A Phase I Study Investigating the Local Tolerability and Pharmacokinetics of Isoniazid (INH) Inhalation by Wet Nebulization in Patients With Tuberculosis (INHalation-01)

Rationale:

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, a local tolerability and pharmacokinetic study of higher doses of INH inhalations will be performed by wet nebulization in patients with TB. The hypothesis is that single doses up to 1200 mg INH are safe.

Future studies will 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.

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

Study design: single-center, single ascending dose tolerability study.

Participants will receive one intravenous dose of 300 mg INH and three inhaled doses of INH by using an eFlow nebulizer in ascending order (200 mg, 600 mg and 1200 mg) with at least 48 hours and maximum seven 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. 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 next to specific other adverse events.

Study population: 8 adult patients with tuberculosis with known drug susceptibility

Main study parameters/endpoints: For the local tolerability, spirometry will be performed and adverse events will be recorded. The following serum pharmacokinetic parameters will be calculated: AUC24 (area under the concentration-time curve over 24 hours), Cmax (maximum serum concentration), Tmax (time to maximum serum concentration), actual dose inhaled.

Nature and extent of the burden and risks associated with participation, benefit and group relatedness: 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-interval 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 blood samples 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. After each inhalation dose the study team will determine if a drop of FEV1 > 15% or relevant adverse events have occurred and whether it is safe for the participant to move on to a higher dose. Halfway through the study a report will be made describing the withdrawals, spirometry results and the cumulative adverse events seen for judgement by the study team. Stop criteria are defined for premature ending of the study at thi