High Dose AMBISOME on a Fluconazole Backbone for Cryptococcal Meningitis Induction Therapy in sub-Saharan Africa: A Randomized Controlled Trial

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.

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.

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.

People

ORCID iD

Publications

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Lawrence DS (2019) Emerging concepts in HIV-associated cryptococcal meningitis. in Current opinion in infectious diseases

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Jarvis JN (2019) Reply to Rajasingham and Boulware. in Clinical infectious diseases : an official publication of the Infectious Diseases Society of America

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Tenforde MW (2019) HIV-associated cryptococcal meningitis: ongoing challenges and new opportunities. in The Lancet. Infectious diseases

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Jarvis JN (2019) Short-course High-dose Liposomal Amphotericin B for Human Immunodeficiency Virus-associated Cryptococcal Meningitis: A Phase 2 Randomized Controlled Trial. 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