학술논문
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
Document Type
Report
Author
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; SaÏdi, Yacine; Hakim, James; Amuge, Pauline; Atwine, Lorna; Musiime, Victor; Burger, David M.; Shakeshaft, Clare; Giaquinto, Carlo; Rojo, Pablo; Gibb, Diana M.; Ford, Deborah; Ali, Shabinah; Babiker, Abdel; Borg, Chiara; Borges Da Silva, Anne-Marie; Calvert, Joanna; Gasa, Joshua; Jamil, Nasir; Lensen, Sarah; Little, Emma; Mohamed, Fatima; Montero, Samuel; Oguntimehin, Rachel; Parker, Anna; Patel, Reena; Phillips, Tasmin; Sarfati, Tatiana; Scott, Karen; Spyer, Moira; Thomason, Margaret; Turner, Rebecca; Van Looy, Nadine; White, Ellen; Widuch, Kaya; Wilkes, Helen; Wynne, Ben; Grossele, Tiziana; Gomez-Pena, Daniel; Bilardi, Davide; Vecchia, Giulio; Saidi, Yacine; Riault, Yoann; Coelho, Alexandra; Picault, Laura; Kouakam, Christelle; Chalermpantmetagul, Suwalai; Chinwong, Dujrudee; Jourdain, Gonzague; Peongjakta, Rukchanok; Sukrakanchana, Pra-ornsuda; Sirirungsi, Wasna; Seeley, Janet; Bernays, Sarah; Conway, Magda; Klein, Nigel; Nastouli, Eleni; De Rossi, Anita; Munoz Fernandez, Maria Angeles; Burger, David; Bollen, Pauline; Colbers, Angela; Waalewijn, Hylke; Kaudha, Elizabeth; Nanduudu, Annet; Mujyambere, Emmanuel; Labeja, Paul Ocitti; Nankunda, Charity; Ategeka, Juliet; Erim, Peter; Makanga, Collin; Nambi, Esther; Keminyeto, Edridah; Tukwasibwe, Deogratiuos; Makumbi, Shafic; Ninsiima, Emily; Tukamushaba, Mercy; Ankunda, Rogers; Natuhurira, Ian; Kasozi, Miriam; Rubinga, Baker; Kekitiinwa, Adeodata R.; Bbuye, Dickson; Nalubwama, Justine; Akobye, Winnie; Kisekka, Muzamil Nsibuka; Kirabira, Anthony; Ninsiima, Gloria; Namanda, Sylvia; Agaba, Gerald; Nagawa, Immaculate; Nalugo, Annet; Namuli, Florence; Kadhuba, Rose; Namuddu, Rachael; Kiyimba, Lameck; Baita, Angella; Atim, Eunice; Kobusingye, Olivia; Namajja, Clementine; Byaruhanga, Africanus; Besigye, Rogers; Murungi, Herbert; Onen, Geoffrey; Musoke, Philippa; Barlow-Mosha, Linda; Ahimbisibwe, Grace; Namwanje, Rose; Etima, Monica; Ssenyonga, Mark; Serunjogi, Robert; Kataike, Hajira; Isabirye, Richard; Balamusani, David; Nolan, Monica; Janese van Rensburg, Anita; Smuts, Marlize; Andrea, Catherine; Pieterse, Sumaya Dadan Sonja; Jaeven, Vinesh; Makola, Candice; Fourie, George; Smith, Kurt; Dobbels, Els; Zuidewind, Peter; Van Huyssteen, Hesti; Isaacs, Mornay; Nentsa, Georgina; Ncgaba, Thabis; MacDonald, Candice; Mtshagi, Mandisa; Bester, Maria; Orange, Wilma; Arendze, Ronelle; Mulder, Mark; Ramsagar, Nastassja; Liberty, Afaaf; Mathiba, Ruth; Maseko, Lindiwe; Kekane, Nakata; Khumlo, Busi; Khunene, Mirriam; Sbisi, Noshalaza; Brown, Jackie; Madonsela, Ryphina; Mbadaliga, Nokuthula; Essack, Zaakirah; Lakha, Reshma; Vadee, Aasia; Frank, Derusha; Akoojee, Nazim; Monametsi, Maletsatsi; Machache, Gladness; Fourie, Yolandie; Nanan-kanjee, Anusha; Erasmus, Juan; Mamiane, Angelous; Daniel, Tseleng; Mayat, Fatima; Maduna, Nomfundo; Baliram, Patsy; Ngampiyasakul, Chaiwat; Greetanukroh, Pisut; Chamjamrat, Wanna; Khannak, Praechadaporn; Techakunakorn, Pornchai; Thapwai, Thitiwat; Puangmalai, Patcharee; Maneekaew, Ampai; Ounchanum, Pradthana; Thaweesombat, Yupawan; Kongponoi, Areerat; Thewsoongnoen, Jutarat; Kanjanavanit, Suparat; Yingyong, Pacharaporn; Namwong, Thida; Junkaew, Rangwit; Srirompotong, Ussanee; Sudsaard, Patamawadee; Nuanbuddee, Siripun; Wimonklang, Sookpanee; Na-Rajsima, Sathaporn; Thongpaen, Suchart; Runarassamee, Pattira; Meethaisong, Watchara; Udomvised, Arttasid; Rakgokong, Modiehi; Scheppers, Dihedile; Moloantoa, Tumelo; Kaka, Abdul Hamid; Masienyane, Tshepiso; Ori, Akshmi; Mmolawa, Kgosimang; Abraham, Pattamukkil; Mosia, Rejoice; Mawlana, Sajeeda; Mngqibisa, Rosie; Nundlal, Rashina; Singh, Elishka; Madlala, Penelope; Naidoo, Allemah; Cebekhulu, Sphiwee; Casey, Petronelle; Pillay, Collin; Sidhoo, Subashinie; Chikowore, Minenhle; Nyantsa, Lungile; Nunkoo, Melisha; Nair, Terence; Pillay, Enbavani; Singh, Sheleika; Rajkumar, Sheroma; Koole, Olivier; Bird, Kristien; Buthelezi, Nomzamo; Mthethwa, Mumsy; Nathoo, Kusum; Bwakura-Dangarembizi, Mutsa; Chidziva, Ennie; Mudzingwa, Shepherd; Bafana, Themelihle; Warambwa, Colin; Musoro, Godfrey; Tinago, Gloria; Mutsai, Shirley; Moyo, Columbus; Nhema, Ruth; Phiri, Misheck Nkalo; Chitongo, Stuart; Choga, Joshua; Bhiri, Joyline; Ishemunyoro, Wilber; Ndlovu, Makhosonke; Kasipong, Naruporn; Chanthaburanun, Sararut; Nanthapisal, Kesdao; Jupimai, Thidarat; Noppakaorattanamanee, Thornthun; Bunupuradah, Torsak; Songtaweesin, Wipaporn Natalie; Saisaengjan, Chutima; Schultze-Straber, Stephan; Konigs, Christoph; Kobbe, Robin; Mantkowski, Felicia; Welch, Steve; Daglish, Jacqui; Thrasyvoulou, Laura; Singadia, Delane; Foxall, Sophie; Acero, Judith; Pasko-Szcech, Gosia; Flynn, Jacquie; Tudor-Williams, Gareth; Abdulla, Farhana; Bandi, Srini; Li, Jin; O'Riordan, Sean; Barker, Dominique; Vowden, Richard; Nsirim, Colin Ball Eniola; McClughlin, Kathleen; Garcia, India; Conejo, Pablo Rojo; Epalza, Cristina; Tato, Luis Prieto; Fernandez, Maite; Garcia, Luis Escosa; Peéa, Maria José Mellado; Costa, Talia Sainz; Guasch, Claudia Fortuny; Julian, Antoni Noguera; Estepa, Carolina; Bruno, Elena; Cabeza, Alba Murciano; Fernandez, Maria Angeles Muéoz; Palau, Paula; Marques, Laura; Teixeira, Carla; Fernandes, Alexandre; Nunes, Rosita; Nascimento, Helena; Padrao, Andreia; Tuna, Joana; Ramos, Helena; Mendes, Ana Constança; Pinheiro, Helena; Matos, Ana Cristina; Kyomuhendo, Flavia; Nakalanzi, Sarah; Williams, Cynthia Mukisa; Ngcobo, Ntombenhle; Pako, Deborah; Crisp, Jacky; Dube, Benedictor; Chandiwana, Precious; Gozhora, Winnie; Weller, Ian; Abrams, Elaine; Apollo, Tsitsi; Clayden, Polly; Leroy, Valériane; Pozniak, Anton; Crawley, Jane; Thiébaut, Rodolphe; McIlleron, Helen; Bamford, Alasdair; Lyall, Hermione; Prendergast, Andrew; Fitzgerald, Felicity; Goodman, Anna
Source
BMC Infectious Diseases. January 4, 2021, Vol. 21 Issue 1
Subject
Language
English
ISSN
1471-2334
Abstract
Author(s): Cecilia L. Moore[sup.1] , Anna Turkova[sup.1] , Hilda Mujuru[sup.2] , Adeodata Kekitiinwa[sup.3] , Abbas Lugemwa[sup.4] , Cissy M. Kityo[sup.5] , Linda N. Barlow-Mosha[sup.6] , Tim R. Cressey[sup.7,8,9] , Avy [...]
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 [greater than or equai to]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%) [greater than or equai to]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 [greater than or equai to]35 kg in ODYSSEY A and extending recruitment (above 700) to allow for [greater than or equai to]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. Keywords: Randomized control trial, Basket trial, HIV, Paediatric, Efficacy, Safety, Pharmacokinetic, Dolutegravir
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 [greater than or equai to]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%) [greater than or equai to]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 [greater than or equai to]35 kg in ODYSSEY A and extending recruitment (above 700) to allow for [greater than or equai to]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. Keywords: Randomized control trial, Basket trial, HIV, Paediatric, Efficacy, Safety, Pharmacokinetic, Dolutegravir