AMBIsome Therapy Induction OptimisatioN (AMBITION): high dose AmBisome for cryptococcal meningitis induction therapy in sub-Saharan Africa: study protocol for a phase 3 randomised controlled non-inferiority trial

AMBIsome Therapy Induction OptimisatioN (AMBITION): high dose AmBisome for cryptococcal meningitis induction therapy in sub-Saharan Africa: study protocol for a phase 3 randomised controlled non-inferiority trial. Lawrence, D. S, Youssouf, N., Molloy, S. F, Alanio, A., Alufandika, M., Boulware, D. R, Boyer-Chammard, T., Chen, T., Dromer, F., Hlupeni, A., Hope, W., Hosseinipour, M. C, Kanyama, C., Lortholary, O., Loyse, A., Meya, D. B, Mosepele, M., Muzoora, C., Mwandumba, H. C, Ndhlovu, C. E, Niessen, L., Schutz, C., Stott, K. E, Wang, D., Lalloo, D. G, Meintjes, G. A, Jaffar, S., Harrison, T. S, & Jarvis, J. N Trials, 19(1):649, BioMed Central, dec, 2018.

Paper doi abstract bibtex

Cryptococcal meningitis (CM) is a major cause of mortality in HIV programmes in Africa despite increasing access to antiretroviral therapy (ART). Mortality is driven in part by limited availability of amphotericin-based treatment, drug-induced toxicities of amphotericin B deoxycholate and prolonged hospital admissions. A single, high-dose of liposomal amphotericin (L-AmB, Ambisome) on a fluconazole backbone has been reported as non-inferior to 14 days of standard dose L-AmB in reducing fungal burden. This trial examines whether single, high-dose L-AmB given with high-dose fluconazole and flucytosine is non-inferior to a seven-day course of amphotericin B deoxycholate plus flucytosine (the current World Health Organization [WHO] recommended treatment regimen). An open-label phase III randomised controlled non-inferiority trial conducted in five countries in sub-Saharan Africa: Botswana, Malawi, South Africa, Uganda and Zimbabwe. The trial will compare CM induction therapy with (1) a single dose (10 mg/kg) of L-AmB given with 14 days of fluconazole (1200 mg/day) and flucytosine (100 mg/kg/day) to (2) seven days amphotericin B deoxycholate (1 mg/kg/day) given alongside seven days of flucytosine (100 mg/kg/day) followed by seven days of fluconazole (1200 mg/day). The primary endpoint is all-cause mortality at ten weeks with a non-inferiority margin of 10% and 90% power. Secondary endpoints are early fungicidal activity, proportion of grade III/IV adverse events, pharmacokinetic parameters and pharmacokinetic/pharmacodynamic associations, health service costs, all-cause mortality within the first two and four weeks, all-cause mortality within the first ten weeks (superiority analysis) and rates of CM relapse, immune reconstitution inflammatory syndrome and disability at ten weeks. A total of 850 patients aged ≥ 18 years with a first episode of HIV-associated CM will be enrolled (425 randomised to each arm). All patients will be followed for 16 weeks. All patients will receive consolidation therapy with fluconazole 800 mg/day to complete ten weeks of treatment, followed by fluconazole maintenance and ART as per local guidance. A safe, sustainable and easy to administer regimen of L-AmB that is non-inferior to seven days of daily amphotericin B deoxycholate therapy may reduce the number of adverse events seen in patients treated with amphotericin B deoxycholate and shorten hospital admissions, providing a highly favourable and implementable alternative to the current WHO recommended first-line treatment. ISRCTN, ISRCTN72509687 . Registered on 13 July 2017.

@article{Lawrence2018,
abstract = {Cryptococcal meningitis (CM) is a major cause of mortality in HIV programmes in Africa despite increasing access to antiretroviral therapy (ART). Mortality is driven in part by limited availability of amphotericin-based treatment, drug-induced toxicities of amphotericin B deoxycholate and prolonged hospital admissions. A single, high-dose of liposomal amphotericin (L-AmB, Ambisome) on a fluconazole backbone has been reported as non-inferior to 14 days of standard dose L-AmB in reducing fungal burden. This trial examines whether single, high-dose L-AmB given with high-dose fluconazole and flucytosine is non-inferior to a seven-day course of amphotericin B deoxycholate plus flucytosine (the current World Health Organization [WHO] recommended treatment regimen). An open-label phase III randomised controlled non-inferiority trial conducted in five countries in sub-Saharan Africa: Botswana, Malawi, South Africa, Uganda and Zimbabwe. The trial will compare CM induction therapy with (1) a single dose (10 mg/kg) of L-AmB given with 14 days of fluconazole (1200 mg/day) and flucytosine (100 mg/kg/day) to (2) seven days amphotericin B deoxycholate (1 mg/kg/day) given alongside seven days of flucytosine (100 mg/kg/day) followed by seven days of fluconazole (1200 mg/day). The primary endpoint is all-cause mortality at ten weeks with a non-inferiority margin of 10{\%} and 90{\%} power. Secondary endpoints are early fungicidal activity, proportion of grade III/IV adverse events, pharmacokinetic parameters and pharmacokinetic/pharmacodynamic associations, health service costs, all-cause mortality within the first two and four weeks, all-cause mortality within the first ten weeks (superiority analysis) and rates of CM relapse, immune reconstitution inflammatory syndrome and disability at ten weeks. A total of 850 patients aged ≥ 18 years with a first episode of HIV-associated CM will be enrolled (425 randomised to each arm). All patients will be followed for 16 weeks. All patients will receive consolidation therapy with fluconazole 800 mg/day to complete ten weeks of treatment, followed by fluconazole maintenance and ART as per local guidance. A safe, sustainable and easy to administer regimen of L-AmB that is non-inferior to seven days of daily amphotericin B deoxycholate therapy may reduce the number of adverse events seen in patients treated with amphotericin B deoxycholate and shorten hospital admissions, providing a highly favourable and implementable alternative to the current WHO recommended first-line treatment. ISRCTN, ISRCTN72509687 . Registered on 13 July 2017.},
author = {Lawrence, David S and Youssouf, Nabila and Molloy, S{\'{i}}le F and Alanio, Alexandre and Alufandika, Melanie and Boulware, David R and Boyer-Chammard, Timoth{\'{e}}e and Chen, Tao and Dromer, Francoise and Hlupeni, Admire and Hope, William and Hosseinipour, Mina C and Kanyama, Cecilia and Lortholary, Oliver and Loyse, Angela and Meya, David B and Mosepele, Mosepele and Muzoora, Conrad and Mwandumba, Henry C and Ndhlovu, Chiratidzo E and Niessen, Louis and Schutz, Charlotte and Stott, Katharine E and Wang, Duolao and Lalloo, David G and Meintjes, Graeme A and Jaffar, Shabbar and Harrison, Thomas S and Jarvis, Joseph N},
doi = {10.1186/s13063-018-3026-4},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Lawrence et al. - 2018 - AMBIsome Therapy Induction OptimisatioN (AMBITION) high dose AmBisome for cryptococcal meningitis induction the.pdf:pdf},
journal = {Trials},
keywords = {OA,fund{\_}not{\_}ack,protocol},
mendeley-tags = {OA,fund{\_}not{\_}ack,protocol},
month = {dec},
number = {1},
pages = {649},
pmid = {30470259},
publisher = {BioMed Central},
title = {{AMBIsome Therapy Induction OptimisatioN (AMBITION): high dose AmBisome for cryptococcal meningitis induction therapy in sub-Saharan Africa: study protocol for a phase 3 randomised controlled non-inferiority trial}},
url = {https://trialsjournal.biomedcentral.com/articles/10.1186/s13063-018-3026-4},
volume = {19},
year = {2018}
}

Downloads: 0

{"_id":"zHmKzZYiPqCGk6cYp","bibbaseid":"lawrence-youssouf-molloy-alanio-alufandika-boulware-boyerchammard-chen-etal-ambisometherapyinductionoptimisationambitionhighdoseambisomeforcryptococcalmeningitisinductiontherapyinsubsaharanafricastudyprotocolforaphase3randomisedcontrollednoninferioritytrial-2018","author_short":["Lawrence, D. S","Youssouf, N.","Molloy, S. F","Alanio, A.","Alufandika, M.","Boulware, D. R","Boyer-Chammard, T.","Chen, T.","Dromer, F.","Hlupeni, A.","Hope, W.","Hosseinipour, M. C","Kanyama, C.","Lortholary, O.","Loyse, A.","Meya, D. B","Mosepele, M.","Muzoora, C.","Mwandumba, H. C","Ndhlovu, C. E","Niessen, L.","Schutz, C.","Stott, K. E","Wang, D.","Lalloo, D. G","Meintjes, G. A","Jaffar, S.","Harrison, T. S","Jarvis, J. N"],"bibdata":{"bibtype":"article","type":"article","abstract":"Cryptococcal meningitis (CM) is a major cause of mortality in HIV programmes in Africa despite increasing access to antiretroviral therapy (ART). Mortality is driven in part by limited availability of amphotericin-based treatment, drug-induced toxicities of amphotericin B deoxycholate and prolonged hospital admissions. A single, high-dose of liposomal amphotericin (L-AmB, Ambisome) on a fluconazole backbone has been reported as non-inferior to 14 days of standard dose L-AmB in reducing fungal burden. This trial examines whether single, high-dose L-AmB given with high-dose fluconazole and flucytosine is non-inferior to a seven-day course of amphotericin B deoxycholate plus flucytosine (the current World Health Organization [WHO] recommended treatment regimen). An open-label phase III randomised controlled non-inferiority trial conducted in five countries in sub-Saharan Africa: Botswana, Malawi, South Africa, Uganda and Zimbabwe. The trial will compare CM induction therapy with (1) a single dose (10 mg/kg) of L-AmB given with 14 days of fluconazole (1200 mg/day) and flucytosine (100 mg/kg/day) to (2) seven days amphotericin B deoxycholate (1 mg/kg/day) given alongside seven days of flucytosine (100 mg/kg/day) followed by seven days of fluconazole (1200 mg/day). The primary endpoint is all-cause mortality at ten weeks with a non-inferiority margin of 10% and 90% power. Secondary endpoints are early fungicidal activity, proportion of grade III/IV adverse events, pharmacokinetic parameters and pharmacokinetic/pharmacodynamic associations, health service costs, all-cause mortality within the first two and four weeks, all-cause mortality within the first ten weeks (superiority analysis) and rates of CM relapse, immune reconstitution inflammatory syndrome and disability at ten weeks. A total of 850 patients aged ≥ 18 years with a first episode of HIV-associated CM will be enrolled (425 randomised to each arm). All patients will be followed for 16 weeks. All patients will receive consolidation therapy with fluconazole 800 mg/day to complete ten weeks of treatment, followed by fluconazole maintenance and ART as per local guidance. A safe, sustainable and easy to administer regimen of L-AmB that is non-inferior to seven days of daily amphotericin B deoxycholate therapy may reduce the number of adverse events seen in patients treated with amphotericin B deoxycholate and shorten hospital admissions, providing a highly favourable and implementable alternative to the current WHO recommended first-line treatment. ISRCTN, ISRCTN72509687 . Registered on 13 July 2017.","author":[{"propositions":[],"lastnames":["Lawrence"],"firstnames":["David","S"],"suffixes":[]},{"propositions":[],"lastnames":["Youssouf"],"firstnames":["Nabila"],"suffixes":[]},{"propositions":[],"lastnames":["Molloy"],"firstnames":["Síle","F"],"suffixes":[]},{"propositions":[],"lastnames":["Alanio"],"firstnames":["Alexandre"],"suffixes":[]},{"propositions":[],"lastnames":["Alufandika"],"firstnames":["Melanie"],"suffixes":[]},{"propositions":[],"lastnames":["Boulware"],"firstnames":["David","R"],"suffixes":[]},{"propositions":[],"lastnames":["Boyer-Chammard"],"firstnames":["Timothée"],"suffixes":[]},{"propositions":[],"lastnames":["Chen"],"firstnames":["Tao"],"suffixes":[]},{"propositions":[],"lastnames":["Dromer"],"firstnames":["Francoise"],"suffixes":[]},{"propositions":[],"lastnames":["Hlupeni"],"firstnames":["Admire"],"suffixes":[]},{"propositions":[],"lastnames":["Hope"],"firstnames":["William"],"suffixes":[]},{"propositions":[],"lastnames":["Hosseinipour"],"firstnames":["Mina","C"],"suffixes":[]},{"propositions":[],"lastnames":["Kanyama"],"firstnames":["Cecilia"],"suffixes":[]},{"propositions":[],"lastnames":["Lortholary"],"firstnames":["Oliver"],"suffixes":[]},{"propositions":[],"lastnames":["Loyse"],"firstnames":["Angela"],"suffixes":[]},{"propositions":[],"lastnames":["Meya"],"firstnames":["David","B"],"suffixes":[]},{"propositions":[],"lastnames":["Mosepele"],"firstnames":["Mosepele"],"suffixes":[]},{"propositions":[],"lastnames":["Muzoora"],"firstnames":["Conrad"],"suffixes":[]},{"propositions":[],"lastnames":["Mwandumba"],"firstnames":["Henry","C"],"suffixes":[]},{"propositions":[],"lastnames":["Ndhlovu"],"firstnames":["Chiratidzo","E"],"suffixes":[]},{"propositions":[],"lastnames":["Niessen"],"firstnames":["Louis"],"suffixes":[]},{"propositions":[],"lastnames":["Schutz"],"firstnames":["Charlotte"],"suffixes":[]},{"propositions":[],"lastnames":["Stott"],"firstnames":["Katharine","E"],"suffixes":[]},{"propositions":[],"lastnames":["Wang"],"firstnames":["Duolao"],"suffixes":[]},{"propositions":[],"lastnames":["Lalloo"],"firstnames":["David","G"],"suffixes":[]},{"propositions":[],"lastnames":["Meintjes"],"firstnames":["Graeme","A"],"suffixes":[]},{"propositions":[],"lastnames":["Jaffar"],"firstnames":["Shabbar"],"suffixes":[]},{"propositions":[],"lastnames":["Harrison"],"firstnames":["Thomas","S"],"suffixes":[]},{"propositions":[],"lastnames":["Jarvis"],"firstnames":["Joseph","N"],"suffixes":[]}],"doi":"10.1186/s13063-018-3026-4","file":":C$\\$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Lawrence et al. - 2018 - AMBIsome Therapy Induction OptimisatioN (AMBITION) high dose AmBisome for cryptococcal meningitis induction the.pdf:pdf","journal":"Trials","keywords":"OA,fund_not_ack,protocol","mendeley-tags":"OA,fund_not_ack,protocol","month":"dec","number":"1","pages":"649","pmid":"30470259","publisher":"BioMed Central","title":"AMBIsome Therapy Induction OptimisatioN (AMBITION): high dose AmBisome for cryptococcal meningitis induction therapy in sub-Saharan Africa: study protocol for a phase 3 randomised controlled non-inferiority trial","url":"https://trialsjournal.biomedcentral.com/articles/10.1186/s13063-018-3026-4","volume":"19","year":"2018","bibtex":"@article{Lawrence2018,\r\nabstract = {Cryptococcal meningitis (CM) is a major cause of mortality in HIV programmes in Africa despite increasing access to antiretroviral therapy (ART). Mortality is driven in part by limited availability of amphotericin-based treatment, drug-induced toxicities of amphotericin B deoxycholate and prolonged hospital admissions. A single, high-dose of liposomal amphotericin (L-AmB, Ambisome) on a fluconazole backbone has been reported as non-inferior to 14 days of standard dose L-AmB in reducing fungal burden. This trial examines whether single, high-dose L-AmB given with high-dose fluconazole and flucytosine is non-inferior to a seven-day course of amphotericin B deoxycholate plus flucytosine (the current World Health Organization [WHO] recommended treatment regimen). An open-label phase III randomised controlled non-inferiority trial conducted in five countries in sub-Saharan Africa: Botswana, Malawi, South Africa, Uganda and Zimbabwe. The trial will compare CM induction therapy with (1) a single dose (10 mg/kg) of L-AmB given with 14 days of fluconazole (1200 mg/day) and flucytosine (100 mg/kg/day) to (2) seven days amphotericin B deoxycholate (1 mg/kg/day) given alongside seven days of flucytosine (100 mg/kg/day) followed by seven days of fluconazole (1200 mg/day). The primary endpoint is all-cause mortality at ten weeks with a non-inferiority margin of 10{\\%} and 90{\\%} power. Secondary endpoints are early fungicidal activity, proportion of grade III/IV adverse events, pharmacokinetic parameters and pharmacokinetic/pharmacodynamic associations, health service costs, all-cause mortality within the first two and four weeks, all-cause mortality within the first ten weeks (superiority analysis) and rates of CM relapse, immune reconstitution inflammatory syndrome and disability at ten weeks. A total of 850 patients aged ≥ 18 years with a first episode of HIV-associated CM will be enrolled (425 randomised to each arm). All patients will be followed for 16 weeks. All patients will receive consolidation therapy with fluconazole 800 mg/day to complete ten weeks of treatment, followed by fluconazole maintenance and ART as per local guidance. A safe, sustainable and easy to administer regimen of L-AmB that is non-inferior to seven days of daily amphotericin B deoxycholate therapy may reduce the number of adverse events seen in patients treated with amphotericin B deoxycholate and shorten hospital admissions, providing a highly favourable and implementable alternative to the current WHO recommended first-line treatment. ISRCTN, ISRCTN72509687 . Registered on 13 July 2017.},\r\nauthor = {Lawrence, David S and Youssouf, Nabila and Molloy, S{\\'{i}}le F and Alanio, Alexandre and Alufandika, Melanie and Boulware, David R and Boyer-Chammard, Timoth{\\'{e}}e and Chen, Tao and Dromer, Francoise and Hlupeni, Admire and Hope, William and Hosseinipour, Mina C and Kanyama, Cecilia and Lortholary, Oliver and Loyse, Angela and Meya, David B and Mosepele, Mosepele and Muzoora, Conrad and Mwandumba, Henry C and Ndhlovu, Chiratidzo E and Niessen, Louis and Schutz, Charlotte and Stott, Katharine E and Wang, Duolao and Lalloo, David G and Meintjes, Graeme A and Jaffar, Shabbar and Harrison, Thomas S and Jarvis, Joseph N},\r\ndoi = {10.1186/s13063-018-3026-4},\r\nfile = {:C$\\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Lawrence et al. - 2018 - AMBIsome Therapy Induction OptimisatioN (AMBITION) high dose AmBisome for cryptococcal meningitis induction the.pdf:pdf},\r\njournal = {Trials},\r\nkeywords = {OA,fund{\\_}not{\\_}ack,protocol},\r\nmendeley-tags = {OA,fund{\\_}not{\\_}ack,protocol},\r\nmonth = {dec},\r\nnumber = {1},\r\npages = {649},\r\npmid = {30470259},\r\npublisher = {BioMed Central},\r\ntitle = {{AMBIsome Therapy Induction OptimisatioN (AMBITION): high dose AmBisome for cryptococcal meningitis induction therapy in sub-Saharan Africa: study protocol for a phase 3 randomised controlled non-inferiority trial}},\r\nurl = {https://trialsjournal.biomedcentral.com/articles/10.1186/s13063-018-3026-4},\r\nvolume = {19},\r\nyear = {2018}\r\n}\r\n","author_short":["Lawrence, D. S","Youssouf, N.","Molloy, S. F","Alanio, A.","Alufandika, M.","Boulware, D. R","Boyer-Chammard, T.","Chen, T.","Dromer, F.","Hlupeni, A.","Hope, W.","Hosseinipour, M. C","Kanyama, C.","Lortholary, O.","Loyse, A.","Meya, D. B","Mosepele, M.","Muzoora, C.","Mwandumba, H. C","Ndhlovu, C. E","Niessen, L.","Schutz, C.","Stott, K. E","Wang, D.","Lalloo, D. G","Meintjes, G. A","Jaffar, S.","Harrison, T. S","Jarvis, J. N"],"key":"Lawrence2018","id":"Lawrence2018","bibbaseid":"lawrence-youssouf-molloy-alanio-alufandika-boulware-boyerchammard-chen-etal-ambisometherapyinductionoptimisationambitionhighdoseambisomeforcryptococcalmeningitisinductiontherapyinsubsaharanafricastudyprotocolforaphase3randomisedcontrollednoninferioritytrial-2018","role":"author","urls":{"Paper":"https://trialsjournal.biomedcentral.com/articles/10.1186/s13063-018-3026-4"},"keyword":["OA","fund_not_ack","protocol"],"metadata":{"authorlinks":{}}},"bibtype":"article","biburl":"https://drive.google.com/uc?export=download&id=1-JLqZ7RwZ3VC2d6ErLGHAtOeMRS_7GCz","dataSources":["Krmt6gt9ktB2s6ARh"],"keywords":["oa","fund_not_ack","protocol"],"search_terms":["ambisome","therapy","induction","optimisation","ambition","high","dose","ambisome","cryptococcal","meningitis","induction","therapy","sub","saharan","africa","study","protocol","phase","randomised","controlled","non","inferiority","trial","lawrence","youssouf","molloy","alanio","alufandika","boulware","boyer-chammard","chen","dromer","hlupeni","hope","hosseinipour","kanyama","lortholary","loyse","meya","mosepele","muzoora","mwandumba","ndhlovu","niessen","schutz","stott","wang","lalloo","meintjes","jaffar","harrison","jarvis"],"title":"AMBIsome Therapy Induction OptimisatioN (AMBITION): high dose AmBisome for cryptococcal meningitis induction therapy in sub-Saharan Africa: study protocol for a phase 3 randomised controlled non-inferiority trial","year":2018}