Building on its past successes, the PanACEA2 Consortium is continuing its innovative programme of work on shorter, simpler and better treatments for TB.

Advancing a suite of TB drug treatments

TB is one of the most difficult infections to treat, and presents major challenges to drug development. Current treatment regimes last six months and require patients to take multiple medications. Shorter and simpler regimens would improve adherence, reduce side effects and lower costs.

Unfortunately, evaluation of new TB drugs, and new combinations and doses of existing drugs, is highly challenging. In particular, methods for determining the impact of drugs on TB bacteria are imperfect, making it harder to determine whether drug treatments should be progressed. In addition, long and costly phase III trials are required, and several promising treatments have failed at this stage. As a result, there are many possible improvements to TB treatment, and a key challenge is to determine as efficiently as possible which are most likely to succeed so they can be rigorously evaluated in large-scale trials.

The challenge

The PanACEA Consortium, funded in the first EDCTP programme, was set up not just to evaluate novel TB drugs and combinations, but also to build capacity for TB drug trials in Africa and, importantly, to advance clinical trial methodology to improve the efficiency of drug development and enhance the likelihood of success. It carried out landmark trials aiming to shorten TB treatment and introduced novel clinical trial designs never before used in infectious disease research.

PanACEA2 will build on this foundation. With higher doses of rifampicin showing promise in trials, it will carry out studies to identify the maximum tolerated dose that could be evaluated in future trials. In addition, it plans to assess the safety of promising new drugs entering the TB drug development pipeline, using a novel design that will allow determination of slow-acting effects and evaluation of multiple combinations in one study.

In a third strand of work, multiple combinations will be assessed in an adaptive trial, allowing for discontinuation of poorly performing therapies. Long-term follow-up will be undertaken – addressing the issue that early responses to drugs do not necessarily provide an accurate indicator of long-term treatment success. This will provide a key step towards reducing the risk of failure in phase III trials.

The project

PanACEA2 will generate key data on TB drug treatments, pilot innovative methodologies for drug evaluation that could greatly accelerate drug development and reduce the risk of failure, and build capacity for trials of the highest international regulatory standard. Furthermore, by operating as an open partnership, it can carry out studies in partnership with multiple drug developers, and also coordinate activities with other international TB drug consortia, minimising duplication of efforts.

Impact


crucial in

widening African

children’s access

to antiretrovirals

Bringing antiretroviral drugs to children

The CHAPAS trials have ensured that many more children with HIV have benefited
from life-saving antiretrovirals.

EDCTP portfolio: HIV & HIV-associated infections

The challenge

TB is one of the most difficult infections to treat, and presents major challenges to drug development. Current treatment regimes last six months and require patients to take multiple medications. Shorter and simpler regimens would improve adherence, reduce side effects and lower costs.

Unfortunately, evaluation of new TB drugs, and new combinations and doses of existing drugs, is highly challenging. In particular, methods for determining the impact of drugs on TB bacteria are imperfect, making it harder to determine whether drug treatments should be progressed. In addition, long and costly phase III trials are required, and several promising treatments have failed at this stage. As a result, there are many possible improvements to TB treatment, and a key challenge is to determine as efficiently as possible which are most likely to succeed so they can be rigorously evaluated in large-scale trials.

The PanACEA Consortium, funded in the first EDCTP programme, was set up not just to evaluate novel TB drugs and combinations, but also to build capacity for TB drug trials in Africa and, importantly, to advance clinical trial methodology to improve the efficiency of drug development and enhance the likelihood of success. It carried out landmark trials aiming to shorten TB treatment and introduced novel clinical trial designs never before used in infectious disease research.

PanACEA2 will build on this foundation. With higher doses of rifampicin showing promise in trials, it will carry out studies to identify the maximum tolerated dose that could be evaluated in future trials. In addition, it plans to assess the safety of promising new drugs entering the TB drug development pipeline, using a novel design that will allow determination of slow-acting effects and evaluation of multiple combinations in one study.

In a third strand of work, multiple combinations will be assessed in an adaptive trial, allowing for discontinuation of poorly performing therapies. Long-term follow-up will be undertaken – addressing the issue that early responses to drugs do not necessarily provide an accurate indicator of long-term treatment success. This will provide a key step towards reducing the risk of failure in phase III trials.

The project

The later CHAPAS-3 trial compared the efficacy and safety of three fixed-dose combinations including two without stavudine (found to have some long-term side effects in adults, leading to a recommendation that its use be discontinued in children). The trial the first of its kind in Africa studied nearly 500 children at four sites in two African countries.

PanACEA2 will generate key data on TB drug treatments, pilot innovative methodologies for drug evaluation that could greatly accelerate drug development and reduce the risk of failure, and build capacity for trials of the highest international regulatory standard. Furthermore, by operating as an open partnership, it can carry out studies in partnership with multiple drug developers, and also coordinate activities with other international TB drug consortia, minimising duplication of efforts.

ratios forfixed-dose combinations and on appropriatedosage according to weight. 

The CHAPAS-3 trial confirmed the effectiveness of fixed-dose combinations, providing further impetus to the rollout of antiretrovirals to children. Its evidence on abacavir informed the WHO recommendation of abacavir-containing combinations for first-line therapy in children. Trial data have also been used to support applications for regulatory approval for new scored efavirenz tablets.

Impact

L’homme RF et al. Nevirapine, stavudine and lamivudine pharmacokinetics in African children on paediatric fixed-dose combination tablets. AIDS. 2008;22(5):557–65.

Mulenga V et al. Abacavir, zidovudine, or stavudine as paediatric tablets for African HIVinfected children (CHAPAS-3): an open-label, parallel-group, randomised controlled trial. Lancet Infect Dis. 2016;16(2):169–79.

WHO. Guidelines on the use of antiretroviral drugs for treating and preventing HIV infection: recommendations for a public health approach. 2010.

WHO. Consolidated guidelines on the use of antiretroviral drugs
for treating and preventing

HIV infection: Recommendations for a public health approach
(second edition). 2016

Projects: Children with HIV in Africa Pharmacokinetics and Adherence of Simple Antiretroviral Regimens (CHAPAS): CHAPAS-1 and -3

Project lead: Professor Chifumbe Chintu, University Teaching Hospital, Zambia (CHAPAS-1); Dr Veronica Mulenga, University Teaching Hospital, Zambia (CHAPAS-3)

Target population(s): Children with HIV

Sample size: 71 (CHAPAS-1); 480 (CHAPAS-3)

Countries involved: Ireland, the Netherlands, the UK, the USA, Zambia (CHAPAS-1); Uganda, Zambia (CHAPAS-3)

Project duration: 2005–2009 (CHAPAS-1); 2010 –2011 (CHAPAS-3)

EDCTP funding: €1.2M (CHAPAS-1); €4.6M (CHAPAS-3)

Total project funding: €1.2M (CHAPAS-1); €5.0M

About us

The European & Developing Countries Clinical Trials Partnership (EDCTP) is a public–public partnership between 14 European and 16 African countries, supported by the European Union. EDCTP’s vision is to reduce the individual, social and economic burden of poverty-related infectious diseases by affecting sub-Saharan Africa. EDCTP’s mission is to accelerate the development of new or improved medicinal products for the identification, treatment and prevention of infectious diseases, including emerging and re-emerging diseases, through pre- and postregistration clinical studies, with emphasis on phase II and III clinical trials. Our approach integrates conduct of research with development of African clinical research capacity and networking. The second EDCTP programme is implemented by the EDCTP Association supported under Horizon 2020, the European Union’s Framework Programme for Research and Innovation.

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