A phase I study investigating local tolerability and pharmacokinetics of Isoniazid (INH) inhalation by wet nebulization in patients with tuberculosis

To halt the global tuberculosis (TB) crisis, and particular the ongoing threat
of drug-resistant TB (DR-TB), it is essential to reduce transmission. This
could be done by shortening the period that patients with pulmonary TB secrete
viable bacilli, and are therefore contagious to others, by prompt initiation of
effective treatment. Pulmonary administration of anti-TB drugs might play an
important role since it yields higher local concentrations and lower systemic
concentrations compared to systemic (oral or parenteral) administration.
Isoniazid (INH) has very high bactericidal activity and is one of the most
effective drugs in the treatment of TB. Although the occurrence of mutations
leading to resistance to INH at systemic concentrations has hindered the use of
this drug, INH can still be effective when administered in a high concentration
at the site of infection even in case of drug resistance. This cannot easily be
achieved by oral dosing because of the associated risk of systemic toxicity.
However, pulmonary administration of INH may be a solution. The concept of
inhalable antimicrobials is not new; for example it is a well-established
therapy for the treatment of Pseudomonas aeruginosa infection in cystic
fibrosis patients. INH has been used by inhalation before in patients with TB
but only up to a dose of 200 mg/day. In this protocol, we will perform a local
tolerability and pharmacokinetic study of higher doses of INH inhalations by
wet nebulization in patients with TB. We hypothesize that single doses up to
1200 mg INH are safe.
In future studies we want to demonstrate that high intrapulmonary
concentrations enhance the initial reduction of the bacterial load in both
drug-susceptible TB (DS-TB) as well as TB with reduced susceptibility to INH.
If proven, this novel inhalation-based approach may lead to a massive decline
in further spread of (drug resistant) TB.

This study has been transitioned to CTIS with ID 2024-517793-25-00 check the CTIS register for the current data.

The primary objective of this study is to investigate the local tolerability of
isoniazid inhalation by wet nebulization at ascending dosages. Secondary
objective is systemic pharmacokinetics of inhaled isoniazid compared to
intravenous dose administration.

multicenter, ascending dose tolerability study Participants will receive one
intravenous dose of 300 mg INH and three inhaled doses of INH by using an
e-Flow nebulizer in ascending order (200 mg, 600 mg and 1200 mg) with at least
48 hours and maximal 7 days in between doses. Before each INH administration,
an indwelling venous cannula will be inserted and before and after each
administration, serum samples will be collected for pharmacokinetic analysis (6
after IV administration and 12 to 13 after every inhalation administration). To
investigate local tolerability, lung function tests will be performed once
before and twice after inhalation of INH and the occurrence of adverse events
will be scored. After every inhalation dose the study team will decide on
escalation to the next dose step whereby a drop of forced expiratory volume in
the first second (FEV1) of >15 % is considered critical and any reported
adverse events will be evaluated.

All participants receive in sequence one intravenous dose of isoniazide 300 mg
and three inhaled dosies isoniazide inhaled via e-Flow nebulizer in increasing
dosing (200 mg, 600 mg and 1200 mg)

Patients with DS-TB receive INH as part of usual care and this will temporarily
be replaced by levofloxacin during the study period in order not to interfere
with the intervention (this is not applicable for other forms of TB). From INH
resistant TB (Hr-TB) it is known that this replacement does not impact on the
efficacy of the treatment or its duration. An electrocardiogram will be
performed before and after initiation of levofloxacin, because of the potential
risk of Qtc prolongation.
There is no benefit with participation in the study. Taking part in the study
takes extra time and the measurements such as spirometry and drawing of
bloodsamples may give slight inconvenience. Participants may also experience
adverse effects of isoniazid inhalations or levofloxacin tablets. Common
adverse effects reported with administration of aerosolized antibiotics include
wheezing, haemoptysis, and dyspnoea.