Prognostic and surrogate markers for outcome in the treatment of pulmonary tuberculosis
Phillips, Patrick Peter John;
(2009)
Prognostic and surrogate markers for outcome in the treatment of pulmonary tuberculosis.
PhD thesis, London School of Hygiene & Tropical Medicine.
DOI: https://doi.org/10.17037/PUBS.01544172
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Phase III trials for new tuberculosis treatment regimens require large numbers
of participants and can take over five years to complete. A surrogate marker
for poor outcome (failure at end of treatment or recurrence following successful
treatment), the established endpoint in such trials, could shorten trial
duration and reduce trial size. Culture results after two months of treatment
have shown the most promise but, prior to this research, no formal evaluation
had been performed.
In this thesis, culture results during treatment are evaluated as prognostic
and surrogate markers for poor outcome using data on 6974 patients from
twelve tuberculosis treatment randomised controlled multi-arm trials conducted
in East Africa and East Asia.
A strong association was found between culture results during treatment
and poor outcome. Nevertheless, culture results were not good patient-specific
predictors of poor outcome with low sensitivities and specificities.
Existing meta-analytic methods for evaluating surrogate markers are not
wholly suited to this setting of multi-arm trials with binary true and surrogate
endpoints. Extending these methods, the two month culture was found to be a
good surrogate marker using data from Hong Kong trials and the three month
culture was found to be a good surrogate marker using data from East African
trials. These results are an indication that cultures during treatment do capture
some of the treatment effect. Further work is needed in understanding
the differences between the Hong Kong and East African trials.
The meta-analytic methods for evaluating surrogate markers in this thesis
included a graphical representation that permitted a clear visual evaluation
of the surrogate. Methods developed in this thesis for modelling the relationship
between the treatment effects on the true and surrogate endpoints were
not satisfactory. The deficiencies were not overcome with the two extensions
proposed. Further work is needed in developing a more appropriate model.