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

Abstract

Background Dolutegravir (DTG)-based antiretroviral therapy (ART) is highly effective and well-tolerated in adults and is rapidly being adopted globally. We describe the design of the ODYSSEY trial which evaluates the efficacy and safety of DTG-based ART compared with standard-of-care in children and adolescents. The ODYSSEY trial includes nested pharmacokinetic (PK) sub-studies which evaluated pragmatic World Health Organization (WHO) weight-band-based DTG dosing and opened recruitment to children < 14 kg while dosing was in development. Methods ODYSSEY (Once-daily DTG based ART in Young people vS. Standard thErapY) is an open-label, randomised, non-inferiority, basket trial comparing the efficacy and safety of DTG + 2 nucleos(t) ides (NRTIs) versus standard-of-care (SOC) in HIV-infected children < 18 years starting first-line ART (ODYSSEY A) or switching to second-line ART (ODYSSEY B). The primary endpoint is clinical or virological failure by 96 weeks. Results Between September 2016 and June 2018, 707 children weighing ≥14 kg were enrolled; including 311 ART-naïve children and 396 children starting second-line. 47% of children were enrolled in Uganda, 21% Zimbabwe, 20% South Africa, 9% Thailand, 4% Europe. 362 (51%) participants were male; median age [range] at enrolment was 12.2 years [2.9–18.0]. 82 (12%) children weighed 14 to < 20 kg, 135 (19%) 20 to < 25 kg, 206 (29%) 25 to < 35 kg, 284 (40%) ≥35 kg. 128 (18%) had WHO stage 3 and 60 (8%) WHO stage 4 disease. Challenges encountered include: (i) running the trial across high- to low-income countries with differing frequencies of standard-of-care viral load monitoring; (ii) evaluating pragmatic DTG dosing in PK sub-studies alongside FDA- and EMA-approved dosing and subsequently transitioning participants to new recommended doses; (iii) delays in dosing information for children weighing 3 to < 14 kg and rapid recruitment of ART-naïve older/heavier children, which led to capping recruitment of participants weighing ≥35 kg in ODYSSEY A and extending recruitment (above 700) to allow for ≥60 additional children weighing between 3 to < 14 kg with associated PK; (iv) a safety alert associated with DTG use during pregnancy, which required a review of the safety plan for adolescent girls. Conclusions By employing a basket design, to include ART-naïve and -experienced children, and nested PK sub-studies, the ODYSSEY trial efficiently evaluates multiple scientific questions regarding dosing and effectiveness of DTG-based ART in children. Trial registration NCT, NCT02259127, registered 7th October 2014; EUDRACT, 2014–002632-14, registered 18th June 2014 (https://www.clinicaltrialsregister.eu/ctr-search/trial/2014-002632-14/ES); ISRCTN, ISRCTN91737921, registered 4th October 2014.

Are we there yet? 40 years of successes and challenges for children and adolescents living with HIV

“…Even as newer medications with high barriers to resistance are rolled out for CAWH (e.g. second‐generation integrase strand transfer inhibitors), scale‐up challenges in the context of implementation, prior relevant ART exposures, and limited availability of formulations may still negatively affect the trajectory and impact of resistance [15]. Largely unknown aspects of resistance (e.g.…”

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

“…The ODYSSEY trial was an open-label, multicentre, randomised, controlled, non-inferiority trial that evaluated the 96-week efficacy and safety of dolutegravir plus two nucleoside reverse transcriptase inhibitors versus standard of care in 792 children living with HIV, aged from 4 weeks to younger than 18 years, starting first-line or second-line ART in Africa, Europe, and Thailand. 10 ODYSSEY included two randomised cohorts: the main trial enrolled 707 children with bodyweight of 14 kg or greater, 11 and an additional randomised cohort enrolled 85 children with bodyweight from 3 kg to less than 14 kg. 12 Most children from Thailand and Africa in the main trial (613 [94%] of 652 children) and in the cohort with bodyweight of less than 14 kg (70 [95%] of 74) continued in ongoing observational follow-up after completion of the randomised phase, with additional consent.…”

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

“…ODYSSEY is an open-label, randomised, parallel-group, non-inferiority trial comparing dolutegravir plus two nucleo side or nucleotide reverse transcriptase inhibitors (NRTIs; dolutegravir arm) versus standard of care (NNRTI, boosted protease inhibitor, or non-dolutegravir integrase inhibitor, plus two NRTIs) in infants, children, and adolescents with HIV (younger than 18 years), starting first-line ART (ODYSSEY-A) or switching to second-line ART after treatment failure with first-line regimens (ODYSSEY-B). 14 The main trial recruitment period was between Sept 20, 2016 and June 22, 2018 and was open to children weighing at least 14 kg, with children weighing less than 14 kg ineligible for random assignment during this period due to absence of an appropriate dolutegravir formulation and dosing for weight bands lower than 14 kg. Recruitment of children weighing less than 14 kg opened on July 5, 2018 using a 5 mg dispersible tablet with dosing based on preliminary IMPAACT P1093 data.…”

“…8,9,[11][12][13] The ODYSSEY trial aimed to compare the efficacy and safety of dolutegravir-based ART versus standard of care in children starting first-line or secondline ART. 14 The main trial recruited children weighing at least 14 kg and showed superiority of dolutegravir-based ART. 15 Based on a nested pharmacokinetic and safety substudy, 16 the US Food and Drug Administration (FDA) and European Medicines Agency approved the adult 50 mg dolutegravir dose in children weighing 20 kg or more.…”