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

Lead Research Organisation: EDCTP

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.
 
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 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 Academic/University 
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 Academic/University 
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 Public 
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 Charity/Non Profit 
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
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 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 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 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 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 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 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