than 
minimal interference 
with usual social & 
functional activities  
Disfiguring changes  
NA  
GASTROINTESTINAL 


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PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-THREATENING 
Anorexia  
Loss of appetite 
without decreased 
oral intake  
Loss of appetite 
associated with 
decreased oral intake 
without significant 
weight loss  
Loss of appetite 
associated with 
significant weight loss  
Life-threatening 
consequences OR 
Aggressive intervention 
indicated (e.g., tube 
feeding, total parenteral 
nutrition)  
Ascites  
No symptoms  
Symptoms AND 
Intervention indicated 
(e.g., diuretics, 
therapeutic 
paracentesis)  
Symptoms recur or 
persist despite 
intervention  
Life-threatening 
consequences  
Bloating or Distension  
Report only one  
Symptoms causing no 
or minimal 
interference with 
usual social & 
functional activities  
Symptoms causing 
greater than minimal 
interference with usual 
social & functional 
activities  
Symptoms causing 
inability to perform 
usual social & functional 
activities  
NA  
Cholecystitis  
NA  
Symptoms AND 
Medical intervention 
indicated  
Radiologic, endoscopic, 
or operative 
intervention indicated  
Life-threatening 
consequences (e.g., 
sepsis, perforation)  
Constipation  
NA  
Persistent constipation 
requiring regular use of 
dietary modifications, 
laxatives, or enemas  
Obstipation with manual 
evacuation indicated  
Life-threatening 
consequences (e.g., 
obstruction)  
Diarrhoea 
≥ 1 year of age  
 
Transient or 
intermittent episodes 
of unformed stools OR 
Increase of ≤ 3 stools 
over baseline per 24-
hour period  
 
Persistent episodes of 
unformed to watery 
stools OR Increase of 4 
to 6 stools over 
baseline per 24-hour 
period  
 
Increase of ≥ 7 stools per 
24-hour period OR IV 
fluid replacement 
indicated  
 
Life-threatening 
consequences (e.g., 
hypotensive shock)  
< 1 year of age  
Liquid stools (more 
unformed than usual) 
but usual number of 
stools  
Liquid stools with 
increased number of 
stools OR Mild 
dehydration  
Liquid stools with 
moderate dehydration  
Life-threatening 
consequences (e.g., 
liquid stools resulting in 
severe dehydration, 
hypotensive shock)  
Dysphagia or 
Odynophagia  
Report only one and 
specify location  
Symptoms but able to 
eat usual diet  
Symptoms causing 
altered dietary intake 
with no intervention 
indicated  
Symptoms causing 
severely altered dietary 
intake with intervention 
indicated  
Life-threatening 
reduction in oral intake  
Gastrointestinal 
Bleeding  
Not requiring 
intervention other 
than iron supplement  
Endoscopic 
intervention indicated  
Transfusion indicated  
Life-threatening 
consequences (e.g., 
hypotensive shock)  
Mucositis or Stomatitis  
Report only one and 
specify location  
Mucosal erythema  
Patchy 
pseudomembranes or 
ulcerations  
Confluent 
pseudomembranes or 
ulcerations OR Mucosal 
bleeding with minor 
trauma  
Life-threatening 
consequences (e.g., 
aspiration, choking) OR 
Tissue necrosis OR 
Diffuse spontaneous 
mucosal bleeding  
Nausea  
Transient (< 24 hours) 
or intermittent AND 
No or minimal 
interference with oral 
intake  
Persistent nausea 
resulting in decreased 
oral intake for 24 to 48 
hours  
Persistent nausea 
resulting in minimal oral 
intake for > 48 hours OR 
Rehydration indicated 
(e.g., IV fluids)  
Life-threatening 
consequences (e.g., 
hypotensive shock)  


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PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-THREATENING 
Pancreatitis  
NA  
Symptoms with 
hospitalization not 
indicated  
Symptoms with 
hospitalization indicated  
Life-threatening 
consequences (e.g., 
circulatory failure, 
hemorrhage, sepsis)  
Perforation  
(colon or rectum)  
NA  
NA  
Intervention indicated  
Life-threatening 
consequences  
Proctitis  
Rectal discomfort with 
no intervention 
indicated  
Symptoms causing 
greater than minimal 
interference with usual 
social & functional 
activities OR Medical 
intervention indicated  
Symptoms causing 
inability to perform 
usual social & functional 
activities OR Operative 
intervention indicated  
Life-threatening 
consequences (e.g., 
perforation)  
Rectal Discharge  
Visible discharge  
Discharge requiring the 
use of pads  
NA  
NA  
Vomiting  
Transient or 
intermittent AND No 
or minimal 
interference with oral 
intake  
Frequent episodes with 
no or mild dehydration  
Persistent vomiting 
resulting in orthostatic 
hypotension OR 
Aggressive rehydration 
indicated (e.g., IV fluids)  
Life-threatening 
consequences (e.g., 
hypotensive shock)  
MUSCULOSCELETAL 
Arthralgia  
Joint pain causing no 
or minimal 
interference with 
usual social & 
functional activities  
Joint pain causing 
greater than minimal 
interference with usual 
social & functional 
activities  
Joint pain causing 
inability to perform 
usual social & functional 
activities  
Disabling joint pain 
causing inability to 
perform basic self-care 
functions  
Arthritis  
Stiffness or joint 
swelling causing no or 
minimal interference 
with usual social & 
functional activities  
Stiffness or joint 
swelling causing 
greater than minimal 
interference with usual 
social & functional 
activities  
Stiffness or joint swelling 
causing inability to 
perform usual social & 
functional activities  
Disabling joint stiffness 
or swelling causing 
inability to perform basic 
self-care functions  
Myalgia (generalized)  
Muscle pain causing 
no or minimal 
interference with 
usual social & 
functional activities  
Muscle pain causing 
greater than minimal 
interference with usual 
social & functional 
activities  
Muscle pain causing 
inability to perform 
usual social & functional 
activities  
Disabling muscle pain 
causing inability to 
perform basic self-care 
functions  
Osteonecrosis  
NA  
No symptoms but with 
radiographic findings 
AND No operative 
intervention indicated  
Bone pain with 
radiographic findings OR 
Operative intervention 
indicated  
Disabling bone pain with 
radiographic findings 
causing inability to 
perform basic self-care 
functions  
Osteopenia6  
≥ 30 years of age  
 
BMD t-score -2.5 to -1  
 
NA  
 
NA  
 
NA  
< 30 years of age  
BMD z-score -2 to -1  
NA  
NA  
NA  
Osteoporosis6  
≥ 30 years of age  
 
NA  
 
BMD t-score < -2.5  
 
Pathologic fracture (e.g., 
compression fracture 
causing loss of vertebral 
height)  
 
Pathologic fracture 
causing life-threatening 
consequences  
< 30 years of age  
NA  
BMD z-score < -2  
Pathologic fracture (e.g., 
compression fracture 
causing loss of vertebral 
height)  
Pathologic fracture 
causing life-threatening 
consequences  


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PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-THREATENING 
NEUROLOGICAL 
Acute CNS Ischaemia  
NA  
NA  
Transient ischemic 
attack  
Cerebral vascular 
accident (e.g., stroke 
with neurological deficit)  
Altered Mental Status 
(for Dementia, see 
Cognitive, Behavioral, 
or Attentional 
Disturbance below)  
Changes causing no or 
minimal interference 
with usual social & 
functional activities  
Mild lethargy or 
somnolence causing 
greater than minimal 
interference with usual 
social & functional 
activities  
Confusion, memory 
impairment, lethargy, or 
somnolence causing 
inability to perform 
usual social & functional 
activities  
Delirium OR Obtundation 
OR Coma  
Ataxia  
Symptoms causing no 
or minimal 
interference with 
usual social & 
functional activities OR 
No symptoms with 
ataxia detected on 
examination  
Symptoms causing 
greater than minimal 
interference with usual 
social & functional 
activities  
Symptoms causing 
inability to perform 
usual social & functional 
activities  
Disabling symptoms 
causing inability to 
perform basic self-care 
functions  
Cognitive, Behavioral, 
or Attentional 
Disturbance 
(includes dementia and 
attention deficit 
disorder)  
Specify type, if 
applicable  
Disability causing no or 
minimal interference 
with usual social & 
functional activities OR 
Specialized resources 
not indicated  
Disability causing 
greater than minimal 
interference with usual 
social & functional 
activities OR 
Specialized resources 
on part-time basis 
indicated  
Disability causing 
inability to perform 
usual social & functional 
activities OR Specialized 
resources on a full-time 
basis indicated  
Disability causing 
inability to perform basic 
self-care functions OR 
Institutionalization 
indicated  
Developmental Delay  
< 18 years of age  
Specify type, if 
applicable  
Mild developmental 
delay, either motor or 
cognitive, as 
determined by 
comparison with a 
developmental 
screening tool 
appropriate for the 
setting  
Moderate 
developmental delay, 
either motor or 
cognitive, as 
determined by 
comparison with a 
developmental 
screening tool 
appropriate for the 
setting  
Severe developmental 
delay, either motor or 
cognitive, as determined 
by comparison with a 
developmental 
screening tool 
appropriate for the 
setting  
Developmental 
regression, either motor 
or cognitive, as 
determined by 
comparison with a 
developmental screening 
tool appropriate for the 
setting  
Headache  
Symptoms causing no 
or minimal 
interference with 
usual social & 
functional activities  
Symptoms causing 
greater than minimal 
interference with usual 
social & functional 
activities  
Symptoms causing 
inability to perform 
usual social & functional 
activities  
Symptoms causing 
inability to perform basic 
self-care functions OR 
Hospitalization indicated 
OR Headache with 
significant impairment of 
alertness or other 
neurologic function  
Weakness  
(includes myopathy and 
neuropathy)  
Specify type, if 
applicable  
Minimal muscle 
weakness causing no 
or minimal 
interference with 
usual social & 
functional activities OR 
No symptoms with 
decreased strength on 
examination  
Muscle weakness 
causing greater than 
minimal interference 
with usual social & 
functional activities  
Muscle weakness 
causing inability to 
perform usual social & 
functional activities  
Disabling muscle 
weakness causing 
inability to perform basic 
self-care functions OR 
Respiratory muscle 
weakness impairing 
ventilation  


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PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-THREATENING 
Neurosensory 
Alteration  
(includes paresthesia 
and painful 
neuropathy)  
Specify type, if 
applicable  
Minimal paresthesia 
causing no or minimal 
interference with 
usual social & 
functional activities OR 
No symptoms with 
sensory alteration on 
examination  
Sensory alteration or 
paresthesia causing 
greater than minimal 
interference with usual 
social & functional 
activities  
Sensory alteration or 
paresthesia causing 
inability to perform 
usual social & functional 
activities  
Disabling sensory 
alteration or paresthesia 
causing inability to 
perform basic self-care 
functions  
Seizures  
New Onset Seizure  
≥ 18 years of age  
 
 
NA  
 
 
NA  
 
 
1 to 3 seizures  
 
 
Prolonged and repetitive 
seizures (e.g., status 
epilepticus) OR Difficult 
to control (e.g., 
refractory epilepsy)  
< 18 years of age 
(includes new or 
pre-existing febrile 
seizures)  
Seizure lasting < 5 
minutes with < 24 
hours postictal state  
Seizure lasting 5 to < 20 
minutes with < 24 
hours postictal state  
Seizure lasting ≥ 20 
minutes OR > 24 hours 
postictal state  
Prolonged and repetitive 
seizures (e.g., status 
epilepticus) OR Difficult 
to control (e.g., 
refractory epilepsy)  
   Pre-existing Seizure  
NA  
Increased frequency 
from previous level of 
control without change 
in seizure character  
Change in seizure 
character either in 
duration or quality (e.g., 
severity or focality)  
Prolonged and repetitive 
seizures (e.g., status 
epilepticus) OR Difficult 
to control (e.g., 
refractory epilepsy)  
Syncope  
Near syncope without 
loss of consciousness 
(e.g., pre-syncope)  
Loss of consciousness 
with no intervention 
indicated  
Loss of consciousness 
AND Hospitalization or 
intervention required  
NA  
PREGNANCY, PEURPERIUM and PERINATAL 
Fetal Death or Stillbirth 
(report using mother’s 
participant ID)  
Report only one  
NA  
NA  
Fetal loss occurring at ≥ 
20 weeks gestation  
NA  
Preterm Delivery7 
(report using mother’s 
participant ID)  
Delivery at 34 to < 37 
weeks gestational age  
Delivery at 28 to < 34 
weeks gestational age  
Delivery at 24 to < 28 
weeks gestational age  
Delivery at < 24 weeks 
gestational age  
Spontaneous Abortion 
or Miscarriage8  
(report using mother’s 
participant ID)  
Report only one  
Chemical pregnancy  
Uncomplicated 
spontaneous abortion 
or miscarriage  
Complicated 
spontaneous abortion or 
miscarriage  
NA  
PSCYCHIATRIC and SLEEP PROBLEMS 
Insomnia  
Mild difficulty falling 
asleep, staying asleep, 
or waking up early  
Moderate difficulty 
falling asleep, staying 
asleep, or waking up 
early  
Severe difficulty falling 
asleep, staying asleep, or 
waking up early  
NA  
Psychiatric Disorders  
(includes anxiety,  
depression, mania, and  
psychosis)  
Specify disorder  
Symptoms with 
intervention not 
indicated OR Behavior 
causing no or minimal 
interference with 
usual social & 
functional activities  
Symptoms with 
intervention indicated 
OR Behavior causing 
greater than minimal 
interference with usual 
social & functional 
activities  
Symptoms with 
hospitalization indicated 
OR Behavior causing 
inability to perform 
usual social & functional 
activities  
Threatens harm to self or 
others OR Acute 
psychosis OR Behavior 
causing inability to 
perform basic self-care 
functions  


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PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-THREATENING 
Suicidal Ideation or 
Attempt  
Report only one  
Preoccupied with 
thoughts of death AND 
No wish to kill oneself  
Preoccupied with 
thoughts of death AND 
Wish to kill oneself 
with no specific plan or 
intent  
Thoughts of killing 
oneself with partial or 
complete plans but no 
attempt to do so OR 
Hospitalization indicated  
Suicide attempted  
RESPIRATORY 
Acute Bronchospasm  
Forced expiratory 
volume in 1 second or 
peak flow reduced to ≥ 
70 to < 80% OR Mild 
symptoms with 
intervention not 
indicated  
Forced expiratory 
volume in 1 second or 
peak flow 50 to < 70% 
OR Symptoms with 
intervention indicated 
OR Symptoms causing 
greater than minimal 
interference with usual 
social & functional 
activities  
Forced expiratory 
volume in 1 second or 
peak flow 25 to < 50% 
OR Symptoms causing 
inability to perform 
usual social & functional 
activities  
Forced expiratory 
volume in 1 second or 
peak flow < 25% OR Life-
threatening respiratory 
or hemodynamic 
compromise OR 
Intubation  
Dyspnea or Respiratory 
Distress  
Report only one  
Dyspnea on exertion 
with no or minimal 
interference with 
usual social & 
functional activities OR 
Wheezing OR Minimal 
increase in respiratory 
rate for age  
Dyspnea on exertion 
causing greater than 
minimal interference 
with usual social & 
functional activities OR 
Nasal flaring OR 
Intercostal retractions 
OR Pulse oximetry 90 
to < 95%  
Dyspnea at rest causing 
inability to perform 
usual social & functional 
activities OR Pulse 
oximetry < 90%  
Respiratory failure with 
ventilator support 
indicated (e.g., CPAP, 
BPAP, intubation)  
SENSORY 
Hearing Loss  
≥ 12 years of age  
 
NA  
 
Hearing aid or 
intervention not 
indicated  
 
Hearing aid or 
intervention indicated  
 
Profound bilateral 
hearing loss (> 80 dB at 2 
kHz and above) OR Non-
serviceable hearing (i.e., 
>50 dB audiogram and 
<50% speech 
discrimination)  
< 12 years of age 
(based on a 1, 2, 3, 4, 
6  and 8 kHz 
audiogram)  
> 20 dB hearing loss at 
≤ 4 kHz  
> 20 dB hearing loss at 
> 4 kHz  
> 20 dB hearing loss at ≥ 
3 kHz in one ear with 
additional speech 
language related 
services indicated 
(where available) OR 
Hearing loss sufficient to 
indicate therapeutic 
intervention, including 
hearing aids  
Audiologic indication for 
cochlear implant and 
additional speech-
language related services 
indicated (where 
available)  
Tinnitus  
Symptoms causing no 
or minimal 
interference with 
usual social & 
functional activities 
with intervention not 
indicated  
Symptoms causing 
greater than minimal 
interference with usual 
social & functional 
activities with 
intervention indicated  
Symptoms causing 
inability to perform 
usual social & functional 
activities  
NA  


ODYSSEY Protocol  
Version 6.0 8th November 2019 
ODYSSEY (PENTA 20)    
 
 
 
 
 
 
 
 
Page 281 of 324 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-THREATENING 
Uveitis  
No symptoms AND 
Detectable on 
examination  
Anterior uveitis with 
symptoms OR 
Medicamylasal 
intervention indicated  
Posterior or pan-uveitis 
OR Operative 
intervention indicated  
Disabling visual loss in 
affected eye(s)  
Vertigo  
Vertigo causing no or 
minimal interference 
with usual social & 
functional activities  
Vertigo causing greater 
than minimal 
interference with usual 
social & functional 
activities  
Vertigo causing inability 
to perform usual social & 
functional activities  
Disabling vertigo causing 
inability to perform basic 
self-care functions  
Visual Changes  
(assessed from 
baseline)  
Visual changes causing 
no or minimal 
interference with 
usual social & 
functional activities  
Visual changes causing 
greater than minimal 
interference with usual 
social & functional 
activities  
Visual changes causing 
inability to perform 
usual social & functional 
activities  
Disabling visual loss in 
affected eye(s)  
SYSTEMIC 
Acute Allergic Reaction  Localized urticaria 
(wheals) with no 
medical intervention 
indicated  
Localized urticaria with 
intervention indicated 
OR Mild angioedema 
with no intervention 
indicated  
Generalized urticaria OR 
Angioedema with 
intervention indicated 
OR Symptoms of mild 
bronchospasm  
Acute anaphylaxis OR 
Life-threatening 
bronchospasm OR 
Laryngeal edema  
Chills  
Symptoms causing no 
or minimal 
interference with 
usual social & 
functional activities  
Symptoms causing 
greater than minimal 
interference with usual 
social & functional 
activities  
Symptoms causing 
inability to perform 
usual social & functional 
activities  
NA  
Cytokine Release 
Syndrome9  
Mild signs and 
symptoms AND 
Therapy (i.e., antibody 
infusion) interruption 
not indicated  
Therapy (i.e., antibody 
infusion) interruption 
indicated AND 
Responds promptly to 
symptomatic 
treatment OR 
Prophylactic 
medications indicated 
for ≤ 24 hours  
Prolonged severe signs 
and symptoms OR 
Recurrence of symptoms 
following initial 
improvement  
Life-threatening 
consequences (e.g., 
requiring pressor or 
ventilator support)  
Fatigue or Malaise  
Report only one  
Symptoms causing no 
or minimal 
interference with 
usual social & 
functional activities  
Symptoms causing 
greater than minimal 
interference with usual 
social & functional 
activities  
Symptoms causing 
inability to perform 
usual social & functional 
activities  
Incapacitating symptoms 
of fatigue or malaise 
causing inability to 
perform basic self-care 
functions  
Fever  
(non-axillary 
temperatures only)  
 
38.0 to < 38.6°C or 
100.4 to < 101.5°F  
 
≥ 38.6 to < 39.3°C or ≥ 
101.5 to < 102.7°F  
 
≥ 39.3 to < 40.0°C or ≥ 
102.7 to < 104.0°F  
 
≥ 40.0°C or ≥ 104.0°F  
Pain10  
(not associated with 
study agent injections 
and not specified 
elsewhere)  
Specify location  
Pain causing no or 
minimal interference 
with usual social & 
functional activities  
Pain causing greater 
than minimal 
interference with usual 
social & functional 
activities  
Pain causing inability to 
perform usual social & 
functional activities  
Disabling pain causing 
inability to perform basic 
self-care functions OR 
Hospitalization indicated  
Serum Sickness11  
Mild signs and 
symptoms  
Moderate signs and 
symptoms AND 
Intervention indicated 
(e.g., antihistamines)  
Severe signs and 
symptoms AND Higher 
level intervention 
indicated (e.g., steroids 
or IV fluids)  
Life-threatening 
consequences (e.g., 
requiring pressor or 
ventilator support)  


ODYSSEY Protocol  
Version 6.0 8th November 2019 
ODYSSEY (PENTA 20)    
 
 
 
 
 
 
 
 
Page 282 of 324 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-THREATENING 
Underweight12  
> 5 to 19 years of age  
 
NA  
 
WHO BMI z-score < -2 
to ≤ -3  
 
WHO BMI z-score < -3  
 
WHO BMI z-score < -3 
with life-threatening 
consequences  
2 to 5 years of age  
NA  
WHO Weight-for-
height z-score  
< -2 to ≤ -3  
WHO Weight-for-height 
z-score < -3  
WHO Weight-for-height 
z-score < -3 with life-
threatening 
consequences  
< 2 years of age  
NA  
WHO Weight-for-
length z-score  
< -2 to ≤ -3  
WHO Weight-for-length 
z-score < -3  
WHO Weight-for-length 
z-score < -3 with life-
threatening 
consequences  
Weight Loss  
(excludes postpartum 
weight loss)  
NA  
5 to < 9% loss in body 
weight from baseline  
≥ 9 to < 20% loss in body 
weight from baseline  
≥ 20% loss in body 
weight from baseline OR 
Aggressive intervention 
indicated (e.g., tube 
feeding, total parenteral 
nutrition)  
URINARY 
Urinary Tract 
Obstruction  
NA  
Signs or symptoms of 
urinary tract 
obstruction without 
hydronephrosis or 
renal dysfunction  
Signs or symptoms of 
urinary tract obstruction 
with hydronephrosis or 
renal dysfunction  
Obstruction causing life-
threatening 
consequences  
SITE REACTIONS TO INJECTIONS AND INFUSIONS 
Injection Site Pain or 
Tenderness  
Report only one  
Pain or tenderness 
causing no or minimal 
limitation of use of 
limb  
Pain or tenderness 
causing greater than 
minimal limitation of 
use of limb  
Pain or tenderness 
causing inability to 
perform usual social & 
functional activities  
Pain or tenderness 
causing inability to 
perform basic self-care 
function OR 
Hospitalization indicated  
Injection Site Erythema 
or Redness13  
Report only one  
> 15 years of age  
 
 
2.5 to < 5 cm in 
diameter OR 6.25 to < 
25 cm2 surface area 
AND Symptoms 
causing no or minimal 
interference with 
usual social & 
functional activities  
 
 
≥ 5 to < 10 cm in 
diameter OR ≥ 25 to < 
100 cm2 surface area 
OR Symptoms causing 
greater than minimal 
interference with usual 
social & functional 
activities  
 
 
≥ 10 cm in diameter OR 
≥ 100 cm2 surface area 
OR Ulceration OR 
Secondary infection OR 
Phlebitis OR Sterile 
abscess OR Drainage OR 
Symptoms causing 
inability to perform 
usual social & functional 
activities  
 
 
Potentially life-
threatening 
consequences (e.g., 
abscess, exfoliative 
dermatitis, necrosis 
involving dermis or 
deeper tissue)  
≤ 15 years of age  
≤ 2.5 cm in diameter  
> 2.5 cm in diameter 
with < 50% surface 
area of the extremity 
segment involved (e.g., 
upper arm or thigh)  
≥ 50% surface area of 
the extremity segment 
involved (e.g., upper arm 
or thigh) OR Ulceration 
OR Secondary infection 
OR Phlebitis OR Sterile 
abscess OR Drainage  
Potentially life-
threatening 
consequences (e.g., 
abscess, exfoliative 
dermatitis, necrosis 
involving dermis or 
deeper tissue)  


ODYSSEY Protocol  
Version 6.0 8th November 2019 
ODYSSEY (PENTA 20)    
 
 
 
 
 
 
 
 
Page 283 of 324 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-THREATENING 
Injection Site 
Induration or Swelling  
Report only one  
> 15 years of age  
 
 
Same as for Injection 
Site Erythema or 
Redness, > 15 years of 
age  
 
 
Same as for Injection 
Site Erythema or 
Redness, > 15 years of 
age  
 
 
Same as for Injection 
Site Erythema or 
Redness, > 15 years of 
age  
 
 
Same as for Injection 
Site Erythema or 
Redness, > 15 years of 
age  
≤ 15 years of age  
Same as for Injection 
Site Erythema or 
Redness, ≤ 15 years of 
age  
Same as for Injection 
Site Erythema or 
Redness, ≤ 15 years of 
age  
Same as for Injection 
Site Erythema or 
Redness, ≤ 15 years of 
age  
Same as for Injection 
Site Erythema or 
Redness, ≤ 15 years of 
age  
Injection Site Pruritus  
Itching localized to the 
injection site that is 
relieved 
spontaneously or in < 
48 hours of treatment  
Itching beyond the 
injection site that is not 
generalized OR Itching 
localized to the 
injection site requiring 
≥ 48 hours treatment  
Generalized itching 
causing inability to 
perform usual social & 
functional activities  
NA  
LABORATORY 
CHEMISTRY 
Acidosis  
NA  
pH ≥ 7.3 to < LLN  
pH < 7.3 without life-
threatening 
consequences  
pH < 7.3 with life-
threatening 
consequences  
Albumin, Low  
(g/dL; g/L)  
3.0 to < LLN 30 to < LLN  ≥ 2.0 to < 3.0 ≥ 20 to < 
30  
< 2.0 < 20  
NA  
Alkaline Phosphatase, 
High  
1.25 to < 2.5 x ULN  
2.5 to < 5.0 x ULN  
5.0 to < 10.0 x ULN  
≥ 10.0 x ULN  
Alkalosis  
NA  
pH > ULN to ≤ 7.5  
pH > 7.5 without life-
threatening 
consequences  
pH > 7.5 with life-
threatening 
consequences  
ALT or SGPT, High  
Report only one  
1.25 to < 2.5 x ULN  
2.5 to < 5.0 x ULN  
5.0 to < 10.0 x ULN  
≥ 10.0 x ULN  
Amylase (Pancreatic) 
or Amylase (Total), 
High  
Report only one  
1.1 to < 1.5 x ULN  
1.5 to < 3.0 x ULN  
3.0 to < 5.0 x ULN  
≥ 5.0 x ULN  
AST or SGOT, High  
Report only one  
1.25 to < 2.5 x ULN  
2.5 to < 5.0 x ULN  
5.0 to < 10.0 x ULN  
≥ 10.0 x ULN  
Bicarbonate, Low 
(mEq/L; mmol/L)  
16.0 to < LLN  
16.0 to < LLN  
11.0 to < 16.0  
11.0 to < 16.0  
8.0 to < 11.0  
8.0 to < 11.0  
< 8.0 < 8.0  
Bilirubin  
Direct Bilirubin14, 
High  
> 28 days of age  
 
 
 
NA  
 
 
 
NA  
 
 
 
> ULN  
> ULN with life-
threatening 
consequences (e.g., signs 
and symptoms of liver 
failure)  
≤ 28 days of age  
ULN to ≤ 1 mg/dL  
> 1 to ≤ 1.5 mg/dL  
> 1.5 to ≤ 2 mg/dL  
> 2 mg/dL  
Total Bilirubin, High  
> 28 days of age  
1.1 to < 1.6 x ULN  
1.6 to < 2.6 x ULN  
2.6 to < 5.0 x ULN  
≥ 5.0 x ULN  
≤ 28 days of age  
See Appendix A in 
DAIDS 2014.  
Total Bilirubin for Term 
and Preterm Neonates  
See Appendix A in 
DAIDS 2014.  
Total Bilirubin for Term 
and Preterm Neonates  
See Appendix A in 
DAIDS 2014.  
Total Bilirubin for Term 
and Preterm Neonates  
See Appendix A in DAIDS 
2014.  
Total Bilirubin for Term 
and Preterm Neonates  


ODYSSEY Protocol  
Version 6.0 8th November 2019 
ODYSSEY (PENTA 20)    
 
 
 
 
 
 
 
 
Page 284 of 324 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-THREATENING 
Calcium, High  
(mg/dL; mmol/L)  
≥ 7 days of age  
 
 
10.6 to < 11.5  
2.65 to < 2.88  
 
 
11.5 to < 12.5  
2.88 to < 3.13  
 
 
12.5 to < 13.5  
3.13 to < 3.38  
 
 
≥ 13.5  
≥ 3.38  
< 7 days of age  
11.5 to < 12.4 2.88 to < 
3.10  
12.4 to < 12.9 3.10 to < 
3.23  
12.9 to < 13.5 3.23 to < 
3.38  
≥ 13.5 ≥ 3.38  
Calcium (Ionized), 
High 
(mg/dL; mmol/L)  
 
> ULN to < 6.0  
> ULN to < 1.5  
 
6.0 to < 6.4  
1.5 to < 1.6  
 
6.4 to < 7.2  
1.6 to < 1.8  
 
≥ 7.2 
 ≥ 1.8  
Calcium, Low 
(mg/dL; mmol/L)  
≥ 7 days of age  
 
 
7.8 to < 8.4  
1.95 to < 2.10  
 
 
7.0 to < 7.8  
1.75 to < 1.95  
 
 
6.1 to < 7.0  
1.53 to < 1.75  
 
 
< 6.1  
< 1.53  
< 7 days of age  
6.5 to < 7.5  
1.63 to < 1.88  
6.0 to < 6.5  
1.50 to < 1.63  
5.50 to < 6.0  
1.38 to < 1.50  
< 5.50  
< 1.38  
Calcium (Ionized), Low  
(mg/dL; mmol/L)  
 
< LLN to 4.0  
< LLN to 1.0  
 
3.6 to < 4.0  
0.9 to < 1.0  
 
3.2 to < 3.6  
0.8 to < 0.9  
 
< 3.2  
< 0.8  
Cardiac Troponin I, 
High  
NA  
NA  
NA  
Levels consistent with 
myocardial infarction or 
unstable angina as 
defined by the local 
laboratory  
Creatine Kinase, High  3 to < 6 x ULN  
6 to < 10 x ULN  
10 to < 20 x ULN  
≥ 20 x ULN  
Creatinine, High  
1.1 to 1.3 x ULN  
> 1.3 to 1.8 x ULN OR 
Increase of > 0.3 mg/dL 
above baseline  
> 1.8 to < 3.5 x ULN OR 
Increase of 1.5 to < 2.0 x 
above baseline  
≥ 3.5 x ULN OR  
Increase of ≥ 2.0 x above 
baseline  
Creatinine Clearance15 
or eGFR, Low  
Report only one  
NA  
< 90 to 60 ml/min or 
ml/min/1.73 m2 OR  
10 to < 30% decrease 
from baseline  
< 60 to 30 ml/min or 
ml/min/1.73 m2 OR  
≥ 30 to < 50% decrease 
from baseline  
< 30 ml/min or 
ml/min/1.73 m2 OR 
 ≥ 50% decrease from 
baseline or dialysis 
needed  
Glucose  
(mg/dL; mmol/L)  
Fasting, High  
 
110 to 125  
6.11 to < 6.95  
 
> 125 to 250  
6.95 to < 13.89  
 
> 250 to 500  
13.89 to < 27.75  
 
> 500  
≥ 27.75  
Nonfasting, High  
116 to 160  
6.44 to < 8.89  
> 160 to 250  
8.89 to < 13.89  
> 250 to 500  
13.89 to < 27.75  
> 500  
≥ 27.75  
Glucose, Low  
(mg/dL; mmol/L)  
≥ 1 month of age  
 
 
55 to 64  
3.05 to 3.55  
 
 
40 to < 55  
2.22 to < 3.05  
 
 
30 to < 40  
1.67 to < 2.22  
 
 
< 30  
< 1.67  
< 1 month of age  
50 to 54  
2.78 to 3.00  
40 to < 50  
2.22 to < 2.78  
30 to < 40  
1.67 to < 2.22  
< 30  
< 1.67  
Lactate, High  
ULN to < 2.0 x ULN 
without acidosis  
≥ 2.0 x ULN without 
acidosis  
Increased lactate with 
pH < 7.3 without life-
threatening 
consequences  
Increased lactate with pH 
< 7.3 with life-
threatening 
consequences  
Lipase, High  
1.1 to < 1.5 x ULN  
1.5 to < 3.0 x ULN  
3.0 to < 5.0 x ULN  
≥ 5.0 x ULN  


ODYSSEY Protocol  
Version 6.0 8th November 2019 
ODYSSEY (PENTA 20)    
 
 
 
 
 
 
 
 
Page 285 of 324 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-THREATENING 
Lipid Disorders  
(mg/dL; mmol/L)  
Cholesterol, Fasting, 
High  
≥ 18 years of age  
 
 
 
 
200 to < 240  
5.18 to < 6.19  
 
 
 
 
240 to < 300  
6.19 to < 7.77  
 
 
 
 
≥ 300  
≥ 7.77  
 
 
 
 
NA  
< 18 years of age  
170 to < 200  
4.40 to < 5.15  
200 to < 300  
5.15 to < 7.77  
≥ 300  
≥ 7.77  
NA  
LDL, Fasting, High  
≥ 18 years of age  
130 to < 160  
3.37 to < 4.12  
160 to < 190  
4.12 to < 4.90  
≥ 190  
≥ 4.90  
NA  
> 2 to < 18 years of 
age  
110 to < 130 2.85 to < 
3.34  
130 to < 190  
3.34 to < 4.90  
≥ 190  
≥ 4.90  
NA  
Triglycerides, 
Fasting, High  
150 to 300  
1.71 to 3.42  
>300 to 500  
>3.42 to 5.7  
>500 to < 1,000  
>5.7 to 11.4  
> 1,000  
> 11.4  
Magnesium16, Low 
(mEq/L; mmol/L)  
1.2 to < 1.4  
0.60 to < 0.70  
0.9 to < 1.2  
0.45 to < 0.60  
0.6 to < 0.9  
0.30 to < 0.45  
< 0.6  
< 0.30  
Phosphate, Low 
(mg/dL; mmol/L)  
> 14 years of age  
 
 
2.0 to < LLN  
0.81 to < LLN  
 
 
1.4 to < 2.0  
0.65 to < 0.81  
 
 
1.0 to < 1.4  
0.32 to < 0.65  
 
 
< 1.0  
< 0.32  
1 to 14 years of age  3.0 to < 3.5  
0.97 to < 1.13  
2.5 to < 3.0  
0.81 to < 0.97  
1.5 to < 2.5  
0.48 to < 0.81  
< 1.5  
< 0.48  
< 1 year of age  
3.5 to < 4.5  
1.13 to < 1.45  
2.5 to < 3.5  
0.81 to < 1.13  
1.5 to < 2.5  
0.48 to < 0.81  
< 1.5  
< 0.48  
Potassium, High 
(mEq/L; mmol/L)  
5.6 to < 6.0  
5.6 to < 6.0  
6.0 to < 6.5  
6.0 to < 6.5  
6.5 to < 7.0  
6.5 to < 7.0  
≥ 7.0  
≥ 7.0  
Potassium, Low 
(mEq/L; mmol/L)  
3.0 to < 3.4  
3.0 to < 3.4  
2.5 to < 3.0  
2.5 to < 3.0  
2.0 to < 2.5  
2.0 to < 2.5  
< 2.0  
< 2.0  
Sodium, High  
(mEq/L; mmol/L)  
146 to < 150  
146 to < 150  
150 to < 154  
150 to < 154  
154 to < 160  
154 to < 160  
≥ 160 
≥ 160  
Sodium, Low  
(mEq/L; mmol/L)  
130 to < 135  
130 to < 135  
125 to < 130  
125 to < 135  
121 to < 125  
121 to < 125  
≤ 120  
≤ 120  
Uric Acid, High 
(mg/dL; mmol/L)  
7.5 to < 10.0  
0.45 to < 0.59  
10.0 to < 12.0  
0.59 to < 0.71  
12.0 to < 15.0  
0.71 to < 0.89  
≥ 15.0  
≥ 0.89  
HAEMATOLOGY 
Absolute CD4+ Count, 
Low  
(cell/mm3; x109cells/L)  
> 5 years of age (not 
HIV infected)  
 
 
300 to < 400  
300 to < 400  
 
 
200 to < 300  
200 to < 300  
 
 
100 to < 200  
100 to < 200  
 
 
< 100  
< 100  
Absolute Lymphocyte 
Count, Low  
(cell/mm3; x109cells/L)  
> 5 years of age  
(not HIV infected)  
 
 
 
600 to < 650  
0.600 to < 0.650  
 
 
 
500 to < 600  
0.500 to < 0.600   
 
 
 
350 to < 500  
0.350 to < 0.500  
 
 
 
< 350  
< 0.350  
Absolute Neutrophil 
Count (ANC), Low17 
(cells/mm3;x109cells/L)  
> 7 days of age  
 
 
 
750 –< 1,000  
0.75 –<1.0 
 
 
 
500 – 749  
0.5 –0.749 
 
 
 
250 – 499  
0.25 –0.499 
 
 
 
< 250  
< 0.250 
2 to 7 days of age  
1,250 to 1,500  
1.250 to 1.500  
1,000 to 1,249  
1.000 to 1.249  
750 to 999  
0.750 to 0.999  
< 750  
< 0.750  


ODYSSEY Protocol  
Version 6.0 8th November 2019 
ODYSSEY (PENTA 20)    
 
 
 
 
 
 
 
 
Page 286 of 324 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-THREATENING 
≤ 1 day of age  
4,000 to 5,000  
4.000 to 5.000  
3,000 to 3,999  
3.000 to 3.999  
1,500 to 2,999  
1.500 to 2.999  
< 1,500  
< 1.500  
Fibrinogen, Decreased 
(mg/dL; g/L)  
100 < 200  
1.00 to < 2.00 OR  
0.75 to < 1.00 x LLN  
75 to < 100  
0.75 to < 1.00 OR  
≥ 0.50 to < 0.75 x LLN  
50 to < 75  
0.50 to < 0.75 OR  
0.25 to < 0.50 x LLN  
< 50  
< 0.50 OR < 0.25 x LLN OR 
Associated with gross 
bleeding  
Hemoglobin, Low 
(g/dL; mmol/L)18  
≥ 13 years of age 
(male only)  
 
 
10.0 to 10.9  
6.19 to 6.76  
 
 
9.0 to < 10.0  
5.57 to < 6.19  
 
 
7.0 to < 9.0  
4.34 to < 5.57  
 
 
< 7.0  
< 4.34  
≥ 13 years of age 
(female only)  
9.5 to 10.4  
5.88 to 6.48  
8.5 to < 9.5  
5.25 to < 5.88  
6.5 to < 8.5  
4.03 to < 5.25  
< 6.5  
< 4.03  
57 days of age to < 
13 years of age 
(male and female)  
 
9.5 to 10.4  
5.88 to 6.48  
 
8.5 to < 9.5  
5.25 to < 5.88  
 
6.5 to < 8.5  
4.03 to < 5.25  
 
< 6.5  
< 4.03  
36 to 56 days of age 
(male and female)  
8.5 to 9.6  
5.26 to 5.99  
7.0 to < 8.5  
4.32 to < 5.26  
6.0 to < 7.0  
3.72 to < 4.32  
< 6.0  
< 3.72  
22 to 35 days of age 
(male and female)  
9.5 to 11.0  
5.88 to 6.86  
8.0 to < 9.5  
4.94 to < 5.88  
6.7 to < 8.0  
4.15 to < 4.94  
< 6.7  
< 4.15  
8 to ≤ 21 days of age 
(male and female)  
11.0 to 13.0  
6.81 to 8.10  
9.0 to < 11.0  
5.57 to < 6.81  
8.0 to < 9.0  
4.96 to < 5.57  
< 8.0  
< 4.96  
≤ 7 days of age 
(male and female)  
13.0 to 14.0  
8.05 to 8.72  
10.0 to < 13.0  
6.19 to < 8.05  
9.0 to < 10.0  
5.59 to < 6.19  
< 9.0  
< 5.59  
INR, High  
(not on 
anticoagulation 
therapy)  
1.1 to < 1.5 x ULN  
1.5 to < 2.0 x ULN  
2.0 to < 3.0 x ULN  
≥ 3.0 x ULN  
Methemoglobin 
(% hemoglobin)  
5.0 to < 10.0%  
10.0 to < 15.0%  
15.0 to < 20.0%  
≥ 20.0%  
PTT, High  
(not on 
anticoagulation 
therapy)  
1.1 to < 1.66 x ULN  
1.66 to < 2.33 x ULN  
2.33 to < 3.00 x ULN  
≥ 3.00 x ULN  
Platelets, Decreased 
(cells/mm3; cells/L)  
100,000 to < 124,999 
100.000 x 109 to < 
124.999 x 109  
50,000 to < 100,000 
50.000 x 109 to < 
100.000 x 109  
25,000 to < 50,000 
25.000 x 109 to < 50.000 
x 109  
< 25,000 < 25.000 x 109  
PT, High  
(not on 
anticoagulation 
therapy  
1.1 to < 1.25 x ULN  
1.25 to < 1.50 x ULN  
1.50 to < 3.00 x ULN  
≥ 3.00 x ULN  
WBC, Decreased  
(cells/mm3;x109cells/L)  
> 7 days of age  
 
2,000 to 2,499  
2.000 to 2.499  
 
1,500 to 1,999  
1.500 x to 1.999  
 
1,000 to 1,499  
1.000 to 1.499  
 
< 1,000  
< 1.000  
≤ 7 days of age  
5,500 to 6,999  
5.500 to 6.999  
4,000 to 5,499  
4.000 to 5.499  
2,500 to 3,999  
2.500 to 3.999 
< 2,500  
< 2.500  
URINALYSIS 
 
 
 
 
Glycosuria  
(random collection 
tested by dipstick)  
Trace to 1+ or  
≤ 250 mg  
2+ or ˃ 250 to  
≤ 500 mg  
> 2+ or > 500 mg  
NA  


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PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-THREATENING 
Hematuria  
(not to be reported 
based on dipstick 
findings or on blood 
believed to be of 
menstrual origin)  
6 to < 10 RBCs per high 
power field  
≥ 10 RBCs per high 
power field  
Gross, with or without 
clots OR With RBC casts 
OR Intervention 
indicated  
Life-threatening 
consequences  
Proteinuria  
(random collection 
tested by dipstick)  
1+  
2+  
3+ or higher  
NA  
 
1 Blood pressure norms for children < 18 years of age can be found in: Expert Panel on Integrated Guidelines for 
Cardiovascular Health and Risk Reduction in Children and Adolescents. Pediatrics 2011;128;S213; originally published 
online November 14, 2011; DOI: 10.1542/peds.2009-2107C. 
2 As per Bazett’s formula.   
3 For pruritus associated with injections or infusions, see the Site Reactions to Injections and Infusions section (page 23).   
4 Definition: A disorder characterized by fat loss in the face, extremities, and buttocks.  
5 Definition: A disorder characterized by abnormal fat accumulation on the back of the neck, breasts, and abdomen.   
6 BMD t and z scores can be found in: Kanis JA on behalf of the World Health Organization Scientific Group (2007). 
Assessment of osteoporosis at the primary health-care level. Technical Report. World Health Organization Collaborating 
Centre for Metabolic Bone Diseases, University of Sheffield, UK. 2007: Printed by the University of Sheffield.   
7 Definition: A delivery of a live-born neonate occurring at ≥ 20 to < 37 weeks gestational age.  
8 Definition: A clinically recognized pregnancy occurring at < 20 weeks gestational age.   
9 Definition: A disorder characterized by nausea, headache, tachycardia, hypotension, rash, and/or shortness of breath.  
10 For pain associated with injections or infusions, see the Site Reactions to Injections and Infusions section (page 23).  
11 Definition: A disorder characterized by fever, arthralgia, myalgia, skin eruptions, lymphadenopathy, marked discomfort, 
and/or dyspnea.   
12 WHO reference tables may be accesed by clicking the desired age range or by accessing the following URLs: 
http://www.who.int/growthref/who2007_bmi_for_age/en/ for participants > 5 to 19 years of age and 
http://www.who.int/childgrowth/standards/chart_catalogue/en/ for those ≤ 5 years of age.   
14 Direct bilirubin > 1.5 mg/dL in a participant < 28 days of age should be graded as grade 2, if < 10% of the total bilirubin.   
15 Use the applicable formula (i.e., Cockroft-Gault in mL/min or Schwatrz in mL/min/1.73m2).   
16 To convert a magnesium value from mg/dL to mmol/L, laboratories should multiply by 0.4114.   
17 Neutrophil grading, are based on WHO 2010 guidelines(2) recognising the lower normal levels in African populations. 
18 The conversion factor used to convert g/dL to mmol/L is 0.6206 and is the most commonly used conversion factor. For 
grading hemoglobin results obtained by an analytic method with a conversion factor other than 0.6206, the result must be 
converted to g/dL using the appropriate conversion factor for the particular laboratory.   
19 Severity grading for total bilirubin in neonates is complex because of rapidly changing total bilirubin normal ranges in 
the first week of life followed by the benign phenomenon of breast milk jaundice after the first week of life. Severity 
grading in this appendix corresponds approximately to cut-offs for indications for phototherapy at grade 3 and for 
exchange transfusion at grade 4.  
 
 
References: 
1. 
Division of AIDS National Institute of Allergy and Infectious Diseases National Institutes of 
Health US Department of Health and Human Services. Division of AIDS (DAIDS) Table for Grading the 
Severity of Adult and Pediatric Adverse Events 2014 [updated Version 2.0 November 2014]. Available 
from: http://rcc.tech-res.com/docs/default-
source/safety/daids_ae_grading_table_v2_nov2014.pdf?sfvrsn=8. 
2. 
WHO. Antiretroviral therapy for HIV infection in infants and children: Towards universal 
access.  Recommendations for a public health approach: 2010 revision. In: WHO, editor. 2010. 
 
 


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28 APPENDIX X  TANNER SCALES 
 
The Five Stages of Female Breast and Pubic Hair Development should be staged separately (1, 2). 
 
 
Stage  
Female Breast  
Pubic Hair 
1 
 
Breasts during childhood. 
The breasts are flat and 
show no signs of 
development. 
 
None 
2 
 
Breast bud stage. Milk 
ducts and fat tissue 
forms a small mound. 
 
Sparse, lightly 
pigmented, straight, 
medial border of labia. 
3 
 
Breasts continue to grow. 
Breasts become rounder 
and fuller. 
 
 
Darker, beginning to 
curl, increased 
amount. 
4 
 
Nipple and areola form 
separate small mound.  
Not all girls go through 
this stage.  Some skip 
stage 4 and go directly to 
stage 5. 
 
 
Coarse, curly, 
abundant but amount 
less than in adult. 
5 
Breast growth enters 
final stage.  Adult breast 
is full and round shaped. 
 
Adult feminine 
triangle, spread to 
medial surface of 
thighs 


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The Five Stages of Male Genitalia and Pubic Hair Development should be staged separately 
 
Stage  
Male Genitalia 
Pubic Hair 
 
 
1 
 
Penis and testicles of a child.  
Testicles between 1 and 3 
milliliters in volume. 
No pubichair.   
2 
 
First signs for penis and 
testicle growth, Testicles 
become larger.  Testicles 
between 4 and 6 millilitres in 
volume. 
Pubic hair beginning to grow:  
appears sparse and downy 
straight.   
3 
 
Penis continues to grow 
getting wider and longer.  
Testicles continue to grow 
larger. Testicles between 7 
and 16 millilitres in volume. 
Pubic hair appears curlier and 
coarser with increased 
pigmentation.   
4 
 
Penis continues to grow 
getting wider and longer.  
Testicles continue to grow 
larger.  Penis gland or head is 
more developed.  Testicles 
between 12 and 24 milliliters 
in volume.  Testicles are about 
1 1/2 inches long. 
Pubic hair becomes adult type, 
but less.   
5 
 
Penis growth enters final 
stage.  Average erect penis 
length 6 1/4 inches.  90% are 5 
- 7 inches. Glans penis or head 
is fully developed.  Testicles  
16 - 27 millilitres in volume. 
Testicles are about 1-3/4 
inches. 
Pubic hair is thick spreading to 
medial thighs.   
 
Copyright© 1998,1999 VirtualKid All Rights Reserved. 
References: 
1.  Marshall WA, Tanner JM. Variations in pattern of pubertal changes in girls. Archives of disease in 
childhood. 1969;44(235):291-303. 
2.  Marshall WA, Tanner JM. Variations in the pattern of pubertal changes in boys. Archives of 
disease in childhood. 1970;45(239):13-23. 
 


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29 APPENDIX XI  SAFE LIMITS OF BLOOD SAMPLE VOLUMES IN CHILDREN 
The blood volumes taken from children for clinical and research purposes should not exceed 
maximum allowable limits. 
 
Allowable blood draw limits for children (1,2): 
 
For healthy children: 
o 3% total blood volume in a 24 hour period 
o 10% total blood volume in a 30 day period 
 
For sick/unwell children: 
o 2.5% total blood volume in a 24 hour period 
o 5% total blood volume in a 30 day period 
Estimated total blood volume for term infants (Wt >2kg) and children is 80 ml/kg. 
 
Table 7: Maximum allowable total blood draw volumes* 
 
Wt, kg 
TBV, ml 
Blood draw volume in 24 hours, ml 
Total volume in 30 days, ml 
 
 
Unwell  
(2.5% TBV) 
Healthy  
(3% TBV) 
Unwell  
(5% TBV) 
Healthy  
(10% TBV) 
3 
240 
6 
7 
12 
24 
4 
320 
8 
10 
16 
32 
5 
400 
10 
12 
20 
40 
6 
480 
12 
14 
24 
48 
7 
560 
14 
17 
28 
56 
8 
640 
16 
19 
32 
64 
9 
720 
18 
22 
36 
72 
10 
800 
20 
24 
40 
80 
11-15 
880-1200 
22-30 
27-36 
44-60 
88-120 
16-20 
1280-1600 
32-40 
38-48 
64-80 
128-160 
21-25 
1680-2000 
42-50 
50-60 
64-100 
168-200 
26-30 
2080-2400 
52-60 
62-72 
104-120 
208-240 
31-35 
2480-2800 
62-70 
74-84 
124-140 
248-280 
36-40 
2880-3200 
72-80 
86-96 
144-160 
288-320 
41-45 
3280-3600 
82-90 
98-108 
164-180 
328-360 
46-50 
3680-4000 
92-100 
110-120 
184-200 
368-400 
*Adapted from Jack 2001 (2). 
 
References:  
1. Howie S. Blood sample volumes in child health research: review of safe limits. Bull World 
Health Organ 2011;89:46–53 
 
Jack R. Maximum allowable total blood draw volumes. Children’s Hospital and Regional 
Medical Center Laboratory, Seattle, WA. August 2001. 
https://www.ucdmc.ucdavis.edu/clinicaltrials/StudyTools/Documents/Blood_Draws_Maxim
um_Allowable.doc 


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30 APPENDIX XII IMMUNOLOGY/VIROLOGY SUBSTUDY 
INTRODUCTION AND RATIONALE 
This proposal is based upon two main observations from using integrase inhibitors in clinical studies. 
The first stems from the STARTMRK study (1, 2). It showed that in adults there was a progressive 
increase in CD4 counts in the raltegravir arm. The reasons were unclear and it has been postulated 
that it could be a negative effect of the efavirenz arm rather than a positive impact of raltegravir. 
However in the recently completed REALITY study of over 1800 patients, raltegravir significantly 
increased the CD4 count after 48 weeks, even though raltegravir had only been taken for the first 12 
weeks of treatment (3). In further analyses by MRC CTU (not published yet), the largest effect was in 
children under 17 with declining impact with increasing age and no impact in adults older than 40 
years of age. This is strongly supportive of an impact of raltegravir on thymic output. Whether this is 
related to a more rapid decline in viral load, the viral reservoir or a direct impact on CD4 cell dynamics 
is unclear, and forms the basis for this proposed study.  Other studies also show that integrase 
inhibitors lead to greater increases in CD4 count than comparator regimes (1-5). The reasons for this 
are unclear but may be due to an increase in naïve CD4 cells (6).   
 
If correct, this finding could have important implications for treating HIV infected children and adults, 
as it may imply that integrase inhibitors can lead to an increase in thymic output.   
 
T-cells produced in the thymus from bone marrow derived precursor cells establish the peripheral 
naïve T-cell pool during the first year of life. The export of T-cells from the thymus (thymic output) 
then gradually declines from its peak at 1 year of age to much lower levels by early adulthood. In 
humans, increased peripheral T-cell division with age is relied upon to maintain the naïve T-cell pool. 
The relative contribution of these two mechanisms therefore changes with age. Our recent work has 
demonstrated the importance of maintaining thymic output in children with HIV infection to optimise 
CD4 reconstitution and we have just completed analysis in the cohort from Children with HIV Early 
antiretroviral trial (CHER) (7), which shows that thymic output is the main determinant of CD4 cell 
reconstitution in HIV infected infants (Payne H et al. Personal communication). Though the mechanism 
is unknown, it is clear therefore that the finding of increased naïve CD4 cells in response to integrase 
inhibitors may be due to increased naïve cell proliferation and/or increased thymic output. 
 
Until recently, thymic output has been commonly estimated from T-cell receptor excision circles 
(TRECS) and/or markers such as CD31 expressed on recent thymic emigrants. Because concentrations 
of TREC and markers of recent thymic emigrants are confounded by peripheral T-cell division they 
cannot in themselves be used as quantitative estimates of thymic output. We have established 
methods using measurements of TRECs and cell division using the marker Ki67 in the total naïve CD4 
T-cell population and a recently described mathematical model to obtain explicit measures of thymic 
output in HIV infected patients (8). We have adapted this methodology for use in frozen cells and 
propose to apply it to stored samples collected from the proposed study quantify T-cell dynamics and 
assess if DTG leads to increased thymic output.  
 
 


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DTG may also be operating to increase CD4 cells through its effects on immune activation, possibly as 
a result of ongoing low level viral replication. HIV establishes latency early after primary infection and 
the resting CD4+ T cells constitute the main pool of cells responsible for persistence (9). Homeostatic 
cell proliferation mechanisms as well as stochastic phenomena of cell activation by different stimuli 
have been proposed as models of persistence in the presence of suppressive cART (9). However it was 
recently shown that persistence is rather an active process driven by the virus aiming at its own 
survival (10). Many of the cells in this pool undergo clonal expansion and strong selection of cells with 
HIV integration sites in specific genes as these seem to offer a survival advantage through expansion 
of infected clones (11). Eliminating the viral reservoir is the main challenge of the functional cure 
agenda (12) and therapeutic strategies should incorporate qualitative and quantitative assessments 
of this compartment. Integrase Strand Transfer Inhibitors (INSTIs) exhibit virological features that 
suggest that these compounds are advantageous for reducing the viral reservoir in patients that 
initiate treatment, as well as those commencing second-line therapy (13).  
 
In view of the absence of resistance even when given as monotherapy (14), dolutegravir appears 
particularly appealing for use in children, and the Odyssey trial offers a unique opportunity to assess 
its impact in both groups of patients. There have been conflicting reports on the effect of raltegravir 
on intensification of cART suggesting that there might be a temporary effect on 2LTR circles (15) 
probably reflecting the absence of consensus on the role of ongoing low level viral replication as a 
mechanism of replenishment of the reservoir (16). The aim of the virological component of this 
substudy is to assess the dynamic impact of dolutegravir on the viral reservoir and its impact on clonal 
expansion selection of infected cells when compared to SOC for treatment naïve and treatment 
experienced patients. 
 
Recent data (14, 17, 18) on the use of dolutegravir in highly experienced patients as well as its use as 
part of dual therapy present us with a potential new paradigm in HIV treatment. Odyssey is therefore 
expected to a) inform policies and treatment strategies in paediatric HIV b) advance our knowledge of 
the viral reservoir and c) add invaluable clinical utility/validity data to the use of emerging virological 
and immunological markers for estimating the size of the viral reservoir (19). It is therefore critical to 
ensure storage of adequate, good quality samples (cells and plasma) in order to maximise the 
potential future benefit maintaining commitment to the trial participants. 
 
This sub-study could provide the data that shows that integrase inhibitors can lead to a greater 
increase in thymic output and/or a decrease in CD4 cell death than other regimes.  It could 
demonstrate the use of this class of ARVs is particularly advantageous for children and would strongly 
support the use of integrase inhibitors in HIV infected children. 
 
OBJECTIVE 
The objective of the substudy is to assess the impact of DTG on the mechanisms of CD4 reconstitution, 
immune activation and HIV reservoir and replication. 
   
METHODS 


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Blood samples for plasma will be collected at each study visit according to the trial assessment 
schedule of the main ODYSSEY trial and separated into plasma prior to storage. PBMCs will be 
collected at enrolment, and at 12, 48 and 96 weeks for sites participating in the immunology/virology 
substudy. 
 
Immunology assays:  T-cell subsets of PBMCs (CD3, CD4 and CD45RA) and activation markers (CD38 
and HLA-DR) will be stained by surface labelling. PBMCs will then be fixed and permeabilized and 
stained for the intranuclear marker Ki67 and levels determined by flow cytometry. CD4+/CD45RA+ T-
cells will be isolated by negative immunoselection using magnetic beads. Genomic DNA will be 
extracted using QIAamp DNA minikits (QIAGEN) and Real-time quantitative PCR (qPCR) will be carried 
out to determine the number of TRECs per cell.  
 
The method for estimating thymic output has been described (8). An explicit expression for thymic 
export in terms of total naïve cell numbers, naïve cell TREC content and Ki67 expression is given as: 
Thymic Export (cells day-1) = 
 
 
where c is a constant representing the average TREC content of thymocytes entering the peripheral 
naïve population, y(t) is the fraction of naïve CD4+ T-cells expressing Ki67, Δ is the duration of Ki67 
expression, τ is the TREC concentration in the peripheral naïve CD4+ T-cell population and N(t) is the 
total size of the naïve CD4+ T-cell pool. Calculations to estimate total body CD4+/CD45RA+ T-cell 
numbers N(t) will be performed as previously described using estimates on the linear relationship 
between blood volume and body weight to estimate total body T-cell numbers.  
 
The impact of treatment on thymic output will be analysed using Non-Linear Mixed Effect modelling 
to ascertain the impact of DTG on thymic output. The requirements for these models are to have 
repeated measurements of multiple individuals over time. In addition to determining fixed effects 
(average of a measure within a population) this method has the ability to estimate how an individual 
differs from the average (random effects). Perhaps most importantly it can be used to assess how 
factors such as treatment determine individual responses. Such an approach has been used 
successfully for predicting long term CD4 counts in HIV infected children following ART (20).  
 
We have recently completed studies in children and adults examining the impact of immune activation 
in response to different ART regimes (21). We will study a range of markers in plasma and cell samples 
that will be stored from baseline and at multiple time points after randomization, and then frozen at 
-80oc or in liquid nitrogen respectively. Samples from Uganda will be stored locally and later 
transferred to the Institute of Child Health, UCL. Samples from Zimbabwe and South African sites will 
be stored locally and then transferred to the African Health Research Institute (AHRI) Laboratories for 
analyses. We will analyse soluble markers (including known markers of immune activation such as 
IL1ra, IL6, TNFalpha, IL10, TF, D-dimers and other markers that we have shown to be sensitive to HIV 
infection) using Meso Scale Discovery assays (MesoScale Discovery, Gaithersburg, MD, US) or by ELISA 
(22). Immunophentyping will be performed as previously described to measure CD45RA and CD45RO 
(t) 
y(t)(t)

d(t)
dt




N(t)
c (t)


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subpopulations of CD4 and CD8 cells as well as CD31, CD38, HLA-DR and Ki67 (21).   All of these assays 
have been established by us and are in regular use within our laboratories (At ICH and AHRI).  
 
Viral assays:  For the reservoir assays we have developed a quantitative Total HIV-1 DNA and RNA by 
digital droplet PCR as well as an ultrasensitive quantitative RNA assay (22), and whole genome 
sequencing methodologies by next-generation sequencing (NGS) (23-24). A modified approach based 
on an already published method will be used for estimating 2LTR-circles and integrated HIV DNA (25). 
For the ODYSSEY substudy NGS of the integrase gene will be used as NGS allows increased sensitivity 
in minor variant detection (26). Clonality of infection will be assessed by integration sites analysis (11). 
A case-control approach with a limited number of matched patients in SOC vs DTG will be used to 
detect low-level replication/seeding of the reservoirs and the replication pathway (viral replication or 
T-cell division); if viral replication predominates DTG has a potential beneficial effect in reducing 
reservoirs.  
 
The results could have important implications for treating HIV infected children and adults, as higher 
long term CD4 counts and smaller viral reservoirs are being extensively studied in their association 
with better long-term health.  
 
Number of patients:  Based on CHER data we estimated that 350 children (175 per arm) would provide 
80% power (2-sided α =0.05) to detect a treatment difference of 0.18 log10 cells in thymic output at 
96 weeks, adjusting for baseline output.  We will describe changes in thymic output, immune 
activation biomarkers and viral reservoirs and replication.  
 
STATISTICAL ANALYSIS PLAN 
The primary outcome, thymic output at week 96, will be analysed using analysis of covariance to 
compare the mean log10 output between the two treatment arms, adjusting for baseline output and 
stratification factors. Secondary outcomes will be analysed by the same approach. 
 
References:  
1. 
DeJesus E, Rockstroh JK, Lennox JL, Saag MS, Lazzarin A, Zhao J, et al. Efficacy of raltegravir 
versus efavirenz when combined with tenofovir/emtricitabine in treatment-naive HIV-1-infected 
patients: week-192 overall and subgroup analyses from STARTMRK. HIV clinical trials. 
2012;13(4):228-32. 
2. 
Rockstroh JK, Lennox JL, Dejesus E, Saag MS, Lazzarin A, Wan H, et al. Long-term treatment 
with raltegravir or efavirenz combined with tenofovir/emtricitabine for treatment-naive human 
immunodeficiency virus-1-infected patients: 156-week results from STARTMRK. Clin Infect Dis. 
2011;53(8):807-16. 
3. 
REALITY Trial Team, editor 12-week raltegravir-intensified quadruple therapy versus triple 
first-line ART reduces viral load more rapidly but does not reduce mortality in severely 
immunosuppressed African HIV-infected adults and older children: the REALITY trial. AIDS July 2016; 
Durban, South Africa. 
4. 
Gotuzzo E, Markowitz M, Ratanasuwan W, Smith G, Prada G, Morales-Ramirez JO, et al. 
Sustained efficacy and safety of raltegravir after 5 years of combination antiretroviral therapy as 
initial treatment of HIV-1 infection: final results of a randomized, controlled, phase II study (Protocol 
004). J Acquir Immune Defic Syndr. 2012;61(1):73-7. 
5. 
Negredo E, Massanella M, Puertas MC, Buzon MJ, Puig J, Perez-Alvarez N, et al. Early but 
limited effects of raltegravir intensification on CD4 T cell reconstitution in HIV-infected patients with 
an immunodiscordant response to antiretroviral therapy. J Antimicrob Chemother. 
2013;68(10):2358-62. 


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6. 
Garrido C, Rallon N, Soriano V, Lopez M, Zahonero N, de Mendoza C, et al. Mechanisms 
involved in CD4 cell gains in HIV-infected patients switched to raltegravir. AIDS. 2012;26(5):551-7. 
7. 
Cotton MF, Violari A, Otwombe K, Panchia R, Dobbels E, Rabie H, et al. Early time-limited 
antiretroviral therapy versus deferred therapy in South African infants infected with HIV: results 
from the children with HIV early antiretroviral (CHER) randomised trial. Lancet. 
2013;382(9904):1555-63. 
8. 
Sandgaard KS, Lewis J, Adams S, Klein N, Callard R. Antiretroviral therapy increases thymic 
output in children with HIV. AIDS. 2014;28(2):209-14. 
9. 
Chomont N, El-Far M, Ancuta P, Trautmann L, Procopio FA, Yassine-Diab B, et al. HIV 
reservoir size and persistence are driven by T cell survival and homeostatic proliferation. Nat Med. 
2009;15(8):893-900. 
10. 
Rouzine IM, Weinberger AD, Weinberger LS. An evolutionary role for HIV latency in 
enhancing viral transmission. Cell. 2015;160(5):1002-12. 
11. 
Maldarelli F, Wu X, Su L, Simonetti FR, Shao W, Hill S, et al. HIV latency. Specific HIV 
integration sites are linked to clonal expansion and persistence of infected cells. Science. 
2014;345(6193):179-83. 
12. 
Siliciano RF, Greene WC. HIV latency. Cold Spring Harb Perspect Med. 2011;1(1):a007096. 
13. 
Mesplede T, Wainberg MA. Resistance against Integrase Strand Transfer Inhibitors and 
Relevance to HIV Persistence. Viruses. 2015;7(7):3703-18. 
14. 
Rojas J BJ, Lonca M, Torres B, Parera M, Gonzalez A, Mallolas J, Tricas A, Moreno L, Garcia F, 
Gatell JM, Martinez E, editor Dolutegravir monotherapy in HIV-infected patients with sustained viral 
suppression: a 24-week pilot study. 15th European AIDS Conference; October 2015; Barcelona. 
15. 
Hatano H, Strain MC, Scherzer R, Bacchetti P, Wentworth D, Hoh R, et al. Increase in 2-long 
terminal repeat circles and decrease in D-dimer after raltegravir intensification in patients with 
treated HIV infection: a randomized, placebo-controlled trial. J Infect Dis. 2013;208(9):1436-42. 
16. 
Kearney MF, Spindler J, Shao W, Yu S, Anderson EM, O'Shea A, et al. Lack of detectable HIV-1 
molecular evolution during suppressive antiretroviral therapy. PLoS Pathog. 2014;10(3):e1004010. 
17. 
Gubavu C, Prazuck T, Niang M, Buret J, Mille C, Guinard J, et al. Dolutegravir-based 
monotherapy or dual therapy maintains a high proportion of viral suppression even in highly 
experienced HIV-1-infected patients. J Antimicrob Chemother. 2016;71(4):1046-50. 
18. 
Katlama C SC, Blanc C, Denis A, Caby F, Schneider L, Valantin MA, Tubiana R, Kirstetter M, 
Valdenassi E, Peytavin G, Calvez V, Marcelin AG, editor Dolutegravir monotherapy in HIV-infected 
patients with suppressed HIV viremia. 15th European AIDS Conference; 2015 October 21-24, 2015; 
Barcelona. 
19. 
Bruner KM, Hosmane NN, Siliciano RF. Towards an HIV-1 cure: measuring the latent 
reservoir. Trends Microbiol. 2015;23(4):192-203. 
20. 
Lewis J, Walker AS, Castro H, De Rossi A, Gibb DM, Giaquinto C, et al. Age and CD4 count at 
initiation of antiretroviral therapy in HIV-infected children: effects on long-term T-cell reconstitution. 
J Infect Dis. 2012;205(4):548-56. 
21. 
Klein N, Sefe D, Mosconi I, Zanchetta M, Castro H, Jacobsen M, et al. The immunological and 
virological consequences of planned treatment interruptions in children with HIV infection. PloS one. 
2013;8(10):e76582. 
22. 
The BREATHER (PENTA 16) Trial Group. Weekends-off efavirenz-based antiretroviral therapy 
in HIV-infected children, adolescents, and young adults (BREATHER): a randomised, open-label, non-
inferiority, phase 2/3 trial. Lancet HIV. 2016;3(9):e421-30. 
23. 
Gall A, Ferns B, Morris C, Watson S, Cotten M, Robinson M, et al. Universal amplification, 
next-generation sequencing, and assembly of HIV-1 genomes. J Clin Microbiol. 2012;50(12):3838-44. 
24. 
Hunt M, Gall A, Ong SH, Brener J, Ferns B, Goulder P, et al. IVA: accurate de novo assembly 
of RNA virus genomes. Bioinformatics. 2015;31(14):2374-6. 
25. 
Vandergeeten C, Fromentin R, Merlini E, Lawani MB, DaFonseca S, Bakeman W, et al. Cross-
clade ultrasensitive PCR-based assays to measure HIV persistence in large-cohort studies. J Virol. 
2014;88(21):12385-96. 


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26. 
Fonager J, Larsson JT, Hussing C, Engsig FN, Nielsen C, Fischer TK. Identification of minority 
resistance mutations in the HIV-1 integrase coding region using next generation sequencing. J Clin 
Virol. 2015;73:95-100. 
 
 


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31 APPENDIX XIII  WEIGHT BAND PHARMACOKINETIC SUBSTUDIES (WB-PK) 1 & 2 
WB-PK1: Pharmacokinetics of dolutegravir in children weighing 3 to <25kg 
 
WB-PK2: A crossover pharmacokinetics substudy of dolutegravir in children 
weighing 25 to <40kg with switch to DTG 50mg QD 
 
INTRODUCTION AND RATIONALE  
Dolutegravir (DTG) is recommended as an alternative to EFV 600mg third drug (to be combined with 
2 NRTIs) for first-line ART in adults and adolescents in the WHO 2016 guidelines. Once DTG becomes 
widely available from generic companies, the regimen is expected to be quickly adopted by most 
countries, for first-line and second-line therapy (1,2). To make DTG-based regimens available for 
children data on dosing according to WHO weight bands using formulations produced by generic 
companies are required. DTG is currently licensed in the EU for children weighing ≥15kg and in the US 
for children weighing ≥30kg based on the results of the ongoing dose-finding study, IMPAACT P1093 
(3). 
 
While IMPAACT P1093 is ongoing, ODYSSEY provides an opportunity to complement their results by 
studying the dosing in children according to WHO weight bands, and in children weighing ≥25kg, to 
align DTG dose with ABC/3TC fixed dose combination (FDC). The adult FDC of DTG/ABC/3TC (Triumeq, 
50/600/300mg) is licensed by EMA for adults and adolescents weighing ≥40kg, whereas adult ABC/3TC 
(600/300mg) is licensed by FDA/EMA for children weighing ≥25kg.  
 
The plan for these DTG pharmacokinetic (PK) substudies are endorsed by the WHO Paediatric 
Antiretrovirals Working Group (PAWG), which includes representatives from WHO, FDA and EMA as 
well as the ODYSSEY and P1093 teams.  The dosing and safety data from these substudies will enable 
the use of formulations that are planned for manufacturing by generic companies. 
 
Children in weight band PK substudies will be dosed with the DTG 5mg dispersible tablets (DT) or DTG 
25mg, 50mg film-coated tablets.   The film-coated pediatric-strength 25mg tablet and 50mg tablets 
are known to have comparable bioavailability.  The DTG 5mg dispersible tablets have higher 
bioavailability than the film coated tablets, with the (dose-normalized) AUC(0-inf) estimated to be 1.6- 
to 1.8-fold higher than that of the 50mg tablets (4,5). 
 
Children weighing 3 to <25kg 
The P1093 team is studying DT, which readily disperse in 2-5 mL of water or can be taken direct to 
mouth. The P1093 team conducts intensive PK analyses in 10 children and sparse PK in 12 children in 
age-groups of 4 weeks to 6 months, 6 months to 2 years and 2 to 6 years using 5mg DT.  
 
In discussion with the P1093 team during the WHO PAWG meetings, it was agreed that ODYSSEY will 
provide complementary PK data for corresponding WHO weight bands.  
 
  
 
AIM OF WB-PK1 AND WB-PK2 SUBSTUDIES 


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To assess the pharmacokinetics, safety and tolerability of DTG in children 3-<40kg using simplified 
formulations and WHO weight band-aligned dosing. 
 
OBJECTIVES 
1) To provide PK data, for children in the first three WHO weight bands (Lower WB-PK1, ongoing)   
2) To provide PK data with DTG film-coated 25mg tablets in children 14-<25kg (WB-PK1, part I, 
completed) 
3) To provide PK data in children 14-<20kg on DTG administered as dispersible tablets and in 
children 20-<25kg on DTG administered as dispersible tablets or film-coated 50mg tablets QD 
(WB_PK1 part II, completed) 
4) To provide PK data with DTG 50mg in children 25-<40kg (WB-PK2, completed)  
5) To provide safety data for new dosing 
 
METHODS 
Study Design: 
Children from ODYSSEY A or B will be enrolled into PK substudies across 7 weight bands with the aim 
to have 8 children per weight band with evaluable PK data on the investigated dose.  
WB-PK1 substudy: Children randomised to DTG in weight bands 3-<6kg, 6-<10kg, 10-<14kg, 14-<20kg 
and 20-<25kg will have a 24h PK curve after at least one week of dolutegravir treatment. WB-PK1 part 
I investigated DTG PK exposures in children 14-<20kg and 20-<25kg on once daily DTG 25mg FCT (the 
study is completed). Lower WB-PK (ongoing) and WB-PK1 part II (completed) investigate DTG PK 
parameters in children 3-<25kg using dispersible DTG formulations, and in children 20-<25kg using 
DTG 50mg FCT.   
 
WB-crossover-PK2 substudy: Children weighing 25-<40kg taking DTG according to the previous version 
of the protocol (25mg for 25-<30kg and 35mg in 30-<40kg) have two 24h PK curves performed: the 
first curve at least one week after taking their pre-switch dose and the second curve at least one week 
after the switch to a 50mg tablet (the study is completed).   
 
The plasma concentrations for DTG are assayed at the department of Pharmacy of the Radboud 
University Medical Center in Nijmegen, the Netherlands. The samples are shipped to the Netherlands 
in batches. A quick turnaround data analysis of PK parameters enables review of PK and short-term 
safety results by ODYSSEY and ViiV experts and the IDMC. 
 
Inclusion criteria:  
Children should meet the inclusion criteria for the main trial (ODYSSEY A or ODYSSEY B) AND be 
randomised to DTG, AND meet the following additional inclusion criteria for the WB-PK substudies: 
 
Weight 3-<25kg for WB-PK1 substudies 
o Weight 3-<14kg for Lower WB-PK1 substudy (ongoing) 
o Weight 14-<25kg for WB-PK1 part I substudy and part II substudy (completed) 
 
Weight 25-<40kg for WB-PK2 substudy (completed) 
 
Parents/carers and children, where applicable, give informed written consent 
 
Exclusion criteria: 
In addition to the exclusion criteria for the main trial: 
 
Children who suffer from illnesses that could influence drug pharmacokinetics, i.e. severe 
diarrhoea, vomiting, renal disease or liver disease  


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 
Children treated with concomitant medications known to have interactions with 
dolutegravir 
 
Children with current acute severe malnutrition 
 
Number of Patients:  We aim to enroll at least 8 children per weight band with evaluable PK curves 
on the investigated doses. If we see large differences within a weight band for a dose/formulation we 
will consider recruiting additional children in the relevant weight-band.  Further PK study with 
different DTG doses may be required if the main PK parameters (AUC0-24h, Ctrough or Cmax) are 
substantially different compared to adults on DTG 50mg QD. 
 
Clinical Sites: The PK substudies are undertaken at clinical sites in Uganda (JCRC Kampala, JCRC 
Mbarara and Baylor), South Africa (PHRU Soweto, PHRU Klerksdorp and Durban International Clinical 
Research Site) and Zimbabwe (UZCRC Harare). 
 
Clinical Procedures: Eligible children for the PK substudies are admitted to the PK unit in the morning 
after an overnight fast. Medication adherence during the last 3 days prior to the PK day is ascertained 
ensuring that none of the doses were missed. PK blood samples are taken via an i.v. cannula. For each 
24 h curve, blood samples are taken at t=0 (prior to DTG dose), and at t= 1, 2, 3, 4, 6 and 24h after the 
dose. Standardised meals are served during the PK day at pre-specified time points. Total blood 
volume for PK samples during a 24-hour PK day is approximately 6-20 ml for all children across 7 
different weight bands between 3kg and ≤40kg and is within the limits of maximum allowable total 
blood draw volumes over 24 hours for children (see Appendix XI). The details are outlined in the MOP.  
 
Safety Assessments:  Children in the PK substudies are reviewed at 2, 4 and 12 weeks after starting 
on DTG or changing to the higher dose. Where scheduled visits for the main protocol do not coincide 
children should attend for additional visits. The safety assessments at these visits include: clinical 
assessment, collection of bloods to assess haematology and biochemistry safety parameters and 
acceptability and sleep questionnaires. Additional safety blood tests or investigations may be 
performed if clinically indicated to investigate symptoms or monitor emergent laboratory test 
abnormalities. Adverse events (as at standard follow-up visits) should be reported on the case report 
form. Adverse events (clinical and laboratory) should be graded using the 2014 Division of AIDS toxicity 
grading tables (see Appendix IX). Notable events (pregnancy, liver toxicity meeting DTG stopping 
criteria, ABC hypersensitivity reactions and possible suicidality-related adverse events), grade 3 and 4 
clinical and laboratory events, and all events resulting in change of ART, should be reported on the 
main trial Event Form, including relationship with DTG or other antiretrovirals. Serious adverse events, 
defined according to ICH GCP, and notable events (pregnancy, liver toxicity meeting DTG stopping 
criteria, ABC hypersensitivity reactions and possible suicidality-related adverse events) should be 
reported to the CTU within 24 hours of the sites being aware. 
 
Design Overview and Dose Rationale:  WB-PK 1 substudy investigates PK of DTG in children 3-<25kg. 
It has four components: 
 
Lower WB-PK: PK of DTG in children in the three lower WHO weight bands 3-<6kg, 6-<10kg 
and 10-<14kg using DTG dispersible tablets QD  
 
WB-PK1 part I: PK of DTG in children 14-<20kg and 20-<25kg using DTG film-coated tablets at 
25mg QD  


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 
WB-PK1 part II: PK of DTG administered as dispersible tablets in children 14-<20kg and 20-
<25kg QD or film-coated 50mg tablets QD in children 20-<25kg  
 
The doses in these substudies provide a range from 0.8 to 3.6mg/kg/day (tables 8a – 8c). DTG doses 
up to 2mg/kg were shown to be safe in adults (see below). Infants ≥6 months old at the lower end of 
the first two weight bands on dispersible tablets and children in the 14-<20kg and 20-<25kg weight 
bands on DTG 50mg FCT receive DTG dose of >2mg/kg but for a limited time as they gain weight 
rapidly.  
 
WB-PK1 part I investigated DTG 25mg film-coated tablet in children 14-<25kg. This substudy is 
completed. The results showed that DTG 25mg QD given as FCT to children 14-<20kg and 20-<25kg 
(table 8a) produced lower DTG Ctrough and AUC0-24h compared to fasted adults on DTG 50mg QD (6). 
 
 
Table 8a: Dolutegravir dosing in WB-PK1 part I substudy (completed) 
WHO 
Wt bands, kg  
Administered DTG once daily (formulations and 
daily dose, mg) 
DTG dose, mg/kg 
5mg dispersible tablet 
25mg tablet 
14-<20 
 
1 (25mg) 
1.25-1.8 
20-<25 
 
1 (25mg) 
1.0-1.25 
 
 
WB-PK1 part II substudy (table 8b) investigate higher doses for the 14-<20kg and 20-<25kg to match 
the PK parameters in adults.  The preliminary results showed that both DTG 30mg DT and 50mg FCT 
in children 20-<25kg produced GM Ctrough comparable to values in adults on DTG 50mg QD and GM 
AUC0-24h in between reference values in adults on DTG 50mg QD and BID doses. GM Cmax on both doses 
exceeded adult GM reference values on DTG 50mg QD and BID. Ongoing safety monitoring is 
reassuring. The results will be presented at CROI 2019 (late-breaker abstract accepted [44]).   
Lower WB-PK1 substudy assesses the doses for the three lowest weight bands (3-<14kg) using 
dispersible tablets based on preliminary results of P1093 (table 8b). The study is ongoing.   
 
Table 8b: Dolutegravir dosing in Lower WB-PK1 and WB-PK1 part II substudies 
WHO 
Wt bands, kg  
Administered DTG once daily (formulations and 
daily dose, mg) 
DTG dose, mg/kg 
5mg dispersible tablet 
50mg tablet 
3-<6 
1 (5mg) / 2 (10mg)* 
 
0.8-1.7 / 1.7-3.3 
6-<10 
3 (15mg)* 
 
1.5-2.5 
10-<14 
4 (20mg)* 
 
1.4-2.0 
14-<20 
5 (25mg) 
 
1.25-1.8 
20-<25 
6 (30mg)§ 
1 (50mg)§ 
1.2-2.5 
. Infants <6 months of age will receive DTG 5mg QD while infants ≥6 months of age will receive DTG 10mg QD, both as dispersible tablets.  
*Dose may be modified based on data from the ongoing P1093 study and the data from this study. 
§ Children 20-<25kg will receive either DTG 30mg QD (six 5mg dispersible tablets) or DTG 50mg QD (one 50mg film-coated tablet) depending 
on site. Participants at UZCRC (Zimbabwe), Baylor (Uganda) and PHRU sites in Soweto and Matlosana (South Africa) will receive dispersible 
DTG 30mg whilst those at JCRC sites in Lubowa and Mbarara (Uganda) and Durban International Clinical Research Centre (South Africa) will 
receive film-coated DTG 50mg. 
 


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Based on population PK modelling and the available results from P1093 and the ODYSSEY WB-PK1 
substudies, the proposed DTG doses are predicted to result in GM Ctrough values that exceed antiviral 
target concentrations across all weight bands.  The predicted GM C trough and AUC0-24h exposures for 
children are expected to be in between values observed in adults receiving 50mg QD and BID used in 
the SPRING-1 and VIKING studies respectively (7-9).  However, given the greater PK variability in 
children, wide confidence intervals are expected and paediatric exposures on the upper limit of the 
confidence interval are expected to exceed those observed in adults.  In the 3-<6kg weight band we 
aim to provide some PK data on the 10mg DT which could align with future FDCs. Following discussions 
with ViiV we will initially use a lower dose in the youngest children (<6 months) where exposures may 
be highest. Depending on the results further PK substudies evaluating different DTG doses and 
formulations may be required to achieve optimal and pragmatic dosing in children.     
 
Children weighing 25 to <40kg  
For children aged 6-<12 years, initially two doses aligning with P1093 were taken forward for use in 
ODYSSEY (protocol version 2.0): 25mg for children 25-<30kg, and 35mg for children 30-<40kg. 
However, issues with this dosing pose some challenges for wide implementation of DTG-based 
regimens for children ≥25kg:  
 
For a WHO weight band 25-<35kg, two different doses of 25mg and 35mg are used which is 
impractical for implementation in countries using WHO weight bands.  
 
Generic companies produce scored 50mg tablets and 5 mg tablets, therefore the dose of 35mg 
can only be made with separate 5mg tablets (7 tablets) or with half of one 50mg tablet plus 
two 5mg tablets. Both options will be inconvenient for families and difficult for programs.  
 
In addition the ABC/3TC fixed dose formulation is licensed at the adult dose (600/300mg QD) 
in children ≥25kg, while the ABC/3TC/DTG co-formulated combination (Triumeq) is licensed 
in children ≥40kg. To align paediatric and adult treatment regimens it would be useful if 
Triumeq could be given to children ≥25kg. This would mean that children in this weight band 
receive a DTG dose of 1.25-2 mg/kg/day which is similar to the daily dose currently 
recommended in treatment-experienced adults i.e. 50mg BID (100mg/day). Adult studies 
reported that QD and BID administration had similar tolerability and toxicity (7, 10-13).  
 
The weight band crossover PK2 substudy (WB-PK2) was set up to investigate PK of DTG in children 
weighing 25-<40kg on the currently used doses (25mg for 25-<30kg, and 35mg for 30-<40kg) and after 
a switch to DTG 50mg. The initial doses provided a range from 0.8 to 1.17mg/kg/day; after the switch 
the dose ranged from 1.25 to 2mg/kg/day. The cross-over study design took advantage of the fact that 
ODYSSEY was already open in the 25-<40kg weight band and allowed within-participant comparisons 
of PK parameters between licensed doses and new proposed doses of DTG. 
 
The results presented at the 10th International Workshop on HIV Pediatrics in Amsterdam, showed 
that the new dose of DTG 50mg QD provided DTG Ctrough and AUC exposures comparable to fasted 
adults on DTG 50mg QD and Cmax has not exceeded Cmax in adults on DTG 50mg BID (14). The dose was 
seen to be safe and acceptable for children within the 25-<40kg weight bands. Following this, children 
in the main trial weighing 25-<40kg were switched to DTG 50mg QD as per previous version of the 
protocol.    
 


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Sparse PK sampling will be done in a subset of children on stored plasma samples collected in the 
main trial to correlate with long term tolerability data (See Trial Assessment Schedule). 
Retrospective data on viral loads will enable PK/PD analyses. 
 
STATISTICAL ANALYSIS PLAN 
Review of tolerability and toxicity data:  The PK results and clinical and laboratory events will be 
reviewed by ODYSSEY and ViiV experts and the IDMC. 
 
Drug levels (particularly Cmax) are anticipated to be higher than BID adult drug levels and levels in 
children treated with lower doses. It is therefore important to monitor tolerability and toxicity, 
particularly in the first month on treatment. Adverse events and treatment discontinuations will 
be described in detail and summarised using descriptive statistics. Comparisons will be made with 
data from P1093, ODYSSEY data (outside of the substudies) and adult studies (Table 9) using 
descriptive statistics with attention to weight and time on treatment.  
 
All available clinical and laboratory safety data and PK data will be reviewed by the IDMC who, if 
there are concerns in any of the weight bands, may recommend to the TSC to extend follow up of 
children in specified weight bands enrolled to the PK substudies or to recruit additional children 
in the weight band before decisions for dosing in the main trial are made. The IDMC will continue 
reviewing safety data during the duration of the randomised phase of the trial. 
 
Table 9: Pharmacokinetic parameters for dolutegravir in literature 
Studies 
AUC0-tau 
(h*mg/L) 
AUC0-24 
(h*mg/L) Cmax (mg/L Tmax (h) 
T1/2 (h) 
Ctrough/ 
C12h/C24h 
(mg/L) 
C0 
(mg/L) Reference 
Adults DTG 50 mg QD (fasted, DTG monotherapy, 
n=10) 
43.4 (20) 3.34 (16) 2.00 
(0.97-4.0) 12.0 (22) 0.83 (26) 
Min 2011 (12) 
Adults DTG  50 mg QD (SPRING-1, n=15) 
48.1 (40) 
3.40 (27) 
1.20 (62) 
Van Lunzen 
2013 (10) 
Adults DTG BID 50 mg (VIKING-3, n=180) 
93.4 (50) 5.41 (40) 2.00 
(0-7.87) 
2.72 (70) 
3.20 
(69) 
VIKING 
(ING112961) (8) 
Healthy adults DTG 50 mg BID (fasted, n=12) 
46.3 (55) 92.7 (55) 5.55 (49) 
9.5 (48) 
2.41 (77) 
Dooley 2013(13) 
12-<18 year olds 
DTG 50 mg QD (n=10) 
43.1 (46) 3.48 (38) 3.00 
(1.0-6.0) 11.9 (43) 0.90 (59) 
Viani et al, 2015 
(15) 
6-<12 year olds, DTG 25mg in 20-<30kg (n=4), DTG 
35mg in 30-<40kg (n=2) and  DTG 25-50mg QD in 
>40kg(n=5) 
50.5 (63) 
0.92 (89) 
Viani et al, 2014 
(16) 
2-<6 year olds DTG ~0.8mg/kg DTG QD (granules) 
(n=10) 
44.4 (36) 
0.51 (68) 
Ruel 2017 (17) 
Table entries are geometric mean (CV%) and for Tmax median (range) 
 
Analysis of PK data: Pharmacokinetic parameters (AUC 0-24, Vd, CL, t1/2) will be calculated using 
WinNonlin/Phoenix (Pharsight Corporation, CA, USA). Cmax, Tmax and Cmin will be determined from 
observed concentration time data. Geometric Mean and 95% confidence intervals will be estimated 
for pharmacokinetic parameters of DTG (except for Tmax). Descriptive statistics for the plasma 
concentrations of DTG will be evaluated.  
In WB-PK2, current DTG dose (25mg or 35 mg) and 50mg DTG will be compared in all children with 
two evaluable PK curves. Within-patient ratios of AUC0-24, Cmax and C min for current dose versus 50mg 
DTG will be calculated. Overall GMRs (geometric mean ratios) for current dose versus 50mg DTG 
daily will be calculated after log-transformation of the within-patient ratios and 95% CI for the GMR 
will be calculated using the t-distribution. 
  
SUBSEQUENT DOSING IN THE MAIN TRIAL  
Based on available PK and safety data from P1093 and the ODYSSEY WB-PK substudies, doses in the 
main ODYSSEY trial for children 3-<14kg are being reviewed and, if necessary, modified (with further 


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PK and safety data if required) leading to a decision on the appropriate DTG dose for children in these 
weight bands. (Appendix XIX). 
 
 
 
References: 
1. Third Conference on Antiretroviral Drug Optimization (CADO III). Johannesburg, SA, Nov 29-
Dec 1, 2017 
2. WHO. Paediatric Antiretroviral Drug Optimization (PADO) Meeting 3. 6-7 December 2016. 
WHO. Available from: http://www.who.int/hiv/pub/meetingreports/paediatric-arv-
optimization-pado3/en/index7.html. 
3. NCT01302847. Safety of and immune response to dolutegravir in HIV-1 infected infants, 
children, and adolescents (IMPAACT P1093) [Internet]. Available from: 
https://clinicaltrials.gov/ct2/show/NCT01302847. 
4. Patel P, Song I, Borland J, et al. Relative bioavailability of a paediatric granule formulation of 
the HIV integrase inhibitor dolutegravir in healthy adult subjects. Antivir Ther. 2014;19(3):229-
33.  
5. Buchanan AM, Holton M, Conn I, Davies M, Choukour M, Wynne BR. Relative Bioavailability 
of a Dolutegravir Dispersible Tablet and the Effects of Low- and High-Mineral-Content Water 
on the Tablet in Healthy Adults. Clin Pharmacol Drug Dev. 2017 Nov;6(6):577-583.  
6. Bollen PDJ, Turkova A, Mujuru H, Musiime V, Amuge P, Lugemwa A, Colbers A, J Spyer MJ, 
Lensen S, Moore CL, Hakim J, Kity C, Bbuye D, Atwine L, Giaquinto C, Ford D, Gibb DM, Burger 
DM, and the ODYSSEY trial team. Steady-state pharmacokinetics and early safety data in HIV-
infected African children weighing 14 to <25kg on film-coated dolutegravir 25mg tablets in 
the ODYSSEY trial. 10th International Workshop on HIV Pediatrics, Amsterdam, the 
Netherlands, 20-21 July 2018, abstract 22 
7. Eron JJ, Clotet B, Durant J, et al. Safety and efficacy of dolutegravir in treatment-experienced 
subjects with raltegravir-resistant HIV type 1 infection: 24-week results of the VIKING Study. J 
Infect Dis. 2013 Mar 1;207(5):740-8.  
8. Castagna A, Maggiolo F, Penco G, et al. Dolutegravir in antiretroviral-experienced patients 
with raltegravir- and/or elvitegravir-resistant HIV-1: 24-week results of the phase III VIKING-3 
study. J Infect Dis. 2014 Aug 1;210(3):354-62.  
9. Akil B, Blick G, Hagins DP, et al. Dolutegravir versus placebo in subjects harbouring HIV-1 
with integrase inhibitor resistance associated substitutions: 48-week results from VIKING-4, 
a randomized study. Antivir Ther. 2015;20(3):343-8.  
10. van Lunzen J, Maggiolo F, Arribas JR, Rakhmanova A, Yeni P, Young B, et al. Once daily 
dolutegravir (S/GSK1349572) in combination therapy in antiretroviral-naive adults with HIV: 
planned interim 48 week results from SPRING-1, a dose-ranging, randomised, phase 2b trial. 
The Lancet infectious diseases. 2012;12(2):111-8. 
11. Raffi F, Jaeger H, Quiros-Roldan E, et al. Once-daily dolutegravir versus twice-daily raltegravir 
in antiretroviral-naive adults with HIV-1 infection (SPRING-2 study): 96 week results from a 
randomised, double-blind, non-inferiority trial. Lancet Infect Dis. 2013 Nov;13(11):927-35.  
12. Min S, Sloan L, DeJesus E, Hawkins T, McCurdy L, Song I, et al. Antiviral activity, safety, and 
pharmacokinetics/pharmacodynamics of dolutegravir as 10-day monotherapy in HIV-1-
infected adults. AIDS. 2011;25(14):1737-45. 
13. Dooley KE, Sayre P, Borland J, Purdy E, Chen S, Song I, et al. Safety, tolerability, and 
pharmacokinetics of the HIV integrase inhibitor dolutegravir given twice daily with rifampin 
or once daily with rifabutin: results of a phase 1 study among healthy subjects. J Acquir 
Immune Defic Syndr. 2013;62(1):21-7. 
14. Turkova A, Bollen PDJ, Kaudha E, Chidziva E, Lugemwa A, Kekitiinwa A, Parker A, Shakeshaft 
C, Montero S, Colbers A, Nanduudu A, Mujuru H, Makumbi S, Amuge P, Rojo P, Ford D, Burger 
DM, Gibb DM, and the ODYSSEY trial team. Steady-state pharmacokinetics and early safety 


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data in HIV-infected African children weighing ≥25kg after switching to 50mg film-coated 
dolutegravir tablets in the ODYSSEY trial. 10th International Workshop on HIV Pediatrics, 
Amsterdam, the Netherlands, 20-21 July 2018, abstract 03 
15. Viani RM, Alvero C, Fenton T, Acosta EP, Hazra R, Townley E, et al. Safety, Pharmacokinetics 
and Efficacy of Dolutegravir in Treatment-experienced HIV-1 Infected Adolescents: Forty-
eight-week Results from IMPAACT P1093. The Pediatric infectious disease journal. 
2015;34(11):1207-13. 
16. Viani R. IMPAACT 1093: Safety Pharmacokinetics and Efficacy of Dolutegravir   in Treatment 
Experienced HIV + Children. P901. CROI 2014 
17. Ruel T. Dolutegravir pharmacokinetics, safety and efficacy in HIV+ children 2 to < 6 years old. 
P806. CROI 2017. 
 
 


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32 APPENDIX XIV  PHARMACOKINETIC SUBSTUDY IN PARTICIPANTS RECEIVING RIFAMPICIN AS 
PART OF ANTI-TB TREATMENT OR TB PREVENTION THERAPY WHILE ON DTG: 
TB-PK substudy: pharmacokinetics of dolutegravir co-administered with 
rifampicin  
 
INTRODUCTION AND RATIONALE 
Rifampicin significantly lowers dolutegravir plasma concentrations. The mechanism behind this 
interaction is increased enzyme activity of UDP-glucuronosyltransferase (UGT) caused by rifampicin 
resulting in increased metabolism and elimination of dolutegravir. It has been shown in HIV-infected 
and uninfected adults receiving rifampicin that increasing dolutegravir dose to 50mg BID results in a 
similar exposure compared with dolutegravir 50mg QD without rifampicin (1,2). A recent study 
showed DTG was effective and well-tolerated in HIV/TB co-infected adults receiving rifampicin-based 
TB treatment (2). Furthermore, in adults with resistant HIV, who received dolutegravir 50mg BID 
without rifampicin, there was no added toxicity (3). Based on the above, we expect that the exposure 
to dolutegravir in children with their daily dose doubled (per protocol dose given BID) while on 
rifampicin will be comparable to QD dosing without rifampicin and with no additional safety problems. 
The dolutegravir dose will need to remain BID for 2 weeks after the last dose of rifampicin has been 
given as the enzyme inducing effect of rifampicin slowly fades away after discontinuing the drug (1).  
 
AIM 
To estimate the impact of rifampicin on dolutegravir plasma concentrations in children. 
 
METHODS 
Study Design: 
The PK substudy is set up in a crossover design in order to estimate the impact of rifampicin on the 
plasma pharmacokinetics of dolutegravir within a child. A first 12h PK curve of dolutegravir with 
rifampicin co-administration (TB-PK1) and a second 24h PK-curve without rifampicin co-administration 
(TB-PK2) will be recorded for each child. TB-PK1 will take place within the last month of rifampicin co-
administration. Rifampicin treatment will then be stopped at the TB treatment completion, 
dolutegravir BID dosing will be continued for another 2 weeks and then reduced to QD. At least 2 
weeks after resuming QD dosing of dolutegravir a ‘steady-state’ for dolutegravir will be reached and 
a second PK-curve (TB-PK2) will be recorded in the same child (Figure 1). 
 
Figure 1. Dolutegravir dosing and timing of TB- PK1 and TB-PK2 
 
 
 
 
Figure 1: 
 
       R= rifampicin, BID= twice daily dosing, QD= once daily dosing. 
Last month of co-
administration  
2 weeks 
2 weeks 
 
R + DTG BID 
DTG BID 
DTG BID 
DTG QD 
DTG QD 
DTG QD 
TB-PK2 
(24h curve) 
TB-PK1 
(12h curve) 


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The plasma concentrations for dolutegravir and rifampicin will be assayed at the department of 
Clinical Pharmacy of the Radboud University Medical Center in Nijmegen, The Netherlands.   
 
Inclusion criteria:  
Children should meet the inclusion criteria for the main trial (ODYSSEY A or ODYSSEY B) AND: 
 
Receive DTG as part of their ART  
 
Receive rifampicin as part of anti-TB treatment or TB prevention therapy 
 
Parents/carers and children, where applicable, give informed written consent 
 
Exclusion Criteria: 
In addition to the exclusion criteria for the main trial: 
 
Illnesses that could influence drug pharmacokinetics, i.e. severe diarrhoea, vomiting, renal 
disease or liver disease  
 
Concomitant medications known to have interactions with dolutegravir 
 
Acute severe malnutrition at the time of PK days 
 
Before enrolling in the TB-PK substudy, parents/carers of HIV-infected children and adolescents will 
be given an information sheet about the substudy and asked to give written consent before any 
substudy-specific procedures are performed. 
 
Number of Patients: 12 children (6 children aged ≥ 6 to <12 years old and 6 children aged 12 to <18 
years old) will be included in this PK substudy in order to achieve 10 evaluable subjects. The sample 
size calculation is outlined elsewhere (1). This number may need to be increased if intersubject 
variability of dolutegravir PK parameters in children appears to be larger than the 33% reported in 
non HIV-infected adults or if less than 2 children per WHO weight band have evaluable PK data. In 
addition, younger children <6 years on DTG-based ART who are diagnosed with TB or TB infection 
and treated with rifampicin-containing regimen will be recruited, however small numbers are 
expected at the PK sites.   
 
Clinical Sites: The PK substudies will be undertaken at clinical sites in Uganda, South Africa, and 
Zimbabwe  
 
Clinical Procedures: Eligible children for the PK substudies will be admitted to the PK unit in the 
morning after an overnight fast. Medication adherence during the last 3 days prior to the PK day will 
be confirmed ensuring that none of the doses were missed. Dolutegravir and rifampicin will be given 
at the same time. PK blood samples will be taken via an i.v. cannula. Dolutegravir concentrations will 
be measured at t=0 (prior to the dose), and at t= 1, 2, 3, 4, 6, 12 or 24h (after the dose). Rifampicin 
concentrations will be measured at t=0, 2, 4, and 6h for children weighing ≥6kg. For children weighing 
3-<6kg only one rifampicin PK sample at t=2hr will be taken, the time points for DTG samples remain 
the same. Standardized meals will be served during the PK day at pre-specified time points. Total blood 
volume drawn for each PK curve will be between 6 to 25 ml depending on the weight of the child.  The 
blood volumes will be within the limits of maximum allowable total blood draw volumes over 24 hours 
for children (see Appendix XI). The procedure details will be outlined in the MOP. 
 


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Safety Assessments: As per the main trial protocol. The clinical examination at each visit will explicitly 
prompt for symptoms relating to possible drug toxicities. Blood will be drawn at trial visits to assess 
laboratory safety parameters as per the main Trial Assessment Schedule. Additional safety blood tests 
or investigations may be performed as guided by clinical decision to investigate symptoms or monitor 
emergent laboratory test abnormalities as clinically indicated. Adverse events will be reported on the 
case report form. Adverse events (clinical and laboratory) will be graded using the 2014 Division of 
AIDS toxicity grading tables (see Appendix IX). Grade 3 and 4 clinical and laboratory events, and all 
events resulting in change of ART, will be reported on the main trial CRFs and relationship with 
medications, the child is taking at the time, will be evaluated. Serious adverse events, defined 
according to ICH GCP, and notable events (pregnancy, liver toxicity meeting DTG stopping criteria, ABC 
hypersensitivity reactions and possible suicidality-related adverse events) will be reported to the CTU 
within 24 hours of the sites being aware.  
 
STATISTICAL ANALYSIS PLAN 
Pharmacokinetic parameters (AUC0-tau, AUC0-24, Vd, CL, t1/2) will be calculated using WinNonlin/Phoenix 
(Pharsight Corporation, CA, USA). Cmax, Tmax and Cmin will be determined from observed concentration 
time data. Geometric Means and 95% confidence intervals will be estimated for pharmacokinetic 
parameters (except for Tmax) of dolutegravir at TB PK1 and TB PK2and rifampicin at TB PK1.  The results 
will be compared to the published adult data (1). 
 
BID DTG (with RIF) and QD DTG will be compared in all children with two evaluable PK curves. Within-
patient ratios of AUC0-24, Cmax and C min for BID DTG (with RIF) versus QD DTG will be calculated. Overall 
GMRs (geometric mean ratios) for BID DTG versus QD DTG daily will be calculated after log-
transformation of the within-patient ratios and 95% CI for the GMR will be calculated using the t-
distribution.  
 
Descriptive statistics (mean (SD) and median (IQR) for the plasma concentrations of DTG and RIF will 
also be evaluated. 
 
References: 
 
1. 
Dooley KE, Sayre P, Borland J, Purdy E, Chen S, Song I, et al. Safety, tolerability, and 
pharmacokinetics of the HIV integrase inhibitor dolutegravir given twice daily with rifampin or once 
daily with rifabutin: results of a phase 1 study among healthy subjects. J Acquir Immune Defic Syndr. 
2013;62(1):21-7. 
2. 
Dooley K, Kaplan R, Mwelase T, Grinsztejn B, Ticona E, Lacerda M, et al. Safety and efficacy 
of dolutegravir-based ART in TB/HIV co-infected adults at week 48. 22nd International AIDS 
Conference, Amsterdam, the Netherlands, 23-27 July 2018, abstract TUAB0206. 
3.  
Castagna A, Maggiolo F, Penco G, Wright D, Mills A, Grossberg R, et al. Dolutegravir in 
antiretroviral-experienced patients with raltegravir- and/or elvitegravir-resistant HIV-1: 24-week 
results of the phase III VIKING-3 study. J Infect Dis. 2014;210(3):354-62. 
 


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33 APPENDIX XV  QUALITATIVE SUBSTUDY  
Optimising adherence to HIV treatment 
 
RATIONALE 
It is known that adherence to chronic illness treatment drops off in adolescence and unfortunately 
HIV is no exception (1). Consequently, a primary reason that a young person may need to be moved 
onto second-line treatment is because they have failed first line treatment due to adherence 
problems. Our previous research has shown that adherence problems in this population are 
predominately caused by social and relational challenges and rarely due to a lack of knowledge about 
the need to take ART (2, 3).  
Three key issues are associated with initiation of the second-line ART in young people. Firstly, the 
increased risk of mortality due to therapeutic and virological failure. Secondly, the socially complex 
reasons behind problematic ART adherence in HIV paediatric populations in general (2-6). Thirdly, the 
awareness that second-line ART has long been used as a deterrent, or threat, to enforce adherence to 
first line treatment in young people which may not be helpful (5). Children and young people reported 
being told by clinic staff and their carers about how much harder second-line treatment would be to 
take, for example because of the pill burden, size of pills and side effects, and that they have no further 
therapeutic alternative(2). Hence, whilst existing challenges to adherence are unlikely to have 
resolved for those young people moving on to second-line treatment, they might also be dealing with 
potentially more challenging second-line regimens and the awareness that these are, effectively, their 
‘last option’.  
 
The intervention arms of ODYSSEY involve participants being put onto dolutegravir. There has been a 
recent WHO alert raising concerns about the possible risks of taking dolutegravir during pregnancy for 
increased chances giving birth to a baby with spinal bifida. The trial sites are conducting specialised 
counselling to advise participants in the intervention arm about this recent alert about Doluegravir. 
This will involve clinic staff explaining the nature of the risks and counselling female participants who 
may be sexually active to take contraception.   
 
AIMS 
1. 
To explore how moving onto second-line treatment affects young people’s treatment 
engagement and identify how best to support them to maintain optimal treatment 
adherence.  
2. 
To explore young people and their caregivers’ understanding of the dolutegravir (DTG) alert 
and their sexual and reproductive health (SRH) needs within the context of the ODYSSEY trial.   
 
OBJECTIVES 
1. 
To understand the experiences of young people moving onto second-line ART, including the 
acceptability and effects of an altered pill burden and other treatment changes where 
applicable. 
2. 
To explore their capacity and engagement in adhering to their second-line treatment and 
whether and how this changes over time, including whether this differs across both arms in 
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3. 
To conduct anonymised, comparative analysis with trial data on self-reported adherence in 
order to triangulate results and contribute to improving questionnaire measurements for data 
collected in the trial. 
4. 
To consider what narratives circulate around second-line treatment and what effect this has 
on young people’s perceptions of their health and well-being in the present and the future. 
5. 
To identify what support is needed and can be put in place to strengthen young people’s 
ability to maintain optimal adherence to second-line treatment.  
6. 
To assess trial participants’ understandings of the DTG alert and explore the impact of related 
discussions on their understanding of the trial and SRH.  
7.  
To describe the attitudes of caregivers to supporting the needs of adolescents living with HIV, 
in particular in relation to trial participation, adherence as well as sexual and reproductive 
health information.  
   
 
METHODS 
This is a 36 month qualitative study conducted in two trial sites, at JCRC in Uganda and at the University 
of Zimbabwe, Harare in Zimbabwe, employing longitudinal qualitative methods.  
In each site we will conduct: 
1) 2 in-depth individual interviews – at approximately 3 and 12 months after initiation onto second-
line treatment  
2) a series of focus group discussions with trial participants at different stages of the trial  
3) consultations with a Youth Trial Board currently being set up in participating countries (through a 
separately ViiV-funded project) to develop our dissemination materials. 
4) in-depth interviews with trial participants to explore the influence of discussions around the DTG 
alert.  
5) in-depth interviews with caregivers of trial participants 
  
 
Inclusion criteria for in-depth interviews and focus group with young people:   
 
Participants enrolled in ODYSSEY trial 
 
Age 10-19 years  
 
Participants have known about their HIV status for a minimum of six months before 
participating in the qualitative study  
 
Inclusion criteria for in-depth interviews with caregivers:  
 
Caregiver of young person enrolled in the ODYSSEY trial and qualitative study 
 
The young person has given consent for their caregiver to be approached to participate.  
 
 
Number of Patients: Up to 60 participants will be included in the study in total. A sample size of 60 
participants is appropriate to explore specific qualitative questions in the two sites identified for the 
qualitative substudy. We will adopt a purposive sampling approach to identify and recruit up to 30 
participants in each site. Participants will be invited from both the intervention and standard of care 
arms across the ODYSSEY trial. We will obtain separate assents/consents (together with caregiver 
consents for participants aged under 18 years old) for this research.  There is a patient information 
sheet, informed consent form and assent form for the in-depth interviews and a separate set of 


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information and consent/assent forms for the focus groups. Additional consent will be collected for 
the third round of interviews. 
 
Number of Caregivers: In addition, up to 30 caregivers (15/site) will be recruited to participate in 
individual in-depth interviews to explore their experience of supporting a young person living with 
HIV, as well as their attitudes to trial participation and SRH informational needs of young people living 
with HIV. Young people already participating in the qualitative study will be asked if they are 
comfortable with their caregivers being invited to participate in the qualitative study. A purposive 
sampling approach will be adopted to identify potential caregivers to be included within the trial, 
reflecting key sampling dimensions of interest.  Subject to the young person’s agreement, their 
caregivers will then be invited to participate.   
 
Data collection:   
Individual interviews: 
Baseline interviews will be conducted approximately three months from starting second-line therapy; 
participants will be interviewed individually. This interview will be organised within the early stages of 
their initiation into the trial and will particularly explore their expectations and early experiences of 
second-line treatment and their reported adherence behaviour.     
The second individual interview will be conducted with the same participants, approximately nine 
months after the first interview, to explore how they are adapting to and managing their second-line 
treatment.  
 
A third round of interviews (maximum of 20 per site) will be conducted with a purposively selected 
sample to explore the influence of DTG-alert related conversations on their understanding, 
experiences of and attitudes towards trial participation, the DTG risk and more broadly sexual and 
reproductive health. Participants taking part in these DTG-related interviews will be selected from 
within the existing qualitative sample (this will be done as third interview) and others from within the 
trial population (their first interview). The sample will be selected to ensure maximum 
representativeness of the trial population. Key sampling characteristics will be gender (both male and 
female will be involved); age; and trial arm.  
 
A maximum of 15 caregiver interviews per site will be conducted to better understand the attitudes 
towards and experiences in supporting the needs of adolescents living with HIV, in particular in 
relation to trial participation and treatment adherence. In these interviews we will also ask caregivers 
about their experiences of supporting adolescents growing up with HIV and their opinions towards 
the provision of sexual and reproductive health information to adolescents living with HIV. 
 
Focus group discussions:  
Two sets of focus group discussions will be held with groups of young people and will include 
subsamples of those who have participated in the interview phases and trial participants not yet 
involved in the qualitative substudy. The group compositions will be decided by the research team 
who will take into account local considerations around gender, age and whether young people are 
known to each other.  
The first set of focus groups will be held at approximately months 14-18 from trial start, to explore the 
participant’s perspectives on the acceptability and sleep questionnaires completed at the beginning 
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in each site. The results of these discussions will be fed back to the trial team and clinicians and may 
inform the design of data collection tools for the remaining duration of the trial, and for future use in 
trials with paediatric HIV populations.   
A final set of focus groups will be held up to approximately 3-6 months after the completion of the 
final interviews. During these focus groups, we will feedback and discuss our preliminary findings with 
the young people as well as discuss their experience of DTG related discussions and their attitudes 
towards their SRH informational needs. This will serve not only as an opportunity to refine and validate 
our findings from the data collected so far, but also to discuss and plan how we disseminate our 
findings both to key stakeholders and young people themselves.  
Subject to feasibility and timing we will seek the collaboration of the linked ODYSSEY Youth Trial Board 
in the design, development and dissemination of any youth-targeted materials. 
 
DATA ANALYSIS 
All the data will be audio recorded, transcribed verbatim and translated.  These transcripts will be 
checked by the local researchers and the PI/co-investigators, who will discuss each interview with the 
research team, checking for completeness and emerging themes to be explored in later interviews.  
Data will be stored securely on the MRC/UVRI/JCRC servers in Uganda and on the CeSHHAR servers in 
Zimbabwe.  
Data analysis will be conducted by the local researchers in collaboration with the PI and co-
investigators. A thematic coding framework, informed by the study objectives will be developed after 
the first interview by the study team, so that emerging findings can inform the thematic coding 
framework.  This framework will be used for coding the study data, with constant comparison across 
the team to ensure consistency in coding. 
 
The qualitative data, both from the in-depth interviews and the focus group discussions, will be subject 
to a thematic analysis with coding undertaken accompanied by the iterative development of analytical 
memos. This will involve comprehensive analysis of the data by case to examine how reported 
adherence behaviour may change over time and to account for these reported changes. Once the 
interviews and focus group data have been analysed separately, a comparative analyses of both will 
be conducted to maximise the benefit of using mixed qualitative methods. The team have 
considerable experience of collecting and analysing dyad data (from the young person and related 
caregiver). These dyad data will be analysed together to explore important relational concerns and 
experience. However, these data will only be presented in dyad form if it can be done in such a way 
that does not enable deductive disclosure. 
 
In addition, a comparative analysis of the qualitative data and the quantitative adherence data to 
compare how young people describe their adherence in the qualitative study and how they report it 
within the trial will be performed, and where appropriate anonymised cases will be examined in more 
detail. 
 
References: 
1. 
Nachega JB, Hislop M, Nguyen H, Dowdy DW, Chaisson RE, Regensberg L, et al. Antiretroviral 
therapy adherence, virologic and immunologic outcomes in adolescents compared with adults in 
southern Africa. J Acquir Immune Defic Syndr. 2009;51(1):65-71. 


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2. 
Kawuma R, Bernays S, Siu G, Rhodes T, Seeley J. 'Children will always be children': exploring 
perceptions and experiences of HIV-positive children who may not take their treatment and why 
they may not tell. African journal of AIDS research : AJAR. 2014;13(2):189-95. 
3. 
Bernays S, Paparini S, Gibb D, Seeley J. When information does not suffice: young people 
living with HIV and communication about ART adherence in the clinic. Vulnerable Child Youth Stud. 
2016;11(1):60-8. 
4. 
Bernays S, Jarrett P, Kranzer K, Ferrand RA. Children growing up with HIV infection: the 
responsibility of success. Lancet. 2014;383(9925):1355-7. 
5. 
Bernays S, Seeley J, Rhodes T, Mupambireyi Z. What am I 'living' with? Growing up with HIV 
in Uganda and Zimbabwe. Sociology of health & illness. 2015;37(2):270-83. 
6. 
Mupambireyi Z, Bernays S, Bwakura-Dangarembizi M, Cowan FM. "I don't feel shy because I 
will be among others who are just like me...": The role of support groups for children perinatally 
infected with HIV in Zimbabwe. Child Youth Serv Rev. 2014;45:106-13. 
 
 
 
 
 
 


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34 APPENDIX XVI  YOUTH TRIAL BOARD  PROJECT 
A multi-country model of user involvement to engage adolescents living with 
HIV in the development and delivery of paediatric clinical trials 
 
RATIONALE 
Patient participation and involvement in clinical trials and studies has been shown to improve the 
patient’s experience and ensure a better quality of trial or study (1, 2). The inclusion of children and 
adolescents in these trials needs a higher level of support than their adult counterparts and although 
this presents particular challenges there is a significant need for effective research to be done with 
this key group (3, 4). However, children and adolescents growing up with HIV are a group whose voices 
are often not heard (5). This is due to a number of factors, such as not informing the child about their 
HIV diagnosis, stigma and fear. Coupled with the continuing challenges in including young people in 
clinical research in general, this group are commonly not involved in research in a meaningful way. 
Current provision tends to rely on one young person’s inclusion on a trial committee and is often 
inadequate to ensure young people are genuinely represented. More proactive models of 
engagement are urgently needed to improve user involvement.   
  
AIM 
The aim of this project is to develop a simple low-cost model of meaningful engagement and 
participation of adolescent patient representatives in paediatric clinical trials and research studies.  
 
OBJECTIVES  
1. To conduct a literature review of the available evidence about existing participation models 
for young people in clinical research to inform the design.  
2. To work with young people living with HIV and key stakeholders to design and pilot a user 
engagement model (participation model) for including young people in development, delivery 
and dissemination of the ODYSSEY trial.  
3. To include practical communication strategies between trialists and young people throughout 
the process. 
4. To ensure the relevance and applicability of the participation model in low and high income 
settings.  
5. Once piloted, to integrate the model into future adolescent trial to ensure its ongoing 
application and refinement and to secure its sustainability.  
6. To identify how this model can be adapted to be used in other clinical trials and research 
outside of HIV to maximise its generalisability.  
 
METHODS 
A model of meaningful engagement and participation of children living with HIV in the development 
and delivery of a paediatric clinical trial, using ODYSSEY trial as an example, will be developed and 
piloted in 4 countries participating in ODYSSEY: the UK, South Africa, Uganda and Zimbabwe for 2 
years. Those children involved will be living with HIV, aged between 15-19. They will be recruited 
through a set criteria to ensure they represent the country demographic of children living with HIV 
(gender, ethnicity, social circumstances). 
 
Stage 1: Developing the model  
A literature review will be conducted to identify and review the published and grey English language 
literature on involving young people in clinical trials. Once this review has been completed, a 
consultation phase with partners in the four sites (based in South Africa, UK, Uganda and Zimbabwe) 


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and other key individuals (young people living with HIV and experts with knowledge and experience 
in this field) who are able to advise us on our approach will be performed.  
 
Stage 2: Piloting the model, including ongoing reflection (2 years)  
The model will involve establishment of a Youth Trial boards (YTB), groups of up to 8 young people in 
four countries; the UK, Uganda, South Africa and Zimbabwe. Consent will be obtained from legal 
guardians and assent/consent depending on their age from the participants prior to any involvement 
in this project. Following this, each YTB will meet in-country a number of times a year for the duration 
of the YTB project. Opportunities to link YTB groups together through face to face or virtual meetings 
will be pursued. The groups will be facilitated by individuals skilled in working with young people and 
in research, with local NGO involvement in some sites. Each YTB will receive training to ensure 
understanding of clinical trials, understand their role and support their participation. The in-country 
staff will work closely with researchers from PENTA and London School of Hygiene and Tropical 
Medicine, to ensure that there is effective communication between the sites and across the project 
team. This will also ensure that there is similarity in the roll out of the pilot model across the sites and 
that information is shared. Participant observations of the group meetings will be arranged in order 
to see ways to improve the model and to ensure that we are consistently capturing the ideas and 
opinions of the young people involved. Once the YTBs are established in each country consent will be 
sought to conduct individual interviews with YTB member and facilitators to understand their 
experiences of taking part in a YTB and to gather their ideas about what they have enjoyed, works well 
and how the YTB model could be improved further.  This will inform the guidance that we produce 
alongside the model. 
 
Stage 3: Beyond ODYSSEY trial 
Once the YTB groups have an understanding of how ODYSSEY and clinical trials work in general, they 
will then be involved at the development stage of a new clinical trial. When the model is finalised, it 
can be used by other investigators inside and outside paediatric HIV trials and studies.  
Inclusion criteria: Young people aged 15-19 years who are fully aware of their positive HIV status.  
Number of Patients: At least 32 young people across the four sites. These young people will be 
purposively selected by each in-country team to broadly represent the characteristics of the clinic/ 
population group.  
Project Timeline: 40 months  
Anticipated Enrolment Rate: From Spring 2017 
Output: A patient participation model in clinical trials for adolescents will be designed and piloted. At 
the end of the project this model will then be adopted and applied to new clinical trials as 
opportunities arise.  
DATA ANALYSIS 
Throughout the project, YTB meetings will be observed and participant observation and field notes 
will be taken. This will form the basis for our reflections on the process of developing and shaping the 
model. Individual in-depth interviews will be audio recorded and summarised. These data will be 
analysed using a thematic analysis approach with the supervision of LSHTM researchers.  
 
References:  
1. Moorcraft, S. Y., Marriott, C., Peckitt, C. , Cunnighman, D., Chau, I., Starling, N., Watkins, D., 
& Rao, S. Patients’ willingness to participate in clinical trials and their views on aspects of 
cancer research: results of a prospective patient survey. Trials. 2016; 17: 17. 
2. Institute of Medicine (US) Committee on Cancer Clinical Trials and the NCI Cooperative Group 
Program; Nass SJ, Moses HL, Mendelsohn J, editors. A National Cancer Clinical Trials System 


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for the 21st Century: Reinvigorating the NCI Cooperative Group Program. Washington (DC): 
National Academies Press (US); 2010. 4, Physician and Patient Participation in Cancer Clinical 
Trials. Available from: https://www.ncbi.nlm.nih.gov/books/NBK220370/ 
3. Moore L, and Kirk S. ‘A Literature Review of Children’s and Young People’s Participation in 
Decisions Relating to Health Care’. Journal of Clinical Nursing 19, no. 15/16 (August 2010): 
2215–25. 
4. Cherrill, J., Hudson, H., Cocking, C., Unsworty, V., Franck, L., Fakis, A., McIntyre, J. & Choonara, 
I. Clinical trials: the viewpoint of children with a chronic illness compared with healthy 
children. Archives of  Disease in Childhood  2010; 95:229-232  
5. Clacherty, G. & Donald, D. Child participation in research: reflections on ethical challenges in 
the southern African context. African Journal Of AIDS Research 2007;  6: 147-156.  
 


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35 APPENDIX XVII  ODYSSEY STRUCTURE 
 
 


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36 APPENDIX XVIII  FOLATE AND VITAMIN B12 SUBSTUDY 
Folate and vitamin B12 status among children and adolescents in the ODYSSEY 
trial 
 
INTRODUCTION AND RATIONALE 
Recent concerns have been raised about the use of dolutegravir (DTG) in pregnant women. 
In a preliminary unscheduled analysis of an ongoing NIH-funded birth surveillance study in 
Botswana, an increased risk of neural tube defects (NTDs) among infants of women who 
became pregnant while taking DTG-based regimens has been reported (1-3). It is well known 
that maternal folate and/or vitamin B12 deficiency increases the risk of NTDs however it is 
unknown whether DTG may affect folate or B12 levels.  
 
ODYSSEY provides an opportunity to compare folate and B12 levels in participants on DTG 
versus non DTG regimens to determine if there is an association between DTG and folate 
status.  
 
Folate and vitamin B12 play a critical role in DNA and RNA synthesis. Folate-requiring 
reactions include the reactions involved in amino acid metabolism, purine and pyrimidine 
synthesis, and the formation of the primary methylating agent, S-adenosylmethionine  (4). 
The key folate metabolite is tetrahydrofolate (THF). Folate coenzymes are compartmentalized 
between the cytosol and the mitochondria and they cannot be transported between 
compartments (4). Folate one-carbon (1C) metabolism serves to activate and transfer 1C units 
for biosynthetic processes. As 1C-loaded folates are known not to transfer across intracellular 
membranes, the 1C-carrying metabolite THF must be generated in both the mitochondria and 
cytosol. Formate, a small 1C metabolite produced in the mitochondria, enters the cytosol and 
provides 70% of the cell’s 1C units. Both pyrimidines and purines (DNA building blocks) require 
folate 1C metabolism for their synthesis. Similarly, DNA methylation, which is involved in gene 
expression regulation, is folate 1C-dependent.  
 
Cobalamin (vitamin B12) serves as a coenzyme in the methionine synthase reaction required 
for the conversion of 5-methyltetrahydrofolate (5-methyl-THF) to THF, an active folate form 
participating in folate-dependent enzymatic reactions. In its absence, folate is "trapped" as 5-
methyl-THF, therefore, vitamin B12 deficiency reduces the regeneration of THF required for 
DNA synthesis, which may result in a secondary folate deficiency and impair cell division (5).  
 
DNA synthesis impairment due to folate and/or vitamin B12 deficiency leads to arrest of the 
red blood cell division at the G2 growth stage, continuation of cell growth and increased mean 
cell volume (MCV) (macrocytosis). The red cell MCV, therefore, could be an indicator of folate 
or B12 deficiency.  
 
Different medications (e.g. methotrexate, trimethoprim, phenytoin, antimalarials, antacids) 
may cause or contribute to folate and/or B12 deficiency by various mechanisms, including 
decreased absorption (due to reduction of gastric acid or competion for the receptors on 
intestinal mucosal cells), effect on enzymes involved in folate metabolism or inhibition of 
cellular utilisation of folate. Since NT development requires both rapid cell proliferation and 
gene expression regulation, then 1C metabolism is crucial for this embryonic event, and could 
represent the cellular process that becomes disturbed by DTG, leading to NTDs. 


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Folate status can be measured using plasma (or serum) and red blood cell (RBC) folate levels. 
The plasma or serum folate level is an informative biomarker of short-term folate status. It 
reflects a recent folate intake and is sensitive to dietary changes or action of folate-decreasing 
medications. RBC folate level tend to reflect long-term folate status and estimates the folate 
stores over the last 3-4 months (5).  
 
ODYSSEY provides an opportunity to compare folate levels in participants on DTG versus non 
DTG regimens to determine if there is a potential association between DTG and folate /B12 
status. 
 
AIM 
 
To compare folate and B12 levels among children and adolescents randomized to a DTG 
containing ART regimen versus those on SOC ART regimen  
 
OBJECTIVES 
1. To compare red cell folate level at 96 weeks or later in participants randomized to  
DTG versus participants randomized to SOC (Primary objective) 
2. To compare change in plasma folate level from baseline to week 4 in participants 
randomized to DTG versus participants randomized to SOC 
3. To compare change in MCV levels from baseline to weeks 48 and 96  in participants 
randomized to DTG versus participants randomized to SOC 
4. To compare vitamin B12 serum level at 96 weeks or later in participants randomized 
to DTG versus participants randomized to SOC 
 
METHODS 
 
Folate and B12 will be assayed in children enrolled in ODYSSEY at sites in Uganda who were 
aged ≥6 years at enrolment (if required the substudy may also extended to other sites).  
 
Red cell folate and B12 will be assayed in prospectively collected samples using the same 
blood draw as for other scheduled blood tests in the trial at 96 weeks or later (for patients 
who have passed their 96 week visit the samples will be collected at their first visit after the 
substudy opens). Where assays cannot be done in real time, the blood samples will be stored 
for subsequent testing. Plasma folate levels will be assayed at baseline and at 4 weeks after 
commencing ART using plasma samples that are routinely stored as part of the main ODYSSEY 
protocol.  
 
Testing plasma folate levels before and after ART initiation will allow us to evaluate the impact 
of treatment on folate levels within an individual.  
 
Blood samples and assays 
EDTA whole blood samples and serum are routinely collected in the ODYSSEY study and 
plasma samples are stored. MCV is captured as part of the haematology assays at screening, 
week 0, 24 and then every 24 weeks, and these data are available to analyse the differences 
in MCV between the arms. The plasma and whole blood folate levels will be performed on 


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the cobas e 411 instrument (Roche diagnostics, Manheim). The Elecsys Folate assay will be 
used for the determination of folate in plasma, and the Folate RBC Hemolyzing Reagent will 
be used in conjunction with the Elecsys Folate RBC assay for the determination of folate in 
erythrocytes. Plasma B12 levels will be performed on the cobas e 411 instrument (Roche 
diagnostics, Manheim). The Elecsys Vitamin B12 II electrochemiluminescence immunoassay 
will be used for the determination of B12 in plasma. 
 
Substantial variation between folate assays used in different laboratories exists, therefore 
testing will be centralised. 
 
SAMPLE SIZE AND STATISTICAL ANALYSIS PLAN 
 
 
The sample size is based on objectives 1 and 2. Since plasma folate levels and red blood cell 
folate levels in children in Africa are unknown we have assumed that a difference of half a 
standard deviation or more between groups may be clinically relevant. 
1. Comparison of red blood cell folate level at week 96 (or later): To detect a difference 
of half a standard deviation in folate levels between DTG and SOC arms, with 80% 
power at the 5% level of significance, a sample size of 124 children is required (62 in 
each treatment arm). 
2. Comparison of plasma folate levels at week 4: To detect a difference of half a standard 
deviation in folate levels between DTG and SOC arms, adjusting for baseline levels, 
using one pre-treatment and one post-treatment measure (assuming correlation 
between pre- and post-treatment levels of 0.3, with 80% power at the 5% level of 
significance, a sample size of 116 children is required (58 in each treatment arm). 
Increasing the sample size to 140 children (70 in each arm) will allow for 10% of samples being 
potentially unanalysable for any reason. 
 
Mean red blood cell folate levels and B12 at week 96 (or later) will be compared between the 
two randomised groups in an intention-to-treat analysis. In an as treated analysis we will look 
at the difference between groups depending on the ART received at the time of the sample. 
 
Mean plasma folate levels at 4 weeks will be compared between the two randomised groups 
with adjustment for values at randomisation by analysis of covariance (ANCOVA). 
 
Mean MCV levels at 48 and 96 weeks will be compared between the two randomised groups 
with adjustment for values at randomisation by ANCOVA. In as treated analysis we will also 
look at the difference between groups depending on the ART received at the time of the 
sample 
  
References: 
1. Zash R, Holmes L, Makhema J, Diseko M, Jacobson DL, Mayondi G, Mmalane M, 
Mofenson L, Gaolathe T, Petlo C, Essex M, Lockman S and Shapiro RL. Surveillance 
for neural tube defects following antiretroviral exposure from conception, the 
Tsepamo study (Botswana).  AIDS 2018. Amsterdam, the Netherlands, 23–27 July 
2018. Symposia session TUSY15. 
http://programme.aids2018.org/Programme/Session/1589 
2. World Health Organization. Statement on DTG. May 18, 2018; Geneva. 


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3. FDA Drug Safety Communication: FDA to evaluate potential risk of neural tube birth 
defects with HIV medicine dolutegravir (Juluca, Tivicay, Triumeq). May 18, 2018. 
4. Bailey LB, Gregory JF 3rd. Folate Metabolism and requirements. J Nutr 1999; 129: 
779-82. Available: https://doi.org/10.1093/jn/129.4.779 
5. Bailey LB, Hausman DB. Folate status in women of reproductive age as basis of 
neural tube defect risk assessment. Ann N Y Acad Sci 2018;1414(1):82-95.  
 


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37 APPENDIX XIX DOLUTEGRAVIR DOSING IN THE ODYSSEY TRIAL ACROSS DIFFERENT PROTOCOL VERSIONS 
  
ODYSSEY v2.0* 
ODYSSEY v3.0 
ODYSSEY v4.0 
ODYSSEY v5.0 onwards 
  
Main trial 
participants  
Main trial 
participants  
WB PK substudy 
participants  
Main trial participants  
WB PK substudy 
participants  
Main trial 
participants  
WB PK substudy 
participants  
3-<6kg 
- 
- 
  
- 
5mg or 10mg DT 
- 
5mg or 10mg DT 
6-<10kg 
- 
- 
  
- 
15mg DT 
- 
15mg DT 
10-<14kg 
- 
- 
  
- 
20mg DT 
- 
20mg DT 
14-<15kg 
- 
- 
25mg 
25mg25mg DT§ 
25mg DT 
25mg DT 
N/A 
15-<20kg 
20mg* 
20mg 
 
 
 
 
 
20-<25kg 
25mg 
25mg 
25mg 
25mg30mg DT or 
50mg¥ 
30mg DT  or 50mg† 
50mgπ  
N/A  
25-<30kg 
25mg 
25mg50mg** 
50mg 
25mg50mg** 
NA 
50mg 
NA 
30-<35kg 
35mg 
35mg50mg** 
50mg 
35mg50mg** 
NA 
50mg 
NA 
35-<40kg 
35mg 
35mg50mg** 
50mg 
35mg50mg** 
NA 
50mg 
NA 
≥40kg 
50mg 
50mg 
NA 
50mg 
NA 
50mg 
NA 
 Infants <6 months of age receive DTG 5mg QD while infants ≥6 months of age receive DTG 10mg QD, both as dispersible tablets.  
* In May 2017 the EMA licensed the use of 20mg DTG in children 15 - <20kg and ≥6years, following this, children were able to be recruited in this weight and age-band.  
** From 1st of April 2018, after ethics notification, sites following protocol version 3.0 and above were recommended to increase the DTG dose of children 25 - <40kg to 50mg 
FCT QD at their next scheduled study visit based on the results of the WB-PK2. WB-PK2 participants remained on DTG 50mg with ongoing follow-up. Non-PK participants 
recruited after implementation were initiated on the 50mg film-coated DTG dose. 
† Both doses are examined in WB-PK1 part II substudy in this weight-band.  
§ Children 15 - <20kg previously receiving DTG 20mg QD were changed to DTG film-coated 25mg tablets upon the approval of protocol v4.0. Subsequently all children 14-<20kg 
changed to DTG 25mg QD dispersible tablets following the review of WB-PK1 part I results and approval by the relevant ethical and regulatory authorities. 
¥ Children 20 - <25kg previously receiving DTG 25mg QD as one 25mg  film-coated tablet changed to either DTG 30mg QD dispersible tablets or DTG 50mg QD (film-coated tablet) 
depending on site  following the review of WB-PK1 part I results and approval by the relevant ethical and regulatory authorities.  
π Following the review of PK and safety data children 20-<25kg receiving DTG 30mg dispersible tablets should be switched to DTG 50mg film-coated tablets. Those who prefer to 
remain on DTG 30mg DT will be able to do so until they move weight band. 
DT=dispersible, otherwise film coated tables 


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38 APPENDIX XX ARRANGEMENTS FOR THE EXTENDED FOLLOW-UP OF ODYSSEY PARTICIPANTS 
GENERAL INFORMATION 
This appendix details planned extended follow-up for all children participating in the ODYSSEY 
(PENTA 20) trial.  
Objectives are two-fold:  
1. to provide safety data for ViiV Healthcare for participants who, in the opinion of the 
treating physician, continue to derive benefit from dolutegravir and receive 
dolutegravir from ViiV Healthcare where it is not available through their country’s 
national HIV treatment programme; 
2. to monitor long-term safety and effectiveness of dolutegravir versus standard of care 
(at selected sites, subject to sufficient funding).  
All children who entered the main trial (weighing ≥14kg) will attend their end of study visit 
for the randomised phase on/after 24 April 2020 (when the last patient recruited into the 
main trial reaches 96 weeks follow-up). Children recruited weighing <14kg will be asked to 
attend their 96 week follow-up visit at/after 96 weeks from their randomisation visit and this 
will be their end of study visit for the randomised phase; they should move to the extended 
follow-up only after their 96 week visit is completed.  The baseline visit for the extended 
follow-up will be the end of study visit for the randomised phase of the trial. 
At the end of study visit for the randomised phase children and carers will be asked to consent 
to extended follow-up. Children’s visit schedules (at least 6 monthly) and care will be as per 
local clinic guidelines. In addition to routine care, clinics will be asked to continue collecting 
urine dipsticks, Sleep and Mood Questionnaire data, waist and hip circumferences and 
bioelectric impedance analysis (BIA) measurements (the latter only at the sites where BIA 
machines are available) as per the Assessment schedule below. Pregnancy tests will also be 
required at every visit for females of childbearing potential. Clinicians will be able to change 
ART according to local supplies and/or in the patient’s best interest.  Laboratory tests will be 
according to local practice.  
Children on DTG at the end of the randomised phase will be moved to local DTG where 
available (up to 6 months’ supply of trial DTG will be provided for transition). Provided 
consent is given for extended follow-up, ViiV Healthcare DTG 5mg DT can continue to be 
provided for participants <20kg in South Africa, Uganda and Zimbabwe who are receiving DTG 
5mg DT at their end of study visit for the randomised phase until DTG DTs are available locally 
or participants move to DTG FCTs or stop benefiting from DTG-based ART (i.e. require 
switching to another regimen). Similarly, provided consent is given for extended follow-up, 
ViiV Healthcare  DTG 50mg FCT can continue to be provided for participants in Thailand 
receiving DTG 50mg FCT at their end of study visit for the randomised phase.  
At each routine clinic visit during extended follow-up, a shortened version of the trial follow-
up CRF will be completed. Serious adverse events must be reported to MRC CTU within 24 
hours of the investigator becoming aware of the event. Annually we will collect participant 
and carer data on sleep and mood. 
Participants receiving ViiV Healthcare DTG must remain in follow-up while this continues or 
they can no longer take ViiV Healthcare DTG provided for the trial. Follow-up of other 
participants will be at selected sites for 3 years after the randomisation phase is completed 


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(until May 2023) providing sufficient funding is available. If sufficient funding cannot be 
sourced then follow-up of these participants (those not receiving ViiV Healthcare DTG) will 
finish at their study visit for the end of the randomised phase on/after 24 April 2020. 
 
ASSESSMENT SCHEDULE FOR EXTENDED FOLLOW- UP 
 
(a)  Clinical assessment: including presence of adverse events and change in HIV disease stage.  
(b)  Frequency of blood tests will be as per local practice but some specific tests above routine care may be 
required, subject to funding. These will be as per the trial assessment schedule for the randomised phase. 
No additional tests will be performed in extended follow-up that were not performed during the 
randomised phase. 
(c) In children aged 8 or over 
(d) Pregnancy test for females of childbearing potential only  
(e) The full acceptability, sleep and mood questionnaire should be completed at the end of study visit for the 
randomised phase, however, only the sleep and mood section should be completed for the extended follow-
up period. The sleep and mood section is only required to be completed for participants ≥6 years old. 
(f) Weight, height, waist and hip circumferences and BIA measurements at the sites where BIA machines are 
available. Replaces previously collected Lipodystrophy assessment data. 
 
 
 
 
WEEK 
Study visit at end of 
randomised phase 
Further follow-up  
(minimum of every 6 
months) 
End of extended follow-
up visit 
Informed consent for 
extended follow-up 
X 
 
 
History and clinical 
assessment a  
X 
As per local practice 
As per local practice 
Tanner scale 
X 
N/A 
N/A 
Lipodystrophy assessment 
X 
N/A 
N/A 
Drug supply to next visit 
X 
As per local practice 
As per local practice 
HIV-1 RNA viral load 
X 
As per local practice 
As per local practice 
HIV-1 resistance tests 
 
As per local practice 
As per local practice 
T cell lymphocyte subsets 
X 
As per local practice 
As per local practice 
Biochemistry b 
X 
As per local practice 
As per local practice 
Haematology 
X 
As per local practice 
As per local practice 
Lipids/glucose b 
X 
As per local practice 
As per local practice  
Bone profile b 
X 
As per local practice 
As per local practice 
Urine dipstick 
X 
Annual 
Annual 
Quality of Life 
questionnaire c 
X 
N/A 
N/A 
Pregnancy test d 
X 
Every clinic visit 
X 
Plasma storage 
X 
N/A 
N/A 
Adherence questionnaire 
X 
N/A 
N/A 
Acceptability, sleep & 
mood questionnaire e 
X d 
Annual d 
X d 
Body composition 
assessment f 
N/A as  full lipodystrophy 
assessment should be 
performed at this visit 
Annual 
Annual 


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SAFETY REPORTING 
Any event fulfilling the criteria of an SAE should be reported within 24 hours of the site team 
becoming aware of the event. Other adverse events and pregnancies should be submitted 
within one week of the site team becoming aware of the event.  
 
CO-ENROLMENT 
Co-enrolment in other studies is allowed. Centres should also adhere to local guidelines 
concerning co-enrolment in other trials.