Inspiring RECOVERY: tuberculous meningitis research community considers a platform trial

31 May 2023
30 researchers gathered on the steps of the meeting venue
31 May 2023

Influenced by the success of the RECOVERY platform trial that investigated treatment options for severe COVID-19, a global network of researchers asked if lessons could be learnt for tuberculous meningitis. The group met on the 24th and 25th of May 2023 in Cape Town to discuss the current state of knowledge, possibilities for research and arrive at consensus on the way forward. The meeting was partially supported by a grant to Sean Wasserman (UCT) and Joseph Dononvan (London School of Hygiene and Tropical Medicine) from the UK’s Grand Challenges Research Fund. 

Tuberculous meningitis (TBM) is a devastating manifestation of infection with the bacterium that usually causes pulmonary tuberculosis (TB). In TBM the bacteria infect the membranes (called meninges) covering the brain and spinal cord, leading to complications including brain damage, seizures, and hearing loss. This type of TB infection is particularly prevalent in countries of the Global South and in populations living with HIV. 

Global map indicating high incidence of TBM in countries of the Global South
Absolute (circle) and per capita (colour gradient) incidence of TBM by country (Dodd et al, 2021*)

Twenty five percent of people who contract TBM will die, while a further 25% will be significantly disabled. Although currently available medication regimens can successfully treat pulmonary TB, the effects on TBM are limited by the inability of some of the antibiotics to penetrate the brain. In addition, the body’s own response to the infection—inflammation—can become damaging to the tissue it should protect. While treatment with steroids can dampen inflammation and improve survival in some patients, they do not prevent disability.

Opening the meeting, CIDRI-Africa director Robert J Wilkinson opined, "we cannot continue to accept that 50- to 100 000 people will die or be disabled every year owing to TBM. Effective research is urgently needed to inform policy and practice for the prevention of TBM-related death and disability."

The RECOVERY platform trial of interventions for treatment of severe COVID-19 provides a model for rapid, powerful, simple, and adaptive clinical trials of multiple interventions across many sites. Could this approach be employed to investigate TBM treatment regimens across the world? The idea has traction: 30 researchers from India, Indonesia, Kenya, Madagascar, the Netherlands, South Africa, Uganda, the United Kingdom, the United States and Vietnam gathered in Cape Town to cultivate ideas and develop a nascent platform trial plan.

The team agreed that any trial should be widely inclusive to ensure that results will be applicable to a broad range of populations, including pregnant people, children, and people living with HIV. Multiple treatment options will be combined to target both the bacterium causing TBM, and the patient’s own dysregulated inflammatory response. In addition, the team are considering investigating options for treatment of downstream complications such as immune reconstitution inflammatory syndrome, which may occur weeks to months after treatment initiation. Treatment outcomes to be measured will be simplified, while also enabling individual research sites to expand their outcome measures if so desired.

Planning will continue over the coming months and years, with an initial target of September 2023 for completed protocol development and thereby potential submission to funding agencies, several of which have been engaged.

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View the meeting programme. Participants included: Rob Aarnoutse (Radboud University Medical Center), James Barnacle (The Francis Crick Institute), David Boulware (University Of Minnesota), Felicia Chow (University Of California, San Francisco), Angharad Davis (The Francis Crick Institute), Joseph Donovan (London School Of Hygiene And Tropical Medicine), Kelly Dooley (Vanderbilt University Medical Center), Anthony Figaji (University Of Cape Town), Fiona Cresswell (Infectious Diseases Institute, Uganda), Diana Gibb (University College London), Julie Huynh (OUCRU), Darma Imran (Dr. Cipto Mangunkusumo Hospital, Jakarta), Evelyne Kestelyn (OUCRU), Suzaan Marais (University of Cape Town), David Meya (Infectious Diseases Institute, College of Health Sciences, Makerere University), Usha Kant Misra (Apollomedics Super Specialty Hospital, Lucknow), Manish Modi (PGIMER, Chandigarh, India), Thomas Nyirenda (European and Developing Countries Clinical Trials Partnership), Mihaja Raberahona (University Hospital Joseph Raseta Befelatanana Antananarivo, Centre D'infectiologie Charles Mérieux Antananarivo), Ahmad Rizal (Faculty Of Medicine, Universitas Padjadjaran, Bandung, Indonesia), Ursula Rohlwink (University Of Cape Town), Rovina Ruslami (Universitas Padjadjaran), James Seddon (Imperial College London), Keira Skolimowska (University of Cape Town), Regan Solomons (Stellenbosch University), Cari Stek (University of Cape Town), Nguyen Thuong (OUCRU), Guy Thwaites (OUCRU), Reinout Van Crevel (Radboud University Medical Center), Sean Wasserman (University of Cape Town), James Watson (OUCRU), Robert J Wilkinson (Centre for Infectious Diseases Research in Africa). 

*Source: Dodd PJ, Osman M, Cresswell FV, Stadelman AM, Lan NH, et al. (2021) The global burden of tuberculous meningitis in adults: A modelling study. PLOS Global Public Health 1(12): e0000069. https://doi.org/10.1371/journal.pgph.0000069 (CC BY 4.0)