Study to Evaluate the Efficacy and Safety of Danirixin Co-administered With Oseltamivir in the Treatment of Adults Hospitalized With Influenza
Condition: Virus Diseases
MeSH terms: Influenza, Human; Virus Diseases
Intervention: Danirixin 15 mg FBE; Danirixin 50 mg FBE; Placebo; Oseltamivir 75 mg
Intervention description: This intervention is available as a 50 mg FBE sterile lyophilized powder containing DNX (hydrobromide salt hemihydrate) equivalent to 50mg of free base along with Beta-cyclodextrin sulfobutylether, mannitol, citric acid and sodium hydroxide. The formulation is supplied as lyophilized powder/cake contained in a 30mL vial. Each vial is reconstituted with 9.5 mL water for injection and further diluted with saline for IV infusion to provide a dose of 15 mg FBE.; This intervention is available as a 50 mg FBE sterile lyophilized powder containing DNX (hydrobromide salt hemihydrate) equivalent to 50mg of free base along with Beta-cyclodextrin sulfobutylether, mannitol, citric acid and sodium hydroxide. The formulation is supplied as lyophilized powder/cake contained in a 30mL vial. Each vial is reconstituted with 9.5 mL water for injection and further diluted with saline for IV infusion.; No vials of placebo to match IV DNX will be provided. A normal saline solution of matched volume will be prepared by unblinded personnel at the site to act as a placebo to DNX. Clear solution of placebo will be administered as IV infusion.; Oseltamivir (Tamiflu - manufactured by Roche) formulation is available as 75 mg Capsule and as powder for oral suspension. After constitution with 55 mL of water, each bottle delivers a usable volume of 60 mL of oral suspension equivalent to 360 mg oseltamivir base (6 mg/mL). No oseltamivir capsules or powder for oral suspension will be provided. Sites will source the OSV locally and it will be provided open-label.
Intervention MeSH terms: Oseltamivir
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 10.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Anti-inflammatory; Danirixin; Influenza; Hospitalized patients

Summary:

      Danirixin (DNX) is a novel, selective, and reversible antagonist of the C-X-C chemokine
      receptor (CXCR) 2 and has been shown to decrease neutrophil transmigration and activation to
      areas of inflammation. An intravenous (IV) formulation of DNX hydrobromide (HBr) is being
      developed as an anti-inflammatory agent for treatment of adults hospitalized with influenza
      (IFV). 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 IFV recommend
      neuraminidase inhibitors as standard of care therapy. IFV studies in animals have
      demonstrated that therapeutic treatment with the combination of a 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 Phase 2, randomized, double-blind (for IV DNX), placebo-controlled
      (for IV DNX) 3-arm study will be the first study to determine the efficacy and safety of IV
      DNX when co-administered (in all groups) with standard of care antiviral treatment
      (open-label oral oseltamivir [OSV]) in subjects hospitalized with IFV. The primary objective
      of the study is to assess the efficacy of treatment with IV DNX twice daily given with oral
      OSV compared to oral OSV twice daily on time to clinical response (TTCR). In this study,
      subjects will be randomized in a 2:2:1 ratio to 15 milligram (mg) free base equivalent (FBE)
      IV DNX, 50 mg FBE IV DNX, or matching placebo twice daily. All subjects will also receive
      open-label 75 mg oral OSV, twice daily (given as standard of care). The study treatment
      duration will be for up to 5 days. The investigator may elect to continue treatment with OSV
      after 5 days of study treatment. Follow up will continue until Day 45 for all subjects. The
      study will begin with enhanced safety monitoring in sentinel cohorts, leading to stepwise
      enrollment of subjects. Subjects will be enrolled based on increasing levels of renal
      impairment, and less severe hospitalized subjects will be enrolled prior to enrollment of
      critically ill subjects, as this is the first study conducted in the hospitalized population
      with severe IFV. Approximately 300 subjects are targeted to be enrolled in the study.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Adults 18 years (as per local laws) of age and older at the time of signing the
             informed consent.

          -  Presence of fever (>=38.0 degree Celsius [>=100.4 degree Fahrenheit] by any route) at
             Baseline (enrollment) or history of fever/feverishness during the 48 hours prior.

          -  Oxygen (O2) saturation <95% on room air by trans-cutaneous method OR need for any
             supplemental oxygenation (non-invasive ventilation, facemask, facetent, nasal canula,
             etc) or ventilator support (mechanical ventilation, bi-level positive airway pressure
             [BIPAP], continuous positive airway pressure [CPAP]) or increase in oxygen
             supplementation requirement of >=2 liters for subjects with chronic oxygen dependency.
             For those subjects with a history of chronic hypoxia (without supplemental oxygen), an
             oxygen saturation of at least 3% below the subject's historical baseline oxygen
             saturation.

          -  And at least 2 out of the following 3: respiratory rate >24 breaths per minute. For
             those subjects who require ventilator support or oxygen supplementation, this
             requirement is waived; heart rate >100 beats per minute; SBP <90 millimeters of
             mercury (mm Hg).

          -  Severity of symptoms at enrollment: 1) Less severe hospitalized subjects are those who
             (but not limited to): are hemodynamically stable; may require oxygenation with
             facemask, facetent, nasal canula, etc; may or may not have radiological signs of lower
             respiratory tract disease; or have exacerbation of underlying chronic disease,
             including asthma, chronic obstructive pulmonary disease (COPD), or other
             cardiovascular conditions not leading to hemodynamic compromise. 2) Critically ill
             hospitalized subjects are those who (but not limited to): require CPAP, BIPAP,
             mechanical ventilation; have hemodynamic instability (with or without pressor
             support); or have central nervous system involvement (example encephalopathy,
             encephalitis).

          -  Presence of influenza that in the Investigator's judgment requires hospitalization for
             treatment and supportive care

          -  Onset of influenza symptoms within 6 days prior to study enrolment. Symptoms may
             include cough, dyspnea, sore throat, feverishness, myalgias, headache, nasal symptoms
             (rhinorrhea, congestion), fatigue, diarrhea, nausea and vomiting.

          -  A positive result from a rapid influenza test (provided by GlaxoSmithKline [GSK]) or
             other available, local laboratory diagnostic test

          -  Baseline renal criteria as follows: 1) Sentinel Cohorts: Normal renal function:
             Baseline creatinine clearance within normal reference ranges (>=80 milliliter per
             minute (mL/min) for the first approximately 30 subjects enrolled; Mild renal
             impairment: Baseline creatinine clearance of 50-79 mL/min for the next approximately
             10 subjects enrolled into the sentinel cohort; Moderate renal impairment: Baseline
             creatinine clearance of 30-49 mL/min for the next approximately 10 subjects enrolled
             into the sentinel cohort. 2) Post-sentinel cohorts: Normal renal function, mild or
             moderate renal impairment: creatinine clearance >30mL/min.

          -  Baseline Liver Function Tests: Subjects will be included if:

               1. ALT is <=5 times the upper limit of normal (ULN) and bilirubin is <=2 times the
                  ULN

               2. ALT is >5 but <=8 times the ULN and bilirubin is < 1.5 times the ULN

          -  Male or Female subjects could be eligible if: Male subjects with female partners of
             child bearing potential must comply with the pre-specified highly effective
             contraception requirements from the time of first dose of study medication until at
             least 36 hours (five half-lives) after the last dose of study medication. 1) Vasectomy
             with documentation of azoospermia 2) Male condom plus partner use of one of the
             contraceptive options below: Contraceptive subdermal implant; Intrauterine device or
             intrauterine system; Oral Contraceptive, either combined or progestogen alone;
             Injectable progestogen; Contraceptive vaginal ring; Percutaneous contraceptive patches

          -  For females, non-reproductive potential defined as: 1) Pre-menopausal females with one
             of the following: Documented tubal ligation; Documented hysteroscopic tubal occlusion
             procedure with follow-up confirmation of bilateral tubal occlusion; Hysterectomy;
             Documented Bilateral Oophorectomy 2) Postmenopausal defined as 12 months of
             spontaneous amenorrhea [in questionable cases a blood sample with simultaneous
             follicle stimulating hormone (FSH) and estradiol levels consistent with menopause
             (refer to laboratory reference ranges for confirmatory levels)]. Females on hormone
             replacement therapy (HRT) and whose menopausal status is in doubt will be required to
             use one of the highly effective contraception methods if they wish to continue their
             HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of
             post-menopausal status prior to study enrolment. 3) Reproductive potential and agrees
             to follow one of the options listed in the Modified List of Highly Effective Methods
             for Avoiding Pregnancy in Females of Reproductive Potential (FRP) from the first dose
             of study medication until at least 36 hours after the last dose of study medication
             and completion of the post treatment (PT) Day 3 visit. The investigator is responsible
             for ensuring that subjects understand how to properly use these methods of
             contraception.

          -  Subjects willing and able to give written informed consent to participate in the study
             and to adhere to the procedures stated in the protocol OR Legally acceptable
             representative (LAR) willing and able to give written informed consent on behalf of
             the subject to participate in the study for unconscious adults, and those incapable of
             consenting themselves due to their medical condition (e.g. too weak or debilitated,
             severe shortness of breath), due to literacy issues or included as permitted by local
             regulatory authorities, institutional review board (IRB)/independent ethics committee
             (IECs) or local laws.

          -  French subjects: In France, a subject will be eligible for inclusion in this study
             only if either affiliated to or a beneficiary of a social security category.

        Exclusion Criteria:

          -  Subjects who, in the opinion of the investigator, are not likely to survive the next
             48 hours beyond Baseline;

          -  Immunosuppression, whether due to primary immunosuppressive conditions, such as
             history of inherited immunodeficiency syndromes, human immunodeficiency virus (HIV)
             infection, or secondary conditions, such as immunosuppressive medication, stem cell or
             solid organ transplantation, or malignancy;

          -  Documented current liver disease (including Hepatitis A, B, or C), or known hepatic or
             biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic
             gallstones);

          -  Baseline Liver Function Tests: Subjects will be excluded if:

               1. ALT >8 times the ULN

               2. Bilirubin is >2 times the ULN

          -  Corrected QT Interval (QTc) Criteria: Corrected QT Interval using Bazette's formula
             (QTcB) or Corrected QT Interval using Fridericia forumula (QTcF) >480 millisecond
             (msec) or >500 msec with bundle branch block;

          -  For subjects enrolled in the sentinel cohorts: diabetes mellitus and chronic kidney
             disease;

          -  Subjects who require dialysis, or are on renal replacement therapies;

          -  Subjects who require extra corporeal membrane oxygenation (ECMO) at baseline (enrolled
             subjects who subsequently require ECMO may continue in the study)

          -  Women who are pregnant as determined by a positive human chorionic gonadotrophin (hCG)
             ultrasensitive test prior to dosing or women who are breastfeeding;

          -  Subjects who received other treatments for influenza including vitaglutam, umifenovir,
             and neuraminidase inhibitors (oseltamivir, zanamivir, peramivir) for more than 72
             hours during current acute illness;

          -  Subjects who received any immunoglobulins within 6 months of screening or planned
             administration of any of these products during the treatment period.

          -  Subjects treated with cytotoxic or immunosuppressive drugs within six months of study
             enrolment. Topical, intra-articularly injected, or inhaled glucocorticoids, topical
             calcineurin inhibitors or imiquimod are allowed.

          -  Known history of drug abuse within 6 months of study start.

          -  History of sensitivity to any of the study medications, or components thereof or a
             history of drug or other allergy that, in the opinion of the investigator or Medical
             Monitor, contraindicates their participation.

          -  Absolute neutrophil count <1.0 giga per Liter (Gi/L)

          -  Subjects who have participated in a clinical trial using an investigational product
             within the following time period prior to the first dosing day in the current study:
             30 days, 5 half-lives or twice the duration of the biological effect of the
             investigational product (whichever is longer).