Clinical trial NCT02259127: 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 type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
PHASE3
Conditions: HIV Infection
Lead sponsor: PENTA Foundation
Sponsor class: NETWORK
Collaborators: name: Institut National de la Santé Et de la Recherche Médicale, France
name: Program for HIV Prevention and Treatment (PHPT)
name: Medical Research Council Clinical Trials Unit at University College London (MRC CTU at UCL)
First posted: 2014-10-08
Enrollment: 792
Sex: ALL
Minimum age (years): 28
Maximum age (years): 18
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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 is an ongoing international randomised trial evaluating dolutegravir based antiretroviral therapy versus standard of care in HIV-infected children aged less than 18 years who are starting first line treatment (ODYSSEY A) or switching to second line treatment (ODYSSEY B). Participants have visits 4 weeks and 12 weeks after randomisation and every 12 weeks subsequent of that. They are followed up for a minimum of 96 weeks. The primary objective of the study is 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 will be invited to consent to extended follow-up. Children's visit schedules and care will be as per local clinic guidelines. Participants will be followed up until May 2023 in this phase of the trial. The objectives of the extended follow-up 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.

Eligibility criteria: Inclusion Criteria:

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 aged 12 years or older who have reached menses must have a negative pregnancy test at screening and be willing to adhere to effective methods of contraception if sexually active
* Children with co-infections who need to start ART can be enrolled into ODYSSEY 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 and/or dosing information has become available from the IMPAACT P1093 DTG dose-finding study.

ADDITIONAL CRITERIA FOR ODYSSEY A:

• Planning to start first-line ART

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
* 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
* In settings where resistance tests are routinely available, at least one new active NRTI from tenofovir disoproxil fumarate, abacavir or zidovudine should have preserved activity based on cumulative results of resistance tests
* 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 tenofovir disoproxil fumarate, abacavir or zidovudine
* Viral load ≥ 500 c/ml at screening visit

Exclusion Criteria:

* History or presence of known allergy or contraindications to dolutegravir
* 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, OR ALT ≥3x upper limit of normal and bilirubin ≥2x upper limit of normal
* 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

Primary outcomes:
measure: Difference in proportion with failure (clinical or virological)
timeFrame: 96 weeks
Secondary outcomes:
measure: Difference in proportion with clinical or virological failure (as defined above)
timeFrame: over 48 weeks.
measure: Time to any new or recurrent AIDS defining event (WHO 4) or severe WHO 3 events adjudicated by the Endpoint Review Committee
timeFrame: after 24 weeks from randomisation
measure: Proportion of children with viral load suppression <50 c/ml
timeFrame: at 48 and 96 weeks
measure: Proportion of children with viral load suppression <400 c/ml
timeFrame: at 48 and 96 weeks
measure: Rate of clinical events : WHO 4, severe WHO 3 events and death
timeFrame: over 96 weeks
measure: Change in CD4 count and percentage and CD4/CD8 ratio from baseline
timeFrame: to weeks 48 and 96
measure: Proportion developing new resistance mutations in those with viral load > 400 c/ml
timeFrame: 96 weeks
measure: Change in total cholesterol, triglycerides and lipid fractions (LDL, HDL)
timeFrame: from baseline to weeks 48 and 96
measure: Incidence of serious adverse events
timeFrame: Through study completion, at least 96 weeks
measure: Incidence of new clinical and laboratory grade 3 and 4 adverse events
timeFrame: Through study completion, at least 96 weeks
measure: Incidence of adverse events (of any grade) leading to treatment modification
timeFrame: Through study completion, at least 96 weeks
measure: Health-related Quality of Life Questionnaire
timeFrame: Through study completion, at least 96 weeks
measure: Adherence Questionnaire
timeFrame: Through study completion, at least 96 weeks
measure: Acceptability Questionnaire
timeFrame: Through study completion, at least 96 weeks
Other outcomes:
Locations:
city: Frankfurt
country: Germany
facility: Universitata Frankfurt
city: Hamburg
country: Germany
facility: UkE Eppendorf Hamburg
city: Porto
country: Portugal
facility: Centro Materno-Infantil de Norte
city: Durban
country: South Africa
facility: King Edward VIII Hospital
city: Hlabisa
country: South Africa
facility: Africa Health Research Institute (AHRI)
city: Klerksdorp
country: South Africa
facility: PHRU Klerksdorp
city: Parow
country: South Africa
facility: Kid-Cru
city: Soweto
country: South Africa
facility: PHRU
city: Barcelona
country: Spain
facility: Hospital San Joan de Defu
city: Madrid
country: Spain
facility: Hospital 12 de Octubre
city: Madrid
country: Spain
facility: Hospital La Paz
city: Chiang Mai
country: Thailand
facility: Nakornping Hospital
city: Chiang Rai
country: Thailand
facility: Chiangrai Prachanukroh Hospital
city: Khon Kaen
country: Thailand
facility: Khon Kaen Hospital
city: Maha Sarakham
country: Thailand
facility: Mahasarakam Hospital
city: Mueang Chanthaburi District
country: Thailand
facility: Prapokklao Hospital
city: Phayao
country: Thailand
facility: Phayao Hospital
city: Kampala
country: Uganda
facility: Baylor
city: Kampala
country: Uganda
facility: JCRC
city: Kampala
country: Uganda
facility: MUJHU
city: Mbarara
country: Uganda
facility: JCRC
city: Birmingham
country: United Kingdom
facility: Birmingham Heartlands Hospital
city: Leeds
country: United Kingdom
facility: Leeds General Infirmary
city: Leicester
country: United Kingdom
facility: Leicester Royal Infirmary
city: London
country: United Kingdom
facility: Great Ormand Street Hospital
city: London
country: United Kingdom
facility: Kings College Hospital
city: London
country: United Kingdom
facility: St Mary's Hospital
city: Harare
country: Zimbabwe
facility: UZCRC
Study officials:
References:
citation: Amuge P, Lugemwa A, Wynne B, Mujuru HA, Violari A, Kityo CM, Archary M, Variava E, White E, Turner RM, Shakeshaft C, Ali S, Nathoo KJ, Atwine L, Liberty A, Bbuye D, Kaudha E, Mngqibisa R, Mosala M, Mumbiro V, Nanduudu A, Ankunda R, Maseko L, Kekitiinwa AR, Giaquinto C, Rojo P, Gibb DM, Turkova A, Ford D; ODYSSEY Trial Team. Once-daily dolutegravir-based antiretroviral therapy in infants and children living with HIV from age 4 weeks: results from the below 14 kg cohort in the randomised ODYSSEY trial. Lancet HIV. 2022 Sep;9(9):e638-e648. doi: 10.1016/S2352-3018(22)00163-1.
citation: Turkova A, Waalewijn H, Chan MK, Bollen PDJ, Bwakura-Dangarembizi MF, Kekitiinwa AR, Cotton MF, Lugemwa A, Variava E, Ahimbisibwe GM, Srirompotong U, Mumbiro V, Amuge P, Zuidewind P, Ali S, Kityo CM, Archary M, Ferrand RA, Violari A, Gibb DM, Burger DM, Ford D, Colbers A; ODYSSEY Trial Team. Dolutegravir twice-daily dosing in children with HIV-associated tuberculosis: a pharmacokinetic and safety study within the open-label, multicentre, randomised, non-inferiority ODYSSEY trial. Lancet HIV. 2022 Sep;9(9):e627-e637. doi: 10.1016/S2352-3018(22)00160-6. Epub 2022 Jul 19.
citation: Turkova A, White E, Mujuru HA, Kekitiinwa AR, Kityo CM, Violari A, Lugemwa A, Cressey TR, Musoke P, Variava E, Cotton MF, Archary M, Puthanakit T, Behuhuma O, Kobbe R, Welch SB, Bwakura-Dangarembizi M, Amuge P, Kaudha E, Barlow-Mosha L, Makumbi S, Ramsagar N, Ngampiyaskul C, Musoro G, Atwine L, Liberty A, Musiime V, Bbuye D, Ahimbisibwe GM, Chalermpantmetagul S, Ali S, Sarfati T, Wynne B, Shakeshaft C, Colbers A, Klein N, Bernays S, Saidi Y, Coelho A, Grossele T, Compagnucci A, Giaquinto C, Rojo P, Ford D, Gibb DM; ODYSSEY Trial Team. Dolutegravir as First- or Second-Line Treatment for HIV-1 Infection in Children. N Engl J Med. 2021 Dec 30;385(27):2531-2543. doi: 10.1056/NEJMoa2108793.
citation: Singh RP, Adkison KK, Baker M, Parasrampuria R, Wolstenholme A, Davies M, Sewell N, Brothers C, Buchanan AM. Development of Dolutegravir Single-entity and Fixed-dose Combination Formulations for Children. Pediatr Infect Dis J. 2022 Mar 1;41(3):230-237. doi: 10.1097/INF.0000000000003366.
citation: Moore CL, Turkova A, Mujuru H, Kekitiinwa A, Lugemwa A, Kityo CM, Barlow-Mosha LN, Cressey TR, Violari A, Variava E, Cotton MF, Archary M, Compagnucci A, Puthanakit T, Behuhuma O, Saiotadi Y, Hakim J, Amuge P, Atwine L, Musiime V, Burger DM, Shakeshaft C, Giaquinto C, Rojo P, Gibb DM, Ford D; ODYSSEY Trial Team. ODYSSEY clinical trial design: a randomised global study to evaluate the efficacy and safety of dolutegravir-based antiretroviral therapy in HIV-positive children, with nested pharmacokinetic sub-studies to evaluate pragmatic WHO-weight-band based dolutegravir dosing. BMC Infect Dis. 2021 Jan 4;21(1):5. doi: 10.1186/s12879-020-05672-6.
citation: Bollen PDJ, Moore CL, Mujuru HA, Makumbi S, Kekitiinwa AR, Kaudha E, Parker A, Musoro G, Nanduudu A, Lugemwa A, Amuge P, Hakim JG, Rojo P, Giaquinto C, Colbers A, Gibb DM, Ford D, Turkova A, Burger DM; ODYSSEY trial team. Simplified dolutegravir dosing for children with HIV weighing 20 kg or more: pharmacokinetic and safety substudies of the multicentre, randomised ODYSSEY trial. Lancet HIV. 2020 Aug;7(8):e533-e544. doi: 10.1016/S2352-3018(20)30189-2.