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
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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, Cecilia L; Turkova, Anna; Mujuru, Hilda; Kekitiinwa, Adeodata; Lugemwa, Abbas; Kityo, Cissy M; Barlow-Mosha, Linda N; Cressey, Tim R; Violari, Avy; Variava, Ebrahim; Cotton, Mark F; Archary, Moherndran; Compagnucci, Alexandra; Puthanakit, Thanyawee; Behuhuma, Osee; Saϊdi, Yacine; Hakim, James; Amuge, Pauline; Atwine, Lorna; Musiime, Victor; Burger, David M; Shakeshaft, Clare; Giaquinto, Carlo; Rojo, Pablo; Gibb, Diana M; Ford, Deborah; ODYSSEY Trial Team; Kobbe, Robin.
In: BMC INFECT DIS, Vol. 21, No. 1, 04.01.2021, p. 5.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research
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T1 - 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
AU - Moore, Cecilia L
AU - Turkova, Anna
AU - Mujuru, Hilda
AU - Kekitiinwa, Adeodata
AU - Lugemwa, Abbas
AU - Kityo, Cissy M
AU - Barlow-Mosha, Linda N
AU - Cressey, Tim R
AU - Violari, Avy
AU - Variava, Ebrahim
AU - Cotton, Mark F
AU - Archary, Moherndran
AU - Compagnucci, Alexandra
AU - Puthanakit, Thanyawee
AU - Behuhuma, Osee
AU - Saϊdi, Yacine
AU - Hakim, James
AU - Amuge, Pauline
AU - Atwine, Lorna
AU - Musiime, Victor
AU - Burger, David M
AU - Shakeshaft, Clare
AU - Giaquinto, Carlo
AU - Rojo, Pablo
AU - Gibb, Diana M
AU - Ford, Deborah
AU - ODYSSEY Trial Team
AU - Kobbe, Robin
PY - 2021/1/4
Y1 - 2021/1/4
N2 - 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.
AB - 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.
KW - Adolescent
KW - Body Weight
KW - Child
KW - Child, Preschool
KW - Cohort Studies
KW - Drug Dosage Calculations
KW - Europe/epidemiology
KW - Female
KW - HIV Infections/drug therapy
KW - HIV Integrase Inhibitors/administration & dosage
KW - HIV-1/genetics
KW - Heterocyclic Compounds, 3-Ring/administration & dosage
KW - Humans
KW - Male
KW - Oxazines/administration & dosage
KW - Piperazines/administration & dosage
KW - Pyridones/administration & dosage
KW - RNA, Viral/genetics
KW - South Africa/epidemiology
KW - Thailand/epidemiology
KW - Treatment Outcome
KW - Uganda/epidemiology
KW - Viral Load/drug effects
KW - World Health Organization
KW - Zimbabwe/epidemiology
U2 - 10.1186/s12879-020-05672-6
DO - 10.1186/s12879-020-05672-6
M3 - SCORING: Journal article
C2 - 33446115
VL - 21
SP - 5
JO - BMC INFECT DIS
JF - BMC INFECT DIS
SN - 1471-2334
IS - 1
ER -