A Phase I/II randomized trial of H56:IC31 vaccination and adjunctive cyclooxygenase-2-inhibitor treatment in tuberculosis patients

Host-directed-therapy strategies are warranted to fight tuberculosis. Here we assess the safety and immunogenicity of adjunctive vaccination with the H56:IC31 candidate and cyclooxygenase-2-inhibitor treatment (etoricoxib) in pulmonary and extra-pulmonary tuberculosis patients in a randomized open-label phase I/II clinical trial (TBCOX2, NCT02503839). A total of 222 patients were screened, 51 enrolled and randomized; 13 in the etoricoxib-group, 14 in the H56:IC31-group, 12 in the etoricoxib+H56:IC31-group and 12 controls. Three Serious Adverse Events were reported in the etoricoxib-groups; two urticarial rash and one possible disease progression, no Serious Adverse Events were vaccine related. H56:IC31 induces robust expansion of antigen-specific T-cells analyzed by fluorospot and flow cytometry, and higher proportion of seroconversions. Etoricoxib reduced H56:IC31-induced T-cell responses. Here, we show the first clinical data that H56:IC31 vaccination is safe and immunogenic in tuberculosis patients, supporting further studies of H56:IC31 as a host-directed-therapy strategy. Although etoricoxib appears safe, our data do not support therapy with adjunctive cyclooxygenase-2-inhibitors.


Reporting for specific materials, systems and methods
We require information from authors about some types of materials, experimental systems and methods used in many studies. Here, indicate whether each material, system or method listed is relevant to your study. If you are not sure if a list item applies to your research, read the appropriate section before selecting a response. No sample size calculation was done as the TBCOX2 study is an exploratory phase I/II safety study and the first of its kind. Although immunogenicity was not the primary objective of this trial, the target for inclusion, 40 patients, 10 in each study group, was based on results in Mtb-uninfected adults where H56:IC31 elicited significant differences in immunogenicity with 10 patients per group (Luabeya AK et al. Vaccine 2015;33(33): 4130-40).
All patients of the randomised set with at least one valid measurement of any of the outcome variables after baseline will be included in the full analysis set (FAS) We will perform intention to treat (ITT) analysis in the FAS, meaning that we treat participants as they were randomized and independent of adherence. Hierarchal ranking of primary and secondary priority outcomes are presented in Supplementary (Appendix) Table 1-3 and secondary and tertiary priority outcomes are presented in Supplementary Figures 2-7. Formal testing were performed on the primary priority outcomes only.
Since this is a phase 1 study with limited clinical material available the analyses were performed once with no replication of the experiments.
In some experiments the analyses (Flurospot) were performed in triplicates to ensure validity. However, the laboratory protocols were validated before the experiments and Standard Operating Procedures (SOP) protocols were performed. We have also written a detailed clinical trial protocol, provide detailed protocols of the laboratory experiments and precisely predefined all statistical analyses in a statistical analysis plan, making replication of the study feasible.
Participants were enrolled at tuberculosis diagnosis and by a computer-generated sequential allocation built into the eCRF software (ViedocTM, Viedoc Technologies AB), randomized to either; etoricoxib, H56:IC31, standard TB treatment only (controls), or etoricoxib +H56:IC31. The final treatment allocation to the four study groups was a 1:1:1:1 ratio with a randomization allocation ratio of first 2:2:1:0 and a subsequent randomization allocation ratio of 0:0:1:2. Prior to the second allocation that included the etoricoxib+H56:IC31-group, an interim safety analysis was performed when the last patient in the 2:2:1:0 groups had reached study day 98, according to protocol. This is a first-in human open Phase I study of Tuberculosis patients with active disease receiving 2 various intervention (vaccine and a drug). We decided to design this as an open study without blinding both due to the potential safety issue for the patients with ongoing disease and the complexity of the study design. The tuberculosis patients were included in the study at the study sites (Oslo University Hospital and Haukeland University Hospital) from November 2015 to December 2018 and followed at regular visits in the hospital wards or at the hospitals out-patients clinics with evaluation of tuberculosis disease and safety of the intervention at days 7, 14, 28, 56, 84, 98, 140, 154, 182, 210, and 238. Blood was drawn during the visits and transported immediately to the hospital research laboratory for further processing. Clinical data was obtained by the study nurse or study doctor from questioning and examining the patients during visits or from the hospital medical records and registrated in the eCRF.
The primary outcome was safety of etoricoxib and H56:IC31 alone or combined in patients that received at least one dose of etoricoxib and/or one dose of H56:IC31. Safety was assessed by the occurrence of AEs, SAEs and SUSARs. These outcomes, including incidence of solicited and unsolicited local (injection site) and systemic AE reported for 14 days after vaccination, were assessed by medical trial investigators on and included questioning of symptoms, clinical examination, radiology, microbiology and routine blood sampling. All AEs/SAEs were coded according to the Medical Dictionary for Regulatory Activities (MedDRA) coding system (https:// www.meddra.org/) and evaluated for its relationship to the study interventions and severity. As participants had TB at baseline, a deterioration in the FDA toxicity grading scale (mild, moderate, severe; Supplementary Data pp. 3-5) was registered as AEs/SAEs. The secondary outcomes were tuberculosis specific cellular (cytokine producing CD4+ T cellls) and humoral (H56 IgG) immune responses defined and priority ranked a priori depending on the hypothesized impact of the interventions an in line with comparable vaccine studies (described in detail in Supplementary Data pp. 6-7). The secondary outcome measures were assessed by Fluorescence IFN"/IL-2 immuno-spot (Fluorospot) assay and Whole blood intracellular cytokine staining (WB-ICS) flow cytometry performed on blood cells and by ELISA quantification of anti-H56 IgG in serum.