Safety, Tolerability and Clinical Effect of Danirixin in Adults With Influenza
Condition: Virus Diseases
MeSH terms: Influenza, Human; Virus Diseases
Intervention: GSK1325756 (Danirixin); Placebo To Match GSK1325756; Oseltamivir Phosphate; Placebo To Match Oseltamivir Phosphate
Intervention description: It will be supplied as capsule shaped white film coated tablet containing 75 mg GSK1325756 for oral use; It will be supplied as capsule shaped white film coated placebo tablet for oral use; It will be supplied as size 0 Swedish Orange capsule containing 75 mg Oseltamivir phosphate and overfill of pre-gelatinized starch for oral use; It will be supplied as size 0 Swedish Orange capsule containing pre-gelatinized starch and magnesium stearate for oral use
Intervention MeSH terms: Oseltamivir
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 45.0
Sex: All
Minimum age: 18 Years
Maximum age: 64 Years
Healthy volunteers: No
Keywords: acute, uncomplicated influenza; Danirixin; oseltamivir

Summary:

      Study 201682 is a Phase IIa, randomized, double blind, placebo-controlled four arm outpatient
      study evaluating the safety, tolerability and clinical effect of danirixin or danirixin +
      oseltamivir combination in comparison to placebo or oseltamivir twice daily for 5 days in
      otherwise healthy adults with laboratory confirmed influenza infection. Danirixin is a
      selective and reversible C-X-C Chemokine Receptor 2 (CXCR2) antagonist that inhibits
      neutrophil transmigration and activation to areas of inflammation. The study endpoints are
      intended to test the hypothesis that inhibition of neutrophil activation by approximately
      50-60% (as previously measured by cluster of differentiation [CD11b] expression in response
      to chemokine [C-X-C motif] ligand 1 [CXCL1] stimulation ex vivo in human studies) will not
      impact safety parameters or worsen clinical manifestations of disease, disease-related events
      of interest, or viral load, and may possibly improve these parameters when administered
      within 48 hours of symptom onset. The aim of this exploratory study is to obtain data on the
      safety, tolerability and clinical effect of GSK1325756 (danirixin [DNX]) alone or in
      combination with oseltamivir (OSV) in otherwise healthy adults with acute, uncomplicated
      influenza prior to future evaluation in hospitalized patients with complicated influenza. The
      primary objective is to assess safety and tolerability of DNX with and without a
      neuraminidase inhibitor through the evaluation of AEs, SAEs, clinical laboratory tests, vital
      signs, and electrocardiogram (ECG) parameters. Safety assessments will also include an
      assessment of disease related events (DREs) of interest and associated antibiotic use. The
      Influenza Intensity and Impact Questionnaire (FluiiQ™) will be used in the study to document
      patient reported outcomes (PROs). The screening visit in Australia will be composed of a
      pre-screen for influenza infection with an influenza rapid antigen test followed by a screen
      for the remaining eligibility criteria for those subjects with a positive result on the
      influenza rapid antigen test. FluiiQ is trademark owned by Measured Solutions for Health
      Private Limited.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Between 18 and 64 years of age inclusive, at the time of signing the informed consent;

          -  Onset of influenza-like illness symptoms within 48 hours prior to study enrollment.
             Onset of symptoms is defined as the time when the subject's temperature was measured
             as elevated (>=38.0°C [>=100.4°F]) OR the time when the subject first experienced at
             least one symptom (cough, sore throat, nasal congestion, headache, feeling feverish,
             body aches and pains, or fatigue);

          -  Subjects have an oral temperature >=38.0°C (>=100.4°F) at screening visit or history
             of feeling feverish within the 24 hours prior to screening visit;

          -  At least one respiratory symptom (cough, sore throat, nasal congestion) and at least
             one systemic symptom (headache, body aches and pain, fatigue) due to influenza
             infection;

          -  A positive influenza rapid antigen test;

          -  Body weight >60 Kilogram (kg) for men and >45 kg for women; and Body Mass Index (BMI)
             between 19 to 35 kilogram per meters squared (kg/m^2), inclusive;

          -  Male or Female subjects could be eligible if :

        Male subjects with female partners of child-bearing potential must comply with the
        following contraception requirements from the time of first dose of study medication until
        at least 36 hours (five half-lives) of study medication after the last dose of study
        medication:

        Vasectomy with documentation of azoospermia; Male condom plus partner use of one of the
        following contraceptive options: Contraceptive subdermal implant; Intrauterine device or
        intrauterine system; Oral Contraceptive, either combined or progestogen alone; Injectable
        progestogen; Contraceptive vaginal ring ; Percutaneous contraceptive patches; This is an
        all-inclusive list of those methods that meet the following GlaxoSmithKline (GSK)
        definition of highly effective: having a failure rate of less than 1% per year when used
        consistently and correctly and, when applicable, in accordance with the product label. For
        non-product methods (e.g., male sterility), the investigator determines what is consistent
        and correct use. The GSK definition is based on the definition provided by the
        International Conference on Harmonisation (ICH). The investigator is responsible for
        ensuring that subjects understand how to properly use these methods of contraception;

          -  Female subject: is eligible to participate if she is not pregnant (as confirmed by a
             negative urine human chorionic gonadotrophin [hCG] test), not lactating, and at least
             one of the following conditions applies

        Non-reproductive potential defined as:

        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; 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). 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.

        Reproductive potential agrees to follow one of the options listed below in the GSK Modified
        List of Highly Effective Methods for Avoiding Pregnancy in Females of Reproductive
        Potential (FRP) requirements from the time of screening, during dosing, and until at least
        36 hrs after the last dose of study medication and completion of the follow-up visit.

        GSK List of Highly Effective Methods for Avoiding Pregnancy in Females of Reproductive
        Potential (FRP) meeting GSK criteria of highly effective: having a failure rate of less
        than 1% per year when used consistently and correctly and, when applicable, in accordance
        with the product label. This list does not apply to FRP with same sex partners, when this
        is their preferred and usual lifestyle or for subjects who are and will continue to be
        abstinent from penilevaginal intercourse on a long term and persistent basis.

        Contraceptive subdermal implant; Intrauterine device or intrauterine system; Combined
        estrogen and progestogen oral contraceptive; Injectable progestogen; Contraceptive vaginal
        ring; Percutaneous contraceptive patches; Male partner sterilization with documentation of
        azoospermia prior to the female subject's entry into the study, and this male is the sole
        partner for that subject.

        These allowed methods of contraception are only effective when used consistently, correctly
        and in accordance with the product label. 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.

        Exclusion Criteria:

        - Subject defined as being at high risk of complications from influenza infection according
        to the World Health Organization (WHO) Guidelines for Pharmacological Management of
        Pandemic Influenza A (H1N1) and other Influenza Viruses: Pregnant women; Persons of any age
        with chronic pulmonary disease (e.g. Mild persistent, Moderate or severe asthma, Chronic
        Obstruction Pulmonary Disease [COPD], cystic fibrosis, bronchiectasis); Persons of any age
        with chronic cardiac disease (e.g. congestive cardiac failure);

          -  Persons with metabolic disorders (e.g. diabetes); Persons with chronic renal disease,
             chronic hepatic disease, certain neurological conditions (including neuromuscular,
             neurocognitive and seizure disorders, but not including autism spectrum disorders);
             Hemoglobinopathies, or immunosuppression, whether due to primary immunosuppressive
             conditions, such as Human Immunodeficiency Virus (HIV) infection, or secondary
             conditions, such as immunosuppressive medication or malignancy;

          -  Subjects in whom treatment with an influenza antiviral is considered essential;

          -  Severity of illness requiring or anticipated to require in-hospital care;

          -  Pulse Oximetry levels <92% (at rest on room air) at screening or requirement for
             supplemental oxygen;

          -  Any complication of respiratory tract infection, signs of severe or progressive
             disease, or worsening of any pre-existing medical condition at the time of enrollment,
             that, in the opinion of the investigator, would place the subject at an unreasonably
             increased risk of participation in this study;

          -  Suspicion or confirmation of bacterial infection (e.g. otitis media, sinusitis,
             bronchitis, focal pneumonia) or who are requiring oral or systemic antibiotics within
             one week before enrollment;

          -  Women who are pregnant as determined by a positive urine human chorionic gonadotrophin
             (hCG) test prior to dosing or women who are breastfeeding;

          -  Current or chronic documented history of liver disease (including Hepatitis A, B, or
             C), or known hepatic or biliary abnormalities (with the exception of Gilbert's
             syndrome or asymptomatic gallstones); In this case "documented" refers to the outcome
             of the investigator's/designee's review of the subject's medical history for study
             eligibility, as obtained via a verbal interview with the subject or from the subject's
             medical records). In questionable cases the subject cannot be enrolled;

          -  Corrected QT interval (QTc) >450 millisecond (msec) or QTc >480 msec in subjects with
             Bundle Branch Block.

          -  Subjects currently using or expected to use: oral or injectable Cytochrome P450 3A4
             (CYP3A4) or Breast Cancer Resistance Protein (BCRP) substrates with a narrow
             therapeutic index, or oral or systemic glucocorticoids during the study period;
             Antacids can be used but should not be taken for at least 3 hours preceding and 2
             hours after administration of study drug; proton pump inhibitors and histamine
             H2-receptor antagonists are prohibited from the screening visit until 12 hours after
             completion of the final dose of study treatment.

          -  Subjects who have taken an approved or investigational anti-influenza medication
             (e.g., oseltamivir, zanamivir, peramivir, laninamivir, amantadine, rimantidine,
             ribavirin) within the past 4 weeks before enrollment;

          -  Subjects who received the live attenuated influenza virus vaccine within the past 21
             days;

          -  Subjects treated with systemic steroids or immunosuppressants within 2 weeks of study
             start.

          -  History of alcohol/drug abuse within 6 months of the study start;

          -  Consumption of >3 alcoholic units for males and females over the past 24 hours. One
             unit is equivalent to 8 grams of alcohol: a half-pint (~240 milliliter [mL]) of beer;
             1 glass (125 mL) of wine or 1 (25 mL) measure of spirits.

          -  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.

          -  Where participation in the study would result in donation of blood or blood products
             in excess of 500 mL within a 56 day period;

          -  The subject has participated in a clinical trial and has received 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);

          -  Exposure to more than four investigational medicinal products within 12 months prior
             to the first dosing day.