TY - JOUR
T1 - Conducting efficacy trials in children with MDR-TB
T2 - What is the rationale and how should they be done?
AU - Seddon, J. A.
AU - Weld, E. D.
AU - Schaaf, H. S.
AU - Garcia-Prats, A. J.
AU - Kim, S.
AU - Hesseling, A. C.
N1 - Publisher Copyright:
© 2018 International Union against Tubercul. and Lung Dis. All rights reserved.
PY - 2018/5/1
Y1 - 2018/5/1
N2 - Paediatric anti-tuberculosis treatment trials have traditionally been limited to Phase I/II studies evaluating the drug pharmacokinetics and safety in children, with assumptions about efficacy made by extrapolating data from adults. However, it is increasingly being recognized that, in some circumstances, efficacy trials are required in children. The current treatment for children with multidrug-resistant tuberculosis (MDR-TB) is long and toxic; shorter, safer regimens, using novel agents, require urgent evaluation. Given the changing pattern of drug metabolism, disease spectrum and rates of TB disease confirmation with age, decisions around inclusion criteria require careful consideration. The most straightforward MDR-TB efficacy trial would include only children with confirmed MDR-TB and no additional drug resistance. Given that it may be unclear at the time treatment is initiated whether the diagnosis will ultimately be confirmed and what the final drug resistance profile will be, this presents a unique challenge in children. Recruiting only these children would, however, limit the generalisability of such a trial, as in reality the majority of children with TB do not have bacteriologically confirmed disease. Given the good existing treatment outcomes with current routine regimens for children with MDR-TB, conducting a superiority trial may not be the optimal design. Demonstrating non-inferiority of efficacy, but superiority with regard to safety, would be an alternative strategy. Using standardised control and experimental MDR-TB treatment regimens is challenging given the wide spectrum of paediatric disease. However, using variable regimens wouldmake interpretation challenging. A paediatric MDR-TB efficacy trial is urgently needed, and with global collaboration and capacity building, is highly feasible.
AB - Paediatric anti-tuberculosis treatment trials have traditionally been limited to Phase I/II studies evaluating the drug pharmacokinetics and safety in children, with assumptions about efficacy made by extrapolating data from adults. However, it is increasingly being recognized that, in some circumstances, efficacy trials are required in children. The current treatment for children with multidrug-resistant tuberculosis (MDR-TB) is long and toxic; shorter, safer regimens, using novel agents, require urgent evaluation. Given the changing pattern of drug metabolism, disease spectrum and rates of TB disease confirmation with age, decisions around inclusion criteria require careful consideration. The most straightforward MDR-TB efficacy trial would include only children with confirmed MDR-TB and no additional drug resistance. Given that it may be unclear at the time treatment is initiated whether the diagnosis will ultimately be confirmed and what the final drug resistance profile will be, this presents a unique challenge in children. Recruiting only these children would, however, limit the generalisability of such a trial, as in reality the majority of children with TB do not have bacteriologically confirmed disease. Given the good existing treatment outcomes with current routine regimens for children with MDR-TB, conducting a superiority trial may not be the optimal design. Demonstrating non-inferiority of efficacy, but superiority with regard to safety, would be an alternative strategy. Using standardised control and experimental MDR-TB treatment regimens is challenging given the wide spectrum of paediatric disease. However, using variable regimens wouldmake interpretation challenging. A paediatric MDR-TB efficacy trial is urgently needed, and with global collaboration and capacity building, is highly feasible.
KW - Children
KW - Multidrug-resistant
KW - Trial
KW - Tuberculosis
UR - http://www.scopus.com/inward/record.url?scp=85055903257&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85055903257&partnerID=8YFLogxK
U2 - 10.5588/ijtld.17.0359
DO - 10.5588/ijtld.17.0359
M3 - Article
C2 - 29665950
AN - SCOPUS:85055903257
SN - 1027-3719
VL - 22
SP - S24-S33
JO - International Journal of Tuberculosis and Lung Disease
JF - International Journal of Tuberculosis and Lung Disease
IS - 5
ER -