Study design and participants

The TBCOX2 study was designed as a randomized, open label, controlled, four group (allocation ratio 1:1:1:1), multi-center (Oslo University Hospital and Haukeland University Hospital), safety and explorative phase I/II clinical trial (Fig. 5). Initially, patients aged ≥18 years with confirmed DS-pulmonary TB (GeneXpert MTB/RIF®) without comorbidities (including a negative HIV test), and willing to participate (written informed consent), were included. Due to slow inclusion, a protocol amendment was approved (17.10.2016, Regional Ethics Committee) to include confirmed extra-pulmonary TB (see ^{Supplementary Information, pp. 1–2} for inclusion/exclusion criteria). All participants received standard TB treatment consisting of rifampicin/isoniazid/pyrazinamide/ethambutol as initial two months treatment and thereafter rifampicin/isoniazid for a total of 182 days (or longer in settings of single-drug resistance, drug intolerance, or inadequate treatment response).

The TBCOX2 study was designed as a randomized, open label, controlled, four group multi-center phase I/II clinical trial with a final allocation ratio 1:1:1:1 to adjunctive interventions. Target number of participants was 10 per arm for the full analysis set (FAS). The first allocation ratio was 2:2:1:0 to (i) etoricoxib, (ii) H56:IC31 and (iii) controls. The second allocation, initiated following a passed interim analysis of safety (when the last participant in the first allocation had reached study day 98), had a ratio of 0:0:1:2 to (iii) controls and (iv) etoricoxib+H56:IC31. Oral administration (p.o.) of etoricoxib 120 mg was initiated within five days of initiation of standard tuberculosis (TB) treatment (182 days), and continued for 140 days. H56:IC31 5 μg intramuscular (i.m) was administered at day 84 and 140. Samples for immunogenicity analyses were harvested at denoted study days.

The protocol was approved by the Regional Ethics Committee (TBCOX2, REK SØ 2015/692) and The Norwegian Medicines Agency (EudraCT Number 2014-004986-26). The study was done in compliance with the Declaration of Helsinki principles and in accordance with the International Conference on Harmonisation’s Good Clinical Practices guidelines, and is registered in ClinicalTrials.gov (TBCOX2, {"type":"clinical-trial","attrs":{"text":"NCT02503839","term_id":"NCT02503839"}}NCT02503839).