High-Dose Isoniazid Among Adult Patients With Different Genetic Variants of INH-Resistant Tuberculosis (TB)

Summary

Isoniazid (INH) is a drug commonly used to treat tuberculosis (TB) worldwide. Sometimes, the bacteria that cause TB can become resistant to INH. Resistance means that bacteria have adapted to a drug and are able to live in the presence of the drug. When TB becomes resistant to INH, INH does not work as well at fighting the bacteria. This study treated people with INH-resistant TB with different doses of INH to see if INH can still fight the bacteria if the dose is increased. We evaluated how well the drug works at higher doses for participants who have resistant TB as well as how well the drug works at regular doses for participants who have TB that is not resistant. The study also evaluated the safety and tolerability of the different doses of INH. Tolerability is how well people can put up with the side effects of a drug. Using increased doses of INH to treat TB that is resistant to INH is experimental and has not been approved by regulatory authorities. While there is some evidence that this approach will work, this has not yet been proven.

Timeline

Start

2014-08-13

Primary completion

2021-09-22

Completion

2021-10-06

Publications

• Gausi K, Ignatius EH, De Jager V, Upton C, Kim S, McKhann A, Moran L, Wiesner L, von Groote-Bidlingmaier F, Marzinek P, Vanker N, Yvetot J, Pierre S, Rosenkranz SL, Swindells S, Diacon AH, Nuermberger EL, Denti P, Dooley KE. High-Dose Isoniazid Lacks EARLY Bactericidal Activity against Isoniazid-resistant Tuberculosis Mediated by katG Mutations: A Randomized Phase II Clinical Trial. Am J Respir Crit Care Med. 2024 Aug 1;210(3):343-351. doi: 10.1164/rccm.202311-2004OC.
• Gausi K, Ignatius EH, Sun X, Kim S, Moran L, Wiesner L, von Groote-Bidlingmaier F, Hafner R, Donahue K, Vanker N, Rosenkranz SL, Swindells S, Diacon AH, Nuermberger EL, Dooley KE, Denti P. A Semimechanistic Model of the Bactericidal Activity of High-Dose Isoniazid against Multidrug-Resistant Tuberculosis: Results from a Randomized Clinical Trial. Am J Respir Crit Care Med. 2021 Dec 1;204(11):1327-1335. doi: 10.1164/rccm.202103-0534OC.
• Dooley KE, Miyahara S, von Groote-Bidlingmaier F, Sun X, Hafner R, Rosenkranz SL, Ignatius EH, Nuermberger EL, Moran L, Donahue K, Swindells S, Vanker N, Diacon AH; A5312 Study Team. Early Bactericidal Activity of Different Isoniazid Doses for Drug-Resistant Tuberculosis (INHindsight): A Randomized, Open-Label Clinical Trial. Am J Respir Crit Care Med. 2020 Jun 1;201(11):1416-1424. doi: 10.1164/rccm.201910-1960OC.

Drugs

Indications