High Dose AMBISOME on a Fluconazole Backbone for Cryptococcal Meningitis Induction Therapy in sub-Saharan Africa: A Randomized Controlled Trial
Lead Research Organisation:
European & Developing Countries Clinical Trials Partnership
Abstract
Cryptococcal meningitis is a leading cause of death in HIV-infected individuals in Africa. The current recommended treatment is a drug called amphotericin B deoxycholate. Treatment with amphotericin B requires 14 days of intravenous infusions given in hospital, making it difficult and costly to administer. It also causes many side effects, including kidney failure and low blood count, making close laboratory monitoring essential. The combination of the costs associated with prolonged hospital admissions, the difficulties in administration and the need for laboratory monitoring make amphotericin B treatment difficult in much of Africa. The only alternative currently available treatment is called fluconazole. Treatment with fluconazole is inadequate, and is associated with death rates of approximately 60%.
A modified form of amphotericin B is available called liposomal amphotericin B (Ambisome). This is considerably less toxic than standard amphotericin B, and is known to be efficacious in treatment of cryptococcal meningitis. Its use has been limited by the high cost of therapy, but recent data suggest that much shorter courses of Ambisome may be effective in the treatment of cryptococcal meningitis. Due to its lower toxicity, higher doses of Ambisome can be given safely, and it also persists for a long time in the tissues, raising the possibility of delivering highly effective induction therapy with very few (1, 2, or 3) doses. A large reduction in the number of doses and duration of hospitalisation, together with reduced pricing of Ambisome, may result in cryptococcal meningitis treatment costs that are not more than those with 2 weeks of conventional amphotericin B, and provide a convenient, safe and efficacious alternative to conventional amphotericin B therapy.
This study aims to define the most effective and most cost-effective schedules for Ambisome use in the treatment of cryptococcal meningitis. A currently ongoing study is testing the safety and effect on rate of clearance of cryptococcal infection of one, two or three dose Ambisome treatment regimens compared to the standard 14-day course. The shortest of these Ambisome regimens that is found to be safe and effective will be utilized in this proposed large clinical trial to determine whether or not it is as effective as the standard 14-day amphotericin B deoxycholate treatment in terms of preventing deaths from cryptococcal meningitis. If short-course Ambisome treatment regimens were shown to be of comparable effectiveness in the treatment of HIV-associated cryptococcal meningitis, the results of this study would lead to changes in international treatment guidelines, and provide an effective and practical treatment option for HIV-associated cryptococcal meningitis with the potential to prevent many thousands of deaths.
A modified form of amphotericin B is available called liposomal amphotericin B (Ambisome). This is considerably less toxic than standard amphotericin B, and is known to be efficacious in treatment of cryptococcal meningitis. Its use has been limited by the high cost of therapy, but recent data suggest that much shorter courses of Ambisome may be effective in the treatment of cryptococcal meningitis. Due to its lower toxicity, higher doses of Ambisome can be given safely, and it also persists for a long time in the tissues, raising the possibility of delivering highly effective induction therapy with very few (1, 2, or 3) doses. A large reduction in the number of doses and duration of hospitalisation, together with reduced pricing of Ambisome, may result in cryptococcal meningitis treatment costs that are not more than those with 2 weeks of conventional amphotericin B, and provide a convenient, safe and efficacious alternative to conventional amphotericin B therapy.
This study aims to define the most effective and most cost-effective schedules for Ambisome use in the treatment of cryptococcal meningitis. A currently ongoing study is testing the safety and effect on rate of clearance of cryptococcal infection of one, two or three dose Ambisome treatment regimens compared to the standard 14-day course. The shortest of these Ambisome regimens that is found to be safe and effective will be utilized in this proposed large clinical trial to determine whether or not it is as effective as the standard 14-day amphotericin B deoxycholate treatment in terms of preventing deaths from cryptococcal meningitis. If short-course Ambisome treatment regimens were shown to be of comparable effectiveness in the treatment of HIV-associated cryptococcal meningitis, the results of this study would lead to changes in international treatment guidelines, and provide an effective and practical treatment option for HIV-associated cryptococcal meningitis with the potential to prevent many thousands of deaths.
Technical Summary
Cryptococcal meningitis (CM) is associated with 10-20% of deaths in HIV-programmes in Africa. Ten-week mortality rates with current treatments range from 30-60%; novel treatments are urgently needed. Use of standard amphotericin B therapy is limited by side effects and the need for intensive nursing care and laboratory monitoring. Recent pharmacokinetic and clinical data show it may be possible to deliver safe and effective therapy for HIV-associated CM with very few large doses of Ambisome (liposomal amphotericin B, L-AmB). L-AmB has low rates of nephrotoxicity, long tissue half-life, and good brain penetration. The concept of single or intermittent dosing with very high doses is also established in prophylaxis in haematology patients and treatment of visceral leishmaniasis (VL). Single doses of 15mg/kg have been safely given, and 10mg/kg doses are routinely given for treatment of VL.
We propose to determine whether short-course high-dose L-AmB is as effective as 14-day amphotericin B therapy (standard of care) in averting all-cause mortality in HIV-associated CM patients in a phase 3 clinical-endpoint trial. 850 patients recruited at 6 east and southern African sites will be randomised to either short course high-dose L-AmB (the shortest-course L-AmB regimen found to be safe and effective in an ongoing phase-II dose finding study) or standard 14-day amphotericin B deoxycholate, both given with fluconazole 1200 mg/d for the first 2 weeks. The primary outcome will be all-cause mortality within the first 10 weeks of treatment. Secondary objectives are to determine the fungicidal activity and safety profile of short-course high-dose L-AmB, and determine the health service costs of the two treatment regimens.
If short-course treatment regimens were shown to be effective, the results of this study would lead to evidenced-based changes in treatment guidelines, and provide a practical treatment option with the potential to prevent many thousands of deaths.
We propose to determine whether short-course high-dose L-AmB is as effective as 14-day amphotericin B therapy (standard of care) in averting all-cause mortality in HIV-associated CM patients in a phase 3 clinical-endpoint trial. 850 patients recruited at 6 east and southern African sites will be randomised to either short course high-dose L-AmB (the shortest-course L-AmB regimen found to be safe and effective in an ongoing phase-II dose finding study) or standard 14-day amphotericin B deoxycholate, both given with fluconazole 1200 mg/d for the first 2 weeks. The primary outcome will be all-cause mortality within the first 10 weeks of treatment. Secondary objectives are to determine the fungicidal activity and safety profile of short-course high-dose L-AmB, and determine the health service costs of the two treatment regimens.
If short-course treatment regimens were shown to be effective, the results of this study would lead to evidenced-based changes in treatment guidelines, and provide a practical treatment option with the potential to prevent many thousands of deaths.
Planned Impact
We aim to demonstrate that it is possible to deliver highly effective induction therapy for HIV-associated cryptococcal meningitis with very few (1, 2, or 3) large doses of Ambisome (liposomal amphotericin B). Ambisome is less nephrotoxic than conventional amphotericin B, allowing much higher doses to be given safely, and has a long tissue half-life. The concept of effective therapy with just one or more doses of high dose Ambisome has recently been established in the treatment of visceral leishmaniasis, and the drug is now made available at a markedly reduced price for this indication. A similar large reduction in the number of doses and duration of hospitalisation required for the treatment of cryptococcal meningitis, together with a negotiated reduction in the pricing of Ambisome for this indication, will likely result in costs that are no more, and possibly less, than 2 weeks conventional amphotericin B therapy.
Use of a safe, sustainable regimen of high dose intermittent Ambisome in African centres still relying on fluconazole monotherapy would lead to reductions in 10-week mortality from approximately 60% to the 25-35% seen with amphotericin B-based combinations. It would also markedly facilitate effective treatment, reduce duration of hospital admissions, and lower the high burden of drug related side effects and other complications such as drip-site sepsis currently seen in centres using conventional amphotericin B based therapy. Overall, if short-course Ambisome treatment regimens were shown to be of comparable microbiological and clinical efficacy in the treatment of HIV-associated cryptococcal meningitis, the results of this study would lead to evidenced-based changes in regional and international treatment guidelines, and provide an effective and practical first-line treatment option with the potential to prevent many thousands of deaths.
In addition to direct benefits to HIV-infected patients with cryptococcal meningitis in low-resource settings, and the doctors and health services treating them, the proposed study will further scientific knowledge, providing pharmacokinetic and pharmacodynamics data applicable to a range of other diseases treated with Ambisome. The planned sub-studies and collaborations will advance understanding of the pathophysiology, immunology and genetics of cryptococcal infection in the context of HIV-infection. The study will also build strong research links between leading European and African research institutions, help to further develop clinical and research capacity at the trial sites, and facilitate the development of local investigators into future research leaders. All of the African partner sites have worked hard to develop clinical trials capability and expertise, and this phase 3 trial will ensure continued expansion and improvement in this research capacity. Ultimately it is planned that the study sites developed will form the basis of an African meningitis research network, providing a framework for future clinical trials investigating urgently needed novel treatments and diagnostics strategies aimed at reducing the morbidity and mortality due to meningitis in Africa.
Use of a safe, sustainable regimen of high dose intermittent Ambisome in African centres still relying on fluconazole monotherapy would lead to reductions in 10-week mortality from approximately 60% to the 25-35% seen with amphotericin B-based combinations. It would also markedly facilitate effective treatment, reduce duration of hospital admissions, and lower the high burden of drug related side effects and other complications such as drip-site sepsis currently seen in centres using conventional amphotericin B based therapy. Overall, if short-course Ambisome treatment regimens were shown to be of comparable microbiological and clinical efficacy in the treatment of HIV-associated cryptococcal meningitis, the results of this study would lead to evidenced-based changes in regional and international treatment guidelines, and provide an effective and practical first-line treatment option with the potential to prevent many thousands of deaths.
In addition to direct benefits to HIV-infected patients with cryptococcal meningitis in low-resource settings, and the doctors and health services treating them, the proposed study will further scientific knowledge, providing pharmacokinetic and pharmacodynamics data applicable to a range of other diseases treated with Ambisome. The planned sub-studies and collaborations will advance understanding of the pathophysiology, immunology and genetics of cryptococcal infection in the context of HIV-infection. The study will also build strong research links between leading European and African research institutions, help to further develop clinical and research capacity at the trial sites, and facilitate the development of local investigators into future research leaders. All of the African partner sites have worked hard to develop clinical trials capability and expertise, and this phase 3 trial will ensure continued expansion and improvement in this research capacity. Ultimately it is planned that the study sites developed will form the basis of an African meningitis research network, providing a framework for future clinical trials investigating urgently needed novel treatments and diagnostics strategies aimed at reducing the morbidity and mortality due to meningitis in Africa.
Organisations
- European & Developing Countries Clinical Trials Partnership (Lead Research Organisation)
- Wellcome Trust (Collaboration)
- Makerere University College of Health Sciences (Collaboration)
- ST GEORGE'S UNIVERSITY OF LONDON (Collaboration)
- Centers for Disease Control and Prevention (CDC) (Collaboration)
- Gilead Sciences, Inc. (Collaboration)
- University of North Carolina System (Collaboration)
- University of Zimbabwe (Collaboration)
- University of the Witwatersrand (Collaboration)
- Pasteur Institute, Paris (Collaboration)
- Drugs for Neglected Diseases initiative (DNDi) (Collaboration)
- Norwegian Institute of Public Health (Collaboration)
- Botswana Harvard AIDS Institute Partnership (Collaboration)
- UNIVERSITY OF LIVERPOOL (Collaboration)
- University of Cape Town (Collaboration)
- Gilead Sciences Limited (Project Partner)
People |
ORCID iD |
Publications
Bile EC
(2023)
Accuracy of point-of-care HIV and CD4 field testing by lay healthcare workers in the Botswana Combination Prevention Project.
in Journal of virological methods
Shiri T
(2020)
Addition of Flucytosine to Fluconazole for the Treatment of Cryptococcal Meningitis in Africa: A Multicountry Cost-effectiveness Analysis.
in Clinical infectious diseases : an official publication of the Infectious Diseases Society of America
Yoon H
(2023)
Association of Antibody Immunity With Cryptococcal Antigenemia and Mortality in a South African Cohort With Advanced Human Immunodeficiency Virus Disease
in Clinical Infectious Diseases
Tenforde MW
(2021)
Cost-effectiveness of cryptococcal antigen screening at CD4 counts of 101-200 cells/µL in Botswana.
in Wellcome open research
Wake RM
(2023)
Cryptococcal Antigenemia in Advanced Human Immunodeficiency Virus Disease: Pathophysiology, Epidemiology, and Clinical Implications.
in Clinical infectious diseases : an official publication of the Infectious Diseases Society of America
Description | Botswana National HIV and TB Guidelines |
Geographic Reach | National |
Policy Influence Type | Membership of a guideline committee |
Impact | I am a guidelines writing group member for the Botswana National HIV and TB guidelines committee. The committee guides the Ministry of Health to help formulate national policy. Recent policy changes include addition of Ambisome and Flucytosine to the national essential medicines list, introduction of TB preventive therapy, and changes in national ART recommendations. |
Description | DSMB Chair - ARTIST Trial (Wellcome Trust funded, South Africa) |
Geographic Reach | Africa |
Policy Influence Type | Participation in a guidance/advisory committee |
URL | https://clinicaltrials.gov/ProvidedDocs/13/NCT03991013/Prot_000.pdf |
Description | DSMB Chair - CASTLE Trial (Wellcome funded, Malawi) |
Geographic Reach | Africa |
Policy Influence Type | Participation in a guidance/advisory committee |
URL | https://clinicaltrials.gov/ct2/show/NCT04545164 |
Description | DSMB Chair - HARVEST Trial (Joint Global Health Trials funded, multi-national) |
Geographic Reach | Multiple continents/international |
Policy Influence Type | Participation in a guidance/advisory committee |
URL | https://gtr.ukri.org/projects?ref=MR%2FS004963%2F1 |
Guideline Title | Malawi National HIV Guidelines |
Description | Malawi National HIV Guidelines |
Geographic Reach | National |
Policy Influence Type | Citation in clinical guidelines |
Impact | Improved cryptococcal meningitis treatment based on AMBITION-cm study. |
Description | NIHR RIGHT Call 3 Stage 2 Funding Committee Member |
Geographic Reach | Multiple continents/international |
Policy Influence Type | Participation in a guidance/advisory committee |
Impact | Funding committee member on the NIHR RIGHT Call 3 Stage 2. Reviewed proposals, participated on funding committee. 2 - 5 February 2021. |
URL | https://www.nihr.ac.uk/documents/nihr-research-and-innovation-for-global-health-transformation-right... |
Guideline Title | National EML Committee (South Africa) |
Description | South African National Guidelines on treatment of cryptococcal disease |
Geographic Reach | National |
Policy Influence Type | Citation in clinical guidelines |
Impact | Updates national treatment guidelines for cryptococcal meningitis in South Africa - the country with the highest burden of disease globally. |
Description | Southern African HIV Clinicians Society Cryptococcal Meningitis Treatment Guidelines |
Geographic Reach | Africa |
Policy Influence Type | Membership of a guideline committee |
Impact | Primary southern African guidelines for prevention, diagnosis, and treatment of cryptococcal disease. |
URL | https://sajhivmed.org.za/index.php/hivmed/article/view/1030 |
Description | Trial Steering Committee Chair - ACACIA Study (NIH funded, Uganda) |
Geographic Reach | Africa |
Policy Influence Type | Participation in a guidance/advisory committee |
URL | https://clinicaltrials.gov/ct2/show/NCT03945448 |
Description | UKRI Expert Panel for Global Effort on COVID-19 (GECO) Health Research |
Geographic Reach | Multiple continents/international |
Policy Influence Type | Participation in a guidance/advisory committee |
Impact | I served as a selection panel member for the UKRI Global Effort on COVID-19 (GECO) Health Research Calls and the NIHR Research and Innovation for Global Health Transformation (RIGHT) call. UKRI Expert Panel for Global Effort on COVID-19 (GECO) Health Research. 1st Panel meeting 22 Jul 2020 (virtual). UKRI Expert Panel for Global Effort on COVID-19 (GECO) Health Research. 2nd Panel meeting 7 Sept 2020 (virtual). UKRI Expert Panel for Global Effort on COVID-19 (GECO) Health Research. 3rd Panel meeting 30 Nov - 2 Dec 2020 (virtual). |
URL | https://www.ukri.org/opportunity/global-effort-on-covid-19-health-research/ |
Description | Updated cryptococcal meningitis treatment guidelines in Botswana - circular |
Geographic Reach | National |
Policy Influence Type | Implementation circular/rapid advice/letter to e.g. Ministry of Health |
Impact | Updated cryptococcal treatment guidelines based on AMBITION-cm study. |
Description | WHO Advanced HIV Disease Guidelines |
Geographic Reach | Multiple continents/international |
Policy Influence Type | Membership of a guideline committee |
Impact | I am a member of the external review group for the WHO Guidelines for Managing Advanced HIV Disease and Rapid Initiation of Antiretroviral Therapy. |
URL | http://www.who.int/hiv/pub/guidelines/advanced-HIV-disease/en/ |
Description | WHO Cryptococcal Guidelines |
Geographic Reach | Multiple continents/international |
Policy Influence Type | Membership of a guideline committee |
Impact | I was a member of the World Health Organization guidelines peer review group for the consolidated HIV guidelines (diagnosis, prevention and management of cryptococcal meningitis in HIV-infected adults and children) 2011-2016, and a guidelines development group member for WHO guidelines on preventing, diagnosing, and managing cryptococcal disease in HIV infected adults, adolescents and children in 2017. |
URL | http://www.who.int/hiv/mediacentre/news/gdg-cryptococcal/en/ |
Guideline Title | Guidelines for diagnosing, preventing and managing cryptococcal disease among adults, adolescents and children living with HIV |
Description | World Health Organization Guidelines on treatment of cryptococcal disease |
Geographic Reach | Multiple continents/international |
Policy Influence Type | Citation in clinical guidelines |
Impact | The primary manuscript reporting the results of the Ambition-CM trial were published by the New England Journal of Medicine in March 2022. This highly effective novel short course treatment, based on a single high dose of liposomal amphotericin, offers a safe and practical treatment regimen for Africa and other low- and middle-income settings, potentially transforming the management of this common and devastating opportunistic infection. Despite only being published in March 2022, the trial results are already having a major impact, having been incorporated into national guidelines in several African countries (Botswana, Zimbabwe, Malawi, Uganda, Eswatini) and incorporated as first-line therapy worldwide in updated WHO guidelines released just one month after publication in April 2022, and launched in a special WHO session at the 24th International AIDS Conference (AIDS 2022) in Montreal in July. The treatment regimen is already being used in routine care in Botswana, Malawi, Uganda, Mozambique, Zimbabwe, and Eswatini, with over 1000 patients receiving the novel regimen in Uganda to date. In addition to the impact in LMICs, the Ambition-CM regimen has been incorporated as first-line therapy in updated European and ISHAM guidelines due for release in early 2023, with research evidence generated in Africa informing European and US practice. |
URL | https://www.who.int/publications/i/item/9789240052178 |
Guideline Title | WHO guidelines for diagnosis, treatment, and management of HIV-associated cryptococcal meningitis |
Description | World Health Organization cryptococcal treatment guidelines |
Geographic Reach | Multiple continents/international |
Policy Influence Type | Citation in clinical guidelines |
Impact | Updated WHO guidelines based on AMBITION trial results. |
Description | EDCTP-TDR Clinical Research and Development Fellowship |
Amount | € 150,000 (EUR) |
Funding ID | TMA2019IF-2858 |
Organisation | Sixth Framework Programme (FP6) |
Department | European and Developing Countries Clinical Trials Partnership |
Sector | Public |
Country | Netherlands |
Start | 03/2022 |
End | 09/2024 |
Description | Fluconazole plus flucytosine vs fluconazole alone for cryptococcal antigen-positive patients identified through screening: A randomised trial |
Amount | £4,572,842 (GBP) |
Funding ID | MR/V005731/1 |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 03/2021 |
End | 03/2025 |
Description | Global Health Group on HIV-associated fungal infections |
Amount | £2,999,679 (GBP) |
Funding ID | NIHR134342 |
Organisation | National Institute for Health Research |
Sector | Public |
Country | United Kingdom |
Start | 07/2022 |
End | 08/2026 |
Description | Implementing novel short-course treatment regimens for HIV-associated Cryptococcal meningitis in sub-Saharan Africa. |
Amount | $1,250,000 (USD) |
Funding ID | NU51CK000318-01-00 |
Organisation | Centers for Disease Control and Prevention (CDC) |
Sector | Public |
Country | United States |
Start | 08/2021 |
End | 09/2026 |
Description | Integrated Cryptococcal and opportunistic infection management to improve outcomes in Advanced HIV Disease. Wellcome Trust Clinical PhD Programme in Global Health Research |
Amount | £375,150 (GBP) |
Funding ID | WT222938/Z/21/Z |
Organisation | Wellcome Trust |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 03/2021 |
End | 04/2025 |
Description | Medical Research Council Clinical Academic Research Partnerships MR/T024917/1: Developing Host-directed therapy in Cryptococcal Meningitis (James Scriven) |
Amount | £313,402 (GBP) |
Funding ID | MR/T024917/1 |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 11/2019 |
End | 11/2022 |
Description | National Institute of Health Research (NIHR) Global Health Professorship RP-2017-08-ST2-012: Translational Research to Reduce Mortality from CNS Infections in Africa |
Amount | £1,951,012 (GBP) |
Funding ID | RP-2017-08-ST2-012 |
Organisation | National Institute of Health Research |
Sector | Public |
Country | Zimbabwe |
Start | 12/2018 |
End | 12/2023 |
Title | Electronic Data Capture System |
Description | We have developed a bespoke electronic data capture system for the Ambition Study, which enables direct entry of all study data into dedicated study laptops, real time data verification and checking, automated SAE reporting, and streamlined central monitoring. All code is open source and freely available. |
Type Of Material | Improvements to research infrastructure |
Year Produced | 2018 |
Provided To Others? | Yes |
Impact | The system can be used or adapted for any similar clinical trials. |
URL | https://github.com/ambition-study/ambition |
Description | Botswana Harvard Partnership (Ambition Phase 3) |
Organisation | Botswana Harvard AIDS Institute Partnership |
Country | Botswana |
Sector | Academic/University |
PI Contribution | I am the PI on the Ambition Study, on which BHP is a partner. |
Collaborator Contribution | Multidisciplinary: clinical, laboratory science, software development. BHP is a recruiting site for the Ambition clinical trial. To date ethical and regulators submissions have been submitted and approved. Recruitment commenced at the site in January 2018. BHP has also developed and hosts the electronic data capture system, coordinates the African Trials Network, and serves as the coordinating site for the clinical trial. BHP collaborate on several laboratory sub studies. |
Impact | The trial is ongoing. There have been no research outputs to date. BHP arranged and hosted the trial launch meeting and the initial African Meningitis Trials Network meeting. They have developed and tested an initial version of the electronic data capture system. |
Start Year | 2016 |
Description | Centers for Disease Control (CDC) collaborative award (Cryptococcal treatment) |
Organisation | Centers for Disease Control and Prevention (CDC) |
Country | United States |
Sector | Public |
PI Contribution | We proposed a collaborative project rolling out novel treatments for cryptococcal meningitis in Malawi, Uganda, Zimbabwe, and Botswana. |
Collaborator Contribution | Financial support, proposal development support, project management and implementation support. |
Impact | CDC collaborative (non-research) award. |
Start Year | 2021 |
Description | Drugs for Neglected Diseases Initiative (DNDi) 5FC PK studies |
Organisation | Drugs for Neglected Diseases initiative (DNDi) |
Country | Switzerland |
Sector | Charity/Non Profit |
PI Contribution | Lead on collaborative NIHR global health group application. |
Collaborator Contribution | Providing 5FC pharmacokinetics study as part of research group activities. |
Impact | Successful NIHR global health group application. |
Start Year | 2021 |
Description | Gilead (Ambition Phase 3) |
Organisation | Gilead Sciences, Inc. |
Department | Gilead |
Country | United Kingdom |
Sector | Private |
PI Contribution | I am the PI on the Ambition Study, to which Gilead have made an in-kind contribution. |
Collaborator Contribution | Gilead have supplied the liposomal amphotericin for the clinical trial (425 patients in the intervention arm at a dose of 10mg/kg). |
Impact | None to date. Recruitment ongoing. |
Start Year | 2016 |
Description | Infectious Diseases Institute Uganda (Ambition Phase 3) |
Organisation | Makerere University College of Health Sciences |
Department | The Infectious Diseases Institute, Kampala |
Country | Uganda |
Sector | Hospitals |
PI Contribution | I am the PI on the Ambition Study, on which IDI Uganda is a partner. |
Collaborator Contribution | IDI Uganda is a recruiting site for the Ambition clinical trial. To date ethical and regulators submissions have been submitted and provisionally approved. Recruitment is projected to start at the site in May 2018. |
Impact | The trial is ongoing. There have been no research outputs to date. |
Start Year | 2016 |
Description | Institut Pasteur (Ambition Phase 3) |
Organisation | Pasteur Institute, Paris |
Country | France |
Sector | Charity/Non Profit |
PI Contribution | I am the PI of the Ambition study project, on which the IP is a collaborating partner. |
Collaborator Contribution | The Institut Pasteur are contributing molecular mycology sub studies and molecular mycology training to the Ambition Study Project. |
Impact | Multidisciplinary: Clinical, Molecular Mycology. The Trial is ongoing with no research outputs to date. |
Start Year | 2016 |
Description | Liverpool School of Tropical Medicine (Ambition Phase 3) |
Organisation | Norwegian Institute of Public Health |
Department | Department of International Public Health |
Country | Norway |
Sector | Academic/University |
PI Contribution | I am the PI of the Ambition study of which LSTM is a collaborating partner. |
Collaborator Contribution | LSTM provide senior clinical input, data management, statistical support, and health economics support for the Ambition Trial. |
Impact | Multidisciplinary: clinical, epidemiology, statistics, health economics. The trial is ongoing with no research outputs to date. |
Start Year | 2016 |
Description | Malawi-Liverpool-Wellcome (Ambition Phase 3) |
Organisation | Wellcome Trust |
Department | Malawi-Liverpool Wellcome Trust Clinical Research Programme |
Country | Malawi |
Sector | Academic/University |
PI Contribution | I am the PI on the Ambition Study, on which MLW is a collaborating partner and a clinical trial recruitment site. |
Collaborator Contribution | MLW is a clinical recruitment site for the Ambition clinical Trial. To date they have applied for and obtained preliminary ethical and regulatory approvals. Patient recruitment is planned to start in May 2018. |
Impact | The trial is ongoing. No research outputs to date. |
Start Year | 2016 |
Description | St.Georges University of London (Ambition Phase 3) |
Organisation | St George's University of London |
Department | Department of Cellular and Molecular Medicine |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | I am the PI on the Ambition study grant, on which St. George's is a collaborating partner. |
Collaborator Contribution | St. George's is a collaborating partner in the Ambition Clinical Trial. The Co-PI of the trial and the trial; epidemiologist are based there, as a further staff member contributing to capacity building and training. |
Impact | Multidisciplinary: clinical, epidemiology. The study is ongoing, with no outputs reported to date. |
Start Year | 2016 |
Description | UNC Project Lilongwe (Ambition Phase 3) |
Organisation | University of North Carolina System |
Country | United States |
Sector | Academic/University |
PI Contribution | I am the PI on the Ambition Study, on which UNC Project Malawi is a partner. |
Collaborator Contribution | UNC Project Malawi is a recruiting site for the Ambition clinical trial. To date ethical and regulators submissions have been submitted and provisionally approved. Recruitment is projected to start at the site in May 2018. |
Impact | The trial is ongoing. There have been no research outputs to date. |
Start Year | 2016 |
Description | University of Cape Town (Ambition Phase 3) |
Organisation | University of Cape Town |
Department | Institute of Infectious Disease and Molecular Medicine (IIDMM) |
Country | South Africa |
Sector | Academic/University |
PI Contribution | I am the PI on the Ambition Study, on which UCT is a partner. |
Collaborator Contribution | UCT is a recruiting site for the Ambition clinical trial. To date ethical and regulators submissions have been submitted and provisionally approved. Recruitment is projected to start at the site in April 2018. |
Impact | The trial is ongoing. There have been no research outputs to date. |
Start Year | 2016 |
Description | University of Liverpool (Ambition Phase 3) |
Organisation | University of Liverpool |
Department | Department of Molecular and Clinical Pharmacology |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | I am the PI on the Ambition study award. |
Collaborator Contribution | The University of Liverpool is providing the pharmacokinetic analysis for the Ambition clinical trial. |
Impact | Multidisciplinary: pharmacology. The trial is ongoing, with no research outputs to date. |
Start Year | 2016 |
Description | University of Witwatersrand (NIHR Global Health Group) |
Organisation | University of the Witwatersrand |
Country | South Africa |
Sector | Academic/University |
PI Contribution | Lead applicant on NIHR Global Health Group application. |
Collaborator Contribution | Co-lead applicant and LMIC partner on NIHR Global Health Group application |
Impact | NIHR Global Health Group award. |
Start Year | 2021 |
Description | University of Zimbabwe (Ambition Phase 3) |
Organisation | University of Zimbabwe |
Country | Zimbabwe |
Sector | Academic/University |
PI Contribution | I am the PI on the Ambition Study, on which UZ is a partner. |
Collaborator Contribution | UZ is a recruiting site for the Ambition clinical trial. To date ethical and regulators submissions have been submitted and the outcomes are pending. Recruitment is projected to start at the site in June 2018. |
Impact | The trial is ongoing. There have been no research outputs to date. |
Start Year | 2016 |
Title | The Ambition Trial - Phase 3 |
Description | A phase 3 multicentre RCT of high doe Ambisome for HIV-asociated cryptococcal meningitis. |
Type | Therapeutic Intervention - Drug |
Current Stage Of Development | Late clinical evaluation |
Year Development Stage Completed | 2018 |
Development Status | Under active development/distribution |
Clinical Trial? | Yes |
Impact | Trial still in progress. |
URL | http://www.isrctn.com/ISRCTN72509687 |
Description | 'Juggling with Health' community event in Kamwokya, Kampala |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Public/other audiences |
Results and Impact | A unique circus-based event was held at Treasure Life Youth Centre in Kamwokya, Kampala, on the day before World AIDS Day 2018. The event aimed to raise awareness in the community about the early symptoms of meningitis and to encourage people to seek early medical care. The event promoted AMBITION alongside the RifT study (which focusses on TB meningitis), and explained to local people how they might access both studies. This was an innovative method of promoting AMBITION to drive recruitment numbers and to improve understanding of clinical trials in the local community. |
Year(s) Of Engagement Activity | 2018 |
URL | https://www.idi-makerere.com/wp-content/uploads/2017/08/Meningitis-community-engagement-circus.pdf |
Description | 20th Congress of the International Society for Human and Animal Mycology (ISHAM), Amsterdam, Netherlands |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Prof. William Hope (Co-Investigator, UoL) gave a presentation on the Ambition Study at this leading international mycology conference on Monday 2 July |
Year(s) Of Engagement Activity | 2018 |
URL | https://www.isham2018.org/resources/uploads/sites/2/ISHAM-2018-Program-Book.pdf |
Description | 2nd African Meningitis Trials Network Meeting (AMNET), 9 July, Cape Town, South Africa |
Form Of Engagement Activity | A formal working group, expert panel or dialogue |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | A meeting of clinical researchers involved in meningitis research from across the African region, primarily (but not exclusively) from sites collaborating on the AMBITION clinical trial and NIHR funded meningitis research projects. Discussed collaborative projects to define meningitis aetiology across east and southern Africa. |
Year(s) Of Engagement Activity | 2019 |
Description | AMBITION Study Newsletters |
Form Of Engagement Activity | A magazine, newsletter or online publication |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | We send a newsletter every one to two months to colleagues at all beneficiaries, and to a few additional interested parties. We provide updates about patient recruitment numbers and share recent events and photographs, in line with our deliverables and milestones. The Newsletters can be accessed on our AMBITION website. |
Year(s) Of Engagement Activity | 2018 |
URL | http://blogs.lshtm.ac.uk/ambition/archive/news-events-publications/ |
Description | AMBITION Twitter Account |
Form Of Engagement Activity | Engagement focused website, blog or social media channel |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Sophia Hafeez, our Project Assistant at LSHTM, has worked to significantly increase our Twitter following during 2018, and tweets regularly with updates on patient recruitment numbers, details of events, photos and with links to relevant articles and opportunities. The African Meningitis Network (AMNET) operates its own Twitter account (https://twitter.com/amnet2020?lang=en), managed by Phum'lani Machao who is based at BHP. She tweets frequently and at the time of writing AMNET's followers stand at 182 (February 2019). |
Year(s) Of Engagement Activity | 2018 |
URL | https://twitter.com/ambitioncm2020 |
Description | AMBITION study patient engagement activities |
Form Of Engagement Activity | A formal working group, expert panel or dialogue |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Patients, carers and/or patient groups |
Results and Impact | Ongoing engagement activities around the Ambition-CM trial have continued, with further stakeholder meetings in Botswana (17/06/2023), Zimbabwe (24/06/2023), and Uganda (28/06/2023), plus a Radio show about CM in Malawi (15/07/2023). |
Year(s) Of Engagement Activity | 2023 |
Description | AMBITION-study Botswana: Organisation of meeting with patient groups, policy-makers and other national stakeholders |
Form Of Engagement Activity | A formal working group, expert panel or dialogue |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Policymakers/politicians |
Results and Impact | Botswana: Participation in workshop (16th October 2021). The trial results were presented at a BHP Community Advisory Board Meeting to trial participants, the general public, and clinicians. Results also presented to Botswana National Guidelines Writing Group. |
Year(s) Of Engagement Activity | 2021 |
Description | AMBITION-study Malawi: Organisation of meeting with policy-makers and other national stakeholders |
Form Of Engagement Activity | A formal working group, expert panel or dialogue |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Policymakers/politicians |
Results and Impact | Malawi: Organisation of meeting with policy-makers and other national stakeholders (20th August 2021).With our Malawian collaborators, a high-profile meeting was arranged in Lilongwe with the Malawian Ministry of Health, which was also well attended by NGO and patient representatives and various scientists and clinicians. Dr. Lusayo Simwinga (Study Doctor, UNC Project) presented the trial results which were received with great interest and enthusiasm. The Ministry of Health subsequently updated its treatment guidelines in conjunction with relevant stakeholders. In addition study results were reported back top trial participants by the study teams in both Blantyre (23rd October 2021) by Prof. Henry Mwandumba and members of the MLW team, and Lilongwe (29th October 2021) by the UNC team. |
Year(s) Of Engagement Activity | 2021 |
Description | AMBITION-study Zimbabwe: Organisation of meeting with policy-makers and other national stakeholders |
Form Of Engagement Activity | A formal working group, expert panel or dialogue |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Professional Practitioners |
Results and Impact | Zimbabwe: Organisation of community engagement event (1st October 2021). The study team presented findings and discussed implications of the results with members of the clinical team at the Opportunistic Infections (OI) clinic, Parirenyatwa Hospital (Harare) and a number of AMBITION participants. |
Year(s) Of Engagement Activity | 2021 |
Description | AVAC Journalist Training |
Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Media (as a channel to the public) |
Results and Impact | The Ambition study team presented the trial to a workshop of local journalists as part of an HIV training and sensitisation project. This resulted in two articles about the study in the national press. |
Year(s) Of Engagement Activity | 2018 |
URL | https://www.themidweeksun.co.bw/news/article.php?article=1728 |
Description | Ambition Study Website |
Form Of Engagement Activity | Engagement focused website, blog or social media channel |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | We have developed a website for the Ambition Study consortium that has undergone significant development during 2018. Of particular note are the following features: - Pages displaying the full suite of Clinical, Laboratory and Trial Management Working Practice Documents (WPDs). We encourage teams at the recruiting sites in Africa to refer to these WPD pages on a frequent basis as they enrol and care for patients. They are also freely available to all other researchers planning or developing similar clinical trials. - YouTube channel produced by Dr. David Lawrence (Lead Clinician), containing 15 videos explaining in detail how to access and use all sections of the AMBITION Electronic Data Capture Tool. - Pages displaying biographies of all colleagues working on AMBITION at each beneficiary organisation. - Pages relating to the AMNET - our African Meningitis Trials Network. |
Year(s) Of Engagement Activity | 2018,2019 |
URL | http://blogs.lshtm.ac.uk/ambition/ |
Description | Botswana Harvard Partnership Community Advisory Board |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Public/other audiences |
Results and Impact | The BHP Community Advisory Board meets every quarter to exchange ideas, challenges and success stories about clinical trials currently being run through BHP and in Gaborone. AMBITION features regularly in the discussions, and members of the team attend to provide information. |
Year(s) Of Engagement Activity | 2018 |
Description | CROI 2017 |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | The Ambition Phase 2 study results were presented as an oral abstract in one of the main sessions at the Conference on Retroviruses and Opportunistic Infections in Seattle, 2017. The Ambition Phase 3 study was highlighted. |
Year(s) Of Engagement Activity | 2017 |
URL | http://www.croiconference.org/sessions/ambition-cm-high-dose-liposomal-amphotericin-hiv-related-cryp... |
Description | Community advisory board (CAB) meeting / workshop |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Public/other audiences |
Results and Impact | The first proposed community advisory board (CAB) meeting / workshop took place on Saturday 2nd November 2019. We obtained a waiver from the Botswana IRB to enable us to contact and recruit the "expert patients" and worked with them to prepare their talks to the CAB. We delivered an educational workshop on lumbar punctures (LPs) in Botswana, aiming to spread the message that receiving an LP is not a death sentence but a lifesaving procedure which allows doctors to rapidly diagnose and treat patients with meningitis. The workshop included a screening of an LP procedure, a review of the anatomy of the spine using models loaned from the nearby University, a tour of the Botswana Harvard Partnership (BHP) laboratory facilities and the testimony of a trial participant who received several LPs during his CM treatment. The workshop was very well attended, interactive and picked up as two separate news stories in a local popular newspaper, demonstrating the public's interest in science and research in particular. The Botswana Harvard Partnership plans to seize on this public interest and run a series of events called 'The Myth busting Series': one workshop per month to help spread medical knowledge in the community and disprove harmful myths. |
Year(s) Of Engagement Activity | 2019 |
Description | Community advisory board presentation - Botswana |
Form Of Engagement Activity | A formal working group, expert panel or dialogue |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Study participants or study members |
Results and Impact | We presented the Ambition study to the Botswana Harvard Partnership Community Advisory Board. |
Year(s) Of Engagement Activity | 2017 |
Description | Conference presentation at the "Neurosciences in Intensive Care International Symposium - 8th edition", Institut Pasteur, Paris |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Professional Practitioners |
Results and Impact | Prof. Olivier Lortholary (Ambition Study Lead, Institut Pasteur) delivered a presentation entitled "Optimal management of cryptococcal meningitis in AIDS: past five years-five major studies", highlighting Ambition. |
Year(s) Of Engagement Activity | 2018 |
URL | https://research.pasteur.fr/en/event/nicis-2018-neuroscience-critical-illness-acute-cns-infection/ |
Description | IAS 2017 - Ambition Presentation |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | The EDCTP hosted a satellite session at the International AIDS Society conference in Paris in 2017, at which the Ambition study was highlighted. |
Year(s) Of Engagement Activity | 2017 |
URL | http://programme.ias2017.org/PAGMaterial/PPT/2707_4031/IAS2017_JARVIS.ppt |
Description | Meningitis Research Foundation Annual Meeting, Meningitis and Septicaemia 2019, British Museum London, 5-6 November. |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | I gave an invited oral presentation about meningitis in HIV-prevalence settings at the annual Meningitis Research Foundation meeting in London. The meeting includes a wide range of health professionals, researchers, industry representatives, patient and carer groups, advocacy groups, and students. |
Year(s) Of Engagement Activity | 2019 |
Description | Mycoses Study Group (Education & Research Consortium) Biennial Meeting, Big Sky, Montana, USA |
Form Of Engagement Activity | A formal working group, expert panel or dialogue |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Dr. David Boulware (Co-Investigator, IDI Uganda [based at the University of Minnesota]) gave a presentation entitled 'Clinical Trials for Cryptococcosis', where the AMBITION Phase II and Phase III trials were both referenced. |
Year(s) Of Engagement Activity | 2018 |
Description | NEJM article - commentary on advanced HIV disease |
Form Of Engagement Activity | A magazine, newsletter or online publication |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | A NEJM commentary highlighting the ongoing importance of advanced HIV disease co-authored with the head of guideline development at the WHO and the head of HIV at teh Gates Foundation. |
Year(s) Of Engagement Activity | 2024 |
URL | https://www.nejm.org/doi/10.1056/NEJMp2313777?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_da... |
Description | Newspaper article in the Botswana Midweek Sun |
Form Of Engagement Activity | A magazine, newsletter or online publication |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Public/other audiences |
Results and Impact | An article was published in this national newspaper to celebrate the enrolment of the first participant in Gaborone, which was also the first participant in the whole trial. |
Year(s) Of Engagement Activity | 2018 |
URL | http://www.themidweeksun.co.bw/3925-botswana-enrolls-first-patient-in-ambition-study/ |
Description | Newspaper article in the Botswana Telegraph |
Form Of Engagement Activity | A magazine, newsletter or online publication |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Public/other audiences |
Results and Impact | An article was published in this national newspaper to celebrate the enrolment of the first participant in Gaborone, which was also the first participant in the whole trial. |
Year(s) Of Engagement Activity | 2018 |
Description | Presentation at the <<38ème Réunion Interdisciplinaire de Chimiothérapie Anti-Infectieuse >> at the Palais des Congrès de Paris, France |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Professional Practitioners |
Results and Impact | Dr. Timothée Boyer Chammard (Ambition Study clinical advisor) gave a presentation on "Management of Cryptococcal Meningitis in 2018" including updates on the Ambition Study. |
Year(s) Of Engagement Activity | 2018 |
Description | Presentation of AMBITION-cm results at the World Health Organization (WHO) / Pan American Health Organization (PAHO) Mycosis in Advanced HIV Virtual Meeting |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Jarvis JN. Presentation of AMBITION-cm results at the World Health Organization (WHO) / Pan American Health Organization (PAHO) Mycosis in Advanced HIV Virtual Meeting. 1 December 2021. |
Year(s) Of Engagement Activity | 2021 |
Description | United Nations General Assembly Science Summit Impact Case Study - AMBITION-cm Trial |
Form Of Engagement Activity | A formal working group, expert panel or dialogue |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Policymakers/politicians |
Results and Impact | A pathway to impact case study presented to the UN General Assembly Science Summit highlighting th eimpact of teh AMBITION-cm Trial on international policy. |
Year(s) Of Engagement Activity | 2022 |
Description | Zimbabwe National stakeholders meeting, AMBITION-cm trial feedback and dissemination |
Form Of Engagement Activity | A formal working group, expert panel or dialogue |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Policymakers/politicians |
Results and Impact | National stakeholders meeting, AMBITION-cm trial feedback and dissemination. Feedback to Zimbabwe Ministry of Health, HIV Programme, and Implementing partners including WHO, CHAI, EGPAF. |
Year(s) Of Engagement Activity | 2022 |