Current Organisation

Kilimanjaro Clinical Research Institute

Current Job Title

Head-Clinical Trial Unit

Biography

Project Title

Evaluation of Pharmacokinetics and Safety/Tolerability of Higher Doses of Rifampicin in Children with Newly Diagnosed, Uncomplicated Tuberculosis

EDCTP Project Call

Career Development Fellowship (CDF)

Host Organisation

Project Objectives

Overall aim and objectives The overall aim of this study is to assess which higher rifampicin doses in children yield similar exposures in plasma to those achieved in adults who received 35 mg/kg rifampicin daily, as it is thought that similar exposures in plasma will yield similar response. The primary objectives of this clinical trial are: To describe the pharmacokinetics of increasing doses of rifampicin when administered as a single drug and when combined with isoniazid, pyrazinamide and ethambutol in children who are newly diagnosed with uncomplicated TB. To establish the incidence and severity of adverse events of increasing dosages of rifampicin administered as a single drug and when combined with isoniazid, pyrazinamide and ethambutol in children who are newly diagnosed with uncomplicated TB. The secondary objective of this trial is: To assess possible relationships between exposure to rifampicin and adverse effects (pharmacodynamics of rifampicin in relation to toxicity).

Study Design

Overall Study Design This is a phase II, dose finding, open label clinical trial conducted in consecutive groups of children. A maximum of 45 subjects who meet all the inclusion criteria and none of the exclusion criteria, aged between 0 and 14 years (inclusive), with newly diagnosed, uncomplicated TB will be included in the study. The control group (15 subjects) will receive the upper limit of the standard dose of rifampicin (20 mg/kg daily) for 7 days, followed by standard TB treatment, i.e. RHZE (this includes the standard dose of rifampicin) for 7 days and thereafter. In a consecutively recruited group of 15 subjects, children will receive high dose rifampicin 35 mg/kg daily as monotherapy for 7 days followed by 7 days in combination therapy with HZE for 7 days. A third group will receive an even higher dose as monotherapy for 7 days followed by 7 days in combination therapy with HZE for 7 days. The dose in this third group will be based on comparisons of exposures achieved in the previous groups with adult data at a 35 mg/kg dose as well as pharmacokinetic calculations on the pediatric pharmacokinetic data in the first groups. The targeted exposures will be similar and not higher than those found in adults who used 35 mg/kg daily. After 7 days of combination therapy, the subjects in the high dose rifampicin groups and the control group will get the same treatment which follows the Tanzanian National TB and Leprosy guidelines. In this period, children are monitored for possible adverse effects even after administration of higher doses of rifampicin. After these 7 days of standard TB treatment, the study will end for the subjects. TB drugs will be administered as fixed dose combinations (FDCs) that contain all first line TB drugs, supplemented with loose rifampicin tablets for the higher doses of rifampicin. The study groups will be balanced in terms of children within various weight bands or age groups. Pharmacokinetic parameters are assessed at day 7 for

Project Summary

Childhood tuberculosis continues to be a public health problem. It contributes 11% of the total TB cases worldwide. There are challenges in diagnosing the TB in children. Also TB treatment outcomes in children are challenged by insufficient consideration of the relationships between doses administered, concentrations achieved and eventual desirable and undesirable effects (pharmacodynamics) of TB drugs. Rifampicin is a pivotal TB drug and data from adults suggest that a much higher dose of rifampicin (35 mg/kg instead of 10 mg/kg), has resulted in much higher rifampicin exposures in plasma; is also safe and tolerable and may provide a higher efficacy. The dose needed in children to achieve the same exposure in plasma is unknown. And the researchers are working had to find the maximum tolerable dose in children. More than 75% of the worldwide estimated cases of TB in children occur in the 30 high burden countries, including Tanzania. Kilimanjaro Region being the area with up to 15% of notification to be children. The enormous burden of paediatric TB in these countries is due to the TB epidemic amongst adults and the simultaneous HIV pandemic and a child less than 14 years of age whether HIV infected or not is at a high risk of developing the disease. Subsequent dissemination of the mycobacterium and progression of the disease is also fast in children. However, knowledge on the efficacy and safety of medicines for children is still very limited and sometimes children are still being treated as small adults. Dosing in children Dosing cannot be logically extrapolated to children according to weight or age because of different pharmacokinetics, i.e. the relationship between doses administered and exposures (drug concentrations) achieved, in children as compared with adults. More specifically, these pharmacokinetic differences occur in the subsequent processes of absorption, distribution, metabolism and elimination of drugs, which are subject to physiological changes due to growth and development in children. Especially in young children, maturation of liver metabolism pathways and renal function are not completed. The World Health Organization revised paediatric TB dosing guidelines in 2010, by recommending considerably higher doses of first-line anti-tuberculosis drugs in children below 25 kg as follows; rifampicin, 10-20 versus 8-12 mg/kg of body weight/day. Overall aim: The overall aim of this study is to evaluate the pharmacokinetic and safety/tolerability of high doses of rifampicin in children and to assess which higher rifampicin doses in children yield similar exposures in plasma to those achieved in adults who received 35 mg/kg rifampicin daily, as it is thought that similar exposures in plasma will yield similar response. The study population will be children (including males and females) aged between 1 to 14 years (inclusive), who are diagnosed to have TB (either with pulmonary TB, extra pulmonary TB, or by physician decision) using WHO score chart. We will successively run three cohorts (arm) of ten children each that are subjected to increasing rifampicin doses (20 mg, 30mg and 40mg per kg body weight). The dose of the fourth arm will depend on the results of the first three arms after the PK analysis and correlation with the safety. Work performed from July 2022 to June 2023 The research team continued with the enrolment of participants for ARM three (40mg per kg body weight). and follow up for the safety of the participants. The team completed the enrolment and followup for all enrolled participants. Different meetings and data verification activities were conducted. Extenal monitor was done virtually and few selected files shared with her. Internal monitoring visits were done to rectify the questions which was asked by external monitor and the research team continued to gain experience on how to conduct good clinical trial on these 2 visits. Progress reports were submitted to local ethics committee, National Institute for Medical Research (NIMR) and Tanzania Medicines and Medical Device Authority (TMDA).