1. AMBITION-CM HIGH-DOSE LIPOSOMAL AMPHOTERICIN FOR HIV-RELATED CRYPTOCOCCAL MENINGITIS

2. Background 36% acute mortality in Vietnam
Day et al. NEJM 2013;368:
41% acute mortality in Africa and Asia
Beardsley et al. NEJM 2016;374:542-54
11% of all HIV-related mortality
Walker et al. CID 2012;55(12):1707–18
EDCTP review comments!

4. Amphotericin B deoxycholate is toxic and difficult to administer in resource-limited settings
Thrombophlebitis
Nosocomial sepsis (15%)
Rajasingham et al. Emerg Infect Dis. 2014
Infusion reactions
Anaemia (mean 2.3g/dL drop over 14 days)
Bicanic et al AAC 2015
Renal impairment
Potassium and magnesium wasting

5. Efficacy of an Abbreviated Induction Regimen of Amphotericin B Deoxycholate for Cryptococcal Meningoencephalitis: 3 Days of Therapy Is Equivalent to 14 Days
Livermore J et al. MBio 2014; 5(1):e
(experimental cryptococcal meningoencephalitis in rabbits)
Abbreviated Amphotericin B Deoxycholate regimens have been tested in humans in the recently completed ACTA randomized controlled trial
Toxicity of abbreviated regimes is significantly less than with standard 14-day regimens
Bicanic et al. AAC 2015
Recent mouse model work suggests that amphotericin courses as short as 3 days may be as effective as full 14-day courses. These murine pharmacokinetic studies suggest that amphotericin B concentrations progressively accumulate in the brain despite plasma concentrations being at “steady state” (figure 2), as the physicochemical properties of amphotericin B enable it to “stick” in the lipid-rich cerebrum and not be readily released back into the circulation4.

6. Daily
Abbr
Efficacy of an Abbreviated Induction Regimen of Amphotericin B Deoxycholate for Cryptococcal Meningoencephalitis: 3 Days of Therapy Is Equivalent to 14 Days
Livermore J et al. MBio 2014; 5(1):e
(experimental cryptococcal meningoencephalitis in rabbits)
Abbreviated Amphotericin B Deoxycholate regimens have been tested in humans in the recently completed ACTA randomized controlled trial
Toxicity of abbreviated regimes is significantly less than with standard 14-day regimens
Bicanic et al. AAC 2015
Recent mouse model work suggests that amphotericin courses as short as 3 days may be as effective as full 14-day courses. These murine pharmacokinetic studies suggest that amphotericin B concentrations progressively accumulate in the brain despite plasma concentrations being at “steady state” (figure 2), as the physicochemical properties of amphotericin B enable it to “stick” in the lipid-rich cerebrum and not be readily released back into the circulation4.

7. What about liposomal amphotericin B?
Less nephrotoxic
- higher doses can be given safely
Excellent tissue penetration and long tissue half life
should be possible to deliver highly effective induction therapy with very few (1, 2, or 3) doses
Effective long-lasting therapy with just one dose of high dose liposomal amphotericin B has been established in the treatment of visceral leishmaniasis
Use in CM previously limited by cost, but short courses and reduced pricing could make it a cost-effective option
Need to define the most effective and most cost-effective schedules

8. The terminal half-life in the plasma and cerebrum is circa 133 hours.
The pharmacokinetics of liposomal amphotericin B in murine plasma (red) and cerebrum (black) in cohorts of mice infected with Cryptococcus neoformans receiving LAmB 20 mg/kg SINGLE DOSE i.v.
The terminal half-life in the plasma and cerebrum is circa 133 hours.
Jodi M. Lestner, Laura McEntee, Adam Johnson, Joanne Livermore, Sarah Whalley, Julie Schwartz, John R. Perfect, Thomas Harrison, William Hope. AAC 2017.

9. The Ambition Phase 2 Study: Primary Endpoint EFA (Jarvis et al
The Ambition Phase 2 Study: Primary Endpoint EFA (Jarvis et al. CROI 2017)

10. The Ambition Phase 2 Study: Primary Endpoint EFA (Jarvis et al
The Ambition Phase 2 Study: Primary Endpoint EFA (Jarvis et al. CROI 2017)
All 3 short course Liposomal Amphotericin B treatment arms were non-inferior to control

11. Adverse Events* Anaemia 6% (5) 0% (0) 11% (2) 15% (3) Renal impairment
All
Control
Single Dose
Two Doses
Three Doses
P-value
Grade 3 AEs
Anaemia
6% (5)
0% (0)
11% (2)
15% (3)
0.11
Renal impairment
5% (4)
6% (1)
0.10
Hypokalemia
1% (1)
5% (1)
0.39
Grade 4 AEs
0.42
*During induction therapy
Anemia grade 4 21% AmB

12. Amphotericin B deoxycholate
Adverse Events*
All
Control
Single Dose
Two Doses
Three Doses
P-value
Grade 3 AEs
Anaemia
6% (5)
0% (0)
11% (2)
15% (3)
0.11
Renal impairment
5% (4)
6% (1)
0.10
Hypokalemia
1% (1)
5% (1)
0.39
Grade 4 AEs
0.42 AA
Amphotericin B deoxycholate
14 doses 0.7-1mg/kg
18%
*During induction therapy
Anemia grade 4 21% AmB

13. % increase in creatinine over 2-week induction therapy
Adverse Events*
73%
All
Control
Single Dose
Two Doses
Three Doses
P-value
Grade 3 AEs
Anaemia
6% (5)
0% (0)
11% (2)
15% (3)
0.11
Renal impairment
5% (4)
6% (1)
0.10
Hypokalemia
1% (1)
5% (1)
0.39
Grade 4 AEs
0.42
% increase in creatinine over 2-week induction therapy
14%
2.3g/dL
drop in hemoglobin over 2-week induction therapy
0.9g/dL
*During induction therapy
L-AmB
AmB-d
Anemia grade 4 18% AmB
Bicanic et al. AAC 2015

14. AMBITION Phase-III study – clinical endpoint non-inferiority trial
L-AmB 10 mg/kg day 1 (single dose) vs
Amphotericin B deoxycholate 1.0 mg/kg/d 14 days (“control arm”)
Hypothesis: Short-course high-dose L-AmB given with high dose fluconazole and flucytosine will be non-inferior to 2 weeks daily-dosed amphotericin B deoxycholate with flucytosine induction therapy for the treatment of HIV-associated cryptococcal meningitis in averting all-cause mortality.
Endpoints:
Primary: All-cause mortality within the first 10 weeks
Secondary: Early Fungicidal Activity (EFA); 2-week mortality; tolerability and adverse events; cost-effectiveness
850 patients total (425 per arm) (10% NI margin)

15. Kampala, Uganda
Infectious Diseases Institute
Lilongwe, Malawi
UNC Project
Blantyre, Malawi
Malawi-Liverpool Wellcome Trust Clinical Research Programme
Harare, Zimbabwe
University of Zimbabwe
Gaborone, Botswana
Botswana-Harvard Partnership and University of Botswana
Cape Town, South Africa
University of Cape Town

16. Liverpool School of Tropical Medicine
Clinical Trial, Health Economics, Statistics
University of Liverpool
Pharmacokinetics / Pharmacodynamics
London School of Hygiene and Tropical Medicine
Overall Project Management
St. George’s University of London
Clinical Trial and Training / Capacity Building
Institut Pasteur
Scientific Substudies and Training / Capacity Building

17. WP-1: Clinical Trial
WP-2: Economic Analysis
WP-3: Scientific Substudies
WP-4: Network Development
WP-5: Training & Capacity Building
WP-6: Project Management

18. Summary
A novel short-course highly effective and safer L-AmB treatment regimen for CM would transform the management of late-stage HIV and markedly improve outcomes in HIV programmes in Africa.
Reductions in the need for laboratory monitoring, lower toxicity rates, and reduced durations of hospital admission, coupled with preferential pricing, are likely to make this a practical and cost-effective treatment for Africa
The study will build strong research links between leading European and African research institutions, develop a unique African clinical trials network, and develop African investigators into research leaders.

19. The Ambition Consortium
LSHTM
Joe Jarvis
David Lawrence
Nabila Youssouf
Philippa Griffin
St George’s
Tom Harrison
Síle Molloy
Angela Loyse
LSTM
David Lalloo
Shabbar Jaffar
Duolao Wang
Louis Niessen
Laura Collett
University of Liverpool
William Hope
Kat Stott
Institut Pasteur
Olivier Lortholary
Françoise Dromer
Timothée Boyer Chammard
Alexandre Alanio
University of Cape Town
Graeme Meintjes
Charlotte Schutz
Tom Crede
University of Zimbabwe
Rati Ndhlovu
Admire Hlupeni
Botswana-Harvard Partnership
Mosepele Mosepele
Tshepo Leeme
Nametso Lekwape
Katlego Tsholo
Norah Mawako
Kwana Lechiile
Simani Gaseitsiwe
Sikhulile Moyo
UNC Project Malawi
Cecilia Kanyama
Mina Hosseinipour
IDI Uganda
David Boulware
David Meya
Malawi-Liverpool Wellcome
Henry Mwandumba
Gilead
EDCTP
Medical Research Council
Wellcome Trust
Department for International Development