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
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., Saϊdi Y., Hakim J., Amuge P., Atwine L., Musiime V., Burger DM., Shakeshaft C., Giaquinto C., Rojo P., Gibb DM., Ford D., Ali S., Babiker A., Borg C., Borges Da Silva AM., Calvert J., Gasa J., Jamil N., Lensen S., Little E., Mohamed F., Montero S., Oguntimehin R., Parker A., Patel R., Phillips T., Sarfati T., Scott K., Spyer M., Thomason M., Turner R., Van Looy N., White E., Widuch K., Wilkes H., Wynne B., Grossele T., Gomez-Pena D., Bilardi D., Vecchia G., Saidi Y., Riault Y., Coelho A., Picault L., Kouakam C., Chalermpantmetagul S., Chinwong D., Jourdain G., Peongjakta R., Sukrakanchana PO., Sirirungsi W., Seeley J., Bernays S., Conway M., Klein N., Nastouli E., De Rossi A., Munoz Fernandez MA., Burger D., Bollen P., Colbers A., Waalewijn H., Kaudha E., Nanduudu A., Mujyambere E., Labeja PO., Nankunda C., Ategeka J., Erim P., Makanga C., Nambi E., Keminyeto E., Tukwasibwe D., Makumbi S., Ninsiima E., Tukamushaba M., Ankunda R., Natuhurira I., Kasozi M., Rubinga B., Bbuye D., Nalubwama J., Akobye W.
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.