A Phase II, global, randomized study to evaluate the efficacy and safety of Danirixin (GSK1325756) co-administered with a standard-of-care antiviral (oseltamivir), in the treatment of adults hospitalized with influenza (study 201023, DAHLIA)

Seasonal influenza affects 5-10% of the world*s population annually, causing
3-5 million severe infections and 250,000 to 500,000 deaths. While early
therapy with antivirals decreases severity and duration of symptoms of
influenza, there are no drugs that have demonstrated clinical efficacy in
randomized clinical trials in this population. Current treatment guidelines for
hospitalized influenza recommend neuraminidase inhibitors as standard of care
therapy. Following infection by a respiratory virus, neutrophils are the most
abundant cells that migrate to the lungs. Influenza studies in animals have
demonstrated that therapeutic treatment with the combination of a C-X-C
chemokine receptor 2 (CXCR2) antagonist and a neuraminidase inhibitor reduced
lung neutrophils and showed trends for improvements in clinical scores, lung
function and pathology with no evidence of worsening outcomes, including viral
load.
This study is designed to investigate an anti-inflammatory agent, danirixin
co-administered with an antiviral treatment oseltamivir for treatment of
patients hospitalized for influenza infection and will be the first study to
evaluate the efficacy and safety of intravenous danirixin in this population.

Primary:
To assess the efficacy of treatment with IV danirixin twice daily given with
oral oseltamivir compared to oral oseltamivir twice daily on time to clinical
response (TTCR)
Secondary:
Time to respiratory response (TTRR), clinical measures of influenza illness
(see protocol page 10 for details), safety and tolerability, pharmacokinetics
(PK).

Phase 2, randomized, double-blind, placebo-controlled 3-arm study in adults.
Randomization to
* IV DNX 15 mg b.i.d. (infusion 250 ml 1 hour) co-administered with open-label
oral 75 mg oseltamivir b.i.d.
* IV DNX 50 mg b.i.d. (infusion 250 ml 1 hour) co-administered with open-label
oral 75 mg oseltamivir b.i.d.
* IV placebo to DNX b.i.d. (infusion 250 ml 1 hour) co-administered with
open-label oral 75 mg oseltamivir b.i.d.
Treatment duration 5 days. Oseltamivir may be continued beyond day 5.
Follow-up 45 days.
Independent Data Monitoring Committee.
300 participants.

Treatment with oseltamivir plus danirixin or placebo to danirixin.

Risk: Adverse events of the study medication.
Burden:
Hospitalized subjects. After discharge up to 2 visits, up to 4 phone calls with
study team. Screening, treatment period (5 days), follow-up 45 days.
10 IV infusions (250 ml, 1 hour).
Physical examination: every day in hospital and every visit thereafter.
Blood draws 30-60 ml/day:
- safety 7 times,
- PK 3 days with 1 sample or in some patients 2 days with 1 and 1 day with 9
samples in 12 hours,
- biomarkers 5-8 times.
Pregnancy test: 3 times.
ECG: 3 times.
Chest X-ray: once.
Swab throat: at least 3 times.
Nasal fluid test: at least 5 times.
Pulmonary fluid test: at least 3 times.
Questionnaires: activities, signs and symptoms, ADL.
Optional: blood sample for pharmacogenetics.