Conducting efficacy trials in children with MDR-TB: what is the rationale and how should they be done?

Abstract

Traditionally paediatric tuberculosis (TB) treatment trials have been limited to phase I/II studies evaluating the pharmacokinetics and safety of drugs in children, with assumptions about efficacy made by extrapolating data from adults. However, it is increasingly recognised that in some circumstances, efficacy trials are warranted and required in children. The current treatment for children with multidrug-resistant (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 with 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 generalizability of such a trial since, 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 standardized control and experimental MDR-TB treatment regimens is challenging given the wide spectrum of paediatric disease. However, using variable regimens would make interpretation challenging. A paediatric MDR-TB efficacy trial is urgently needed, and with global collaboration and capacity building, is highly feasible.

Immunological Aspects of Diagnosis and Management of Childhood Tuberculosis

“…Diverse clinical forms in childhood TB enhance the treatment choice dilemma, suggesting that patients with isolated lymph node or pulmonary disease might require only a short treatment with few drugs; meanwhile, complicated or severe TB clinical forms might need a more prolonged therapy with more drugs. [99][100][101] Preclinical models of each type of TB presentation, supported by new diagnostic tools, such as mass spectrometry, dynamic positron emission tomography bioimaging, and pharmacokinetic modeling, will give access to remarkable information for clinical trials design and development, solving the divergences in clinical decision making. 102 Current guidelines for the management of TB in children contemplate regimes adjusted to sex, age, weight, and drug-sensitivity.…”

The importance of pharmacokinetics/pharmacodynamics assessment in Phase IIB/III trials for MDR-TB treatment

“…29 It is important to embed PK/PD assessment into the prospective study designs of TB treatment for adults and children. 7,8,30 To increase feasibility, limited sampling strategies in combination with population PK modelling can be used. This will reduce the number of samples to be collected per patient, thereby reducing the burden for patient and staff, as well as costs, including the total number of samples to be analysed in the laboratory.…”

A framework for considering the risk‐benefit trade‐off in designing noninferiority trials using composite outcome approaches

“…This is even more relevant in consideration of treatment for children with MDR-TB, where a higher proportion of favorable treatment outcomes have been observed compared with adults with the disease, and children are more severely debilitated by the harmful side effects of several of the drugs used to treat MDR-TB. 32 For example, aminoglycosides and cyclic peptides are painful because they are administered by intramuscular injections and may cause permanent hearing loss, which can have repercussions on neurocognitive development and quality of life. Thus, Seddon et al 32 TA B L E 6 MADE using the weighted component outcome for noninferiority.…”

“…Given the toxicity and poor tolerability associated with many of the drugs used in standard regimens for treating MDR‐TB, an alternative regimen that may have small improvements in, or slightly worse, efficacy may have a more favorable risk‐benefit profile if it is less toxic and more tolerable. This is even more relevant in consideration of treatment for children with MDR‐TB, where a higher proportion of favorable treatment outcomes have been observed compared with adults with the disease, and children are more severely debilitated by the harmful side effects of several of the drugs used to treat MDR‐TB 32 . For example, aminoglycosides and cyclic peptides are painful because they are administered by intramuscular injections and may cause permanent hearing loss, which can have repercussions on neurocognitive development and quality of life.…”

“…For example, aminoglycosides and cyclic peptides are painful because they are administered by intramuscular injections and may cause permanent hearing loss, which can have repercussions on neurocognitive development and quality of life. Thus, Seddon et al 32 made the case for the need for pediatric MDR‐TB treatment efficacy trials designed for noninferiority. Kim et al 33 also discussed the value of using a noninferiority efficacy trial to “identify regimens that are expected to be better or not unacceptably worse than the control and, because of the potential improvements in risk‐benefit profile, may be useful in evaluating a shortened, all‐oral MDR‐TB regimen in children.” However, the choice of the noninferiority margin continues to be a major design issue, not only in pediatric trials but in adult trials as well 33 .…”