Publications

Funding for clinical research |drugs, vaccines, microbicides, diagnostics | HIV/AIDS, tuberculosis, malaria, other infectious diseases |sub-Saharan Africa

The CLICK-TB study is adopting a novel approach to identify the most promising new treatment options for TB.

Advancing new options for treatment of TB

The rise of drug resistance is making treatment of TB even more difficult. Treatment of multidrug-resistant TB typically lasts at least a year, involves up to 10 drugs, and cures only around half of all patients. Hence new drugs are urgently required.

Phase III clinical trials of TB treatments are large, lengthy and expensive. It is therefore critical that resources are focused on drugs with the greatest likelihood of success.

The challenge

The CLICK-TB study aims to identify the most promising combinations of TB drugs from a pool of early-stage candidates from new chemical classes. It is focusing on three novel compounds, two of which have already completed early-stage clinical trials: sanfetrinem cilexetil, a broad-spectrum antibiotic with potential for repurposing for TB; GSK3036656, an inhibitor of an enzyme pivotal to mycobacterial protein synthesis (LeuRS); and two inhibitors of DprE1, an enzyme involved in cell wall synthesis, which are in late pre-clinical development.

The CLICK-TB team will assess each of these drugs in combination with newly approved anti-TB drugs, delamanid or pretomanid and bedaquiline. Up to 10 combinations will be evaluated in rapid (two-week) assays examining early potency against TB bacteria. As well as bacterial culture results, the team will also collect radiological and immunological data, providing an additional readout of treatment responses.

The team will then develop a statistical model to compare results across the different combinations and to determine the relative contributions of each drug component. This model will be used to identify the likely most potent combinations, which will be evaluated in a four-week trial using the same response readouts alongside traditional phase IIb trial endpoints.

The project

The CLICK-TB study has adopted a novel trial methodology that will rapidly generate a wealth of data on a suite of candidate TB drugs, efficiently identifying the most promising combination for a definitive phase III trial.

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

The rise of drug resistance is making treatment of TB even more difficult. Treatment of multidrug-resistant TB typically lasts at least a year, involves up to 10 drugs, and cures only around half of all patients. Hence new drugs are urgently required.

Phase III clinical trials of TB treatments are large, lengthy and expensive. It is therefore critical that resources are focused on drugs with the greatest likelihood of success.

The CLICK-TB study aims to identify the most promising combinations of TB drugs from a pool of early-stage candidates from new chemical classes. It is focusing on three novel compounds, two of which have already completed early-stage clinical trials: sanfetrinem cilexetil, a broad-spectrum antibiotic with potential for repurposing for TB; GSK3036656, an inhibitor of an enzyme pivotal to mycobacterial protein synthesis (LeuRS); and two inhibitors of DprE1, an enzyme involved in cell wall synthesis, which are in late pre-clinical development.

The CLICK-TB team will assess each of these drugs in combination with newly approved anti-TB drugs, delamanid or pretomanid and bedaquiline. Up to 10 combinations will be evaluated in rapid (two-week) assays examining early potency against TB bacteria. As well as bacterial culture results, the team will also collect radiological and immunological data, providing an additional readout of treatment responses.

The team will then develop a statistical model to compare results across the different combinations and to determine the relative contributions of each drug component. This model will be used to identify the likely most potent combinations, which will be evaluated in a four-week trial using the same response readouts alongside traditional phase IIb trial endpoints.

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.

The CLICK-TB study has adopted a novel trial methodology that will rapidly generate a wealth of data on a suite of candidate TB drugs, efficiently identifying the most promising combination for a definitive phase III trial.

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