{'fraction_non_alphanumeric': 0.026497695852534562, 'fraction_numerical': 0.012672811059907835, 'mean_word_length': 5.386029411764706, 'pattern_counts': {'":': 0, '<': 0, '<?xml version=': 0, '>': 0, 'https://': 0, 'lorem ipsum': 0, 'www.': 0, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 0, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
Optimizing the Design of Latent Tuberculosis Treatment Trials: Insights from Mathematical Modeling.

RATIONALE
Noninferiority trials of latent tuberculosis (LTBI) treatment are challenging because of imperfect LTBI diagnostic tests.


OBJECTIVES
To assess the effect on study outcomes of different enrollment strategies for a noninferiority trial of LTBI treatment.


METHODS
We mathematically simulated a two-arm, randomized, controlled trial of LTBI in which the experimental therapy was 50% efficacious and the control was 80% efficacious, with an absolute 0.75% noninferiority margin. Five enrollment strategies were assessed: 1) Enroll based on no LTBI diagnostic test, 2) Enroll based on a positive tuberculin skin test (TST), 3) Enroll based on a positive interferon gamma release assay (IGRA), 4) Enroll based on either a positive TST or IGRA, 5) Enroll regardless of test result, assuming 70% had negative TSTs, 20% positive TSTs, and 10% unknown results.


MEASUREMENTS AND MAIN RESULTS
Under most LTBI prevalence assumptions, enrolling based on a positive IGRA was least likely to result in falsely declaring noninferiority of the experimental regimen. Enrolling based on no test or regardless of test result resulted in falsely declaring noninferiority unless underlying population LTBI prevalence was over 45%. Enrolling based on a mix of TST and IGRA substantially reduced the likelihood of falsely declaring noninferiority over enrolling based on TST alone, even if as many as 70% of participants were enrolled based on positive TST.


CONCLUSIONS
Noninferiority trials of LTBI should enroll based on the most specific diagnostic tests available (IGRAs) to avoid misclassifying inferior treatment regimens as noninferior.