Clinical trial NCT02469298: Safety, Tolerability and Clinical Effect of Danirixin in Adults With Influenza
Official title: A Randomized, Double-blind, Placebo Controlled Study to Evaluate the Safety, Tolerability and Clinical Effect of Oral Danirixin (GSK1325756) in the Treatment of Healthy Adults With Acute, Uncomplicated Influenza (201682)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Virus Diseases
Keywords: acute, uncomplicated influenza
Danirixin
oseltamivir
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2015-06-11
Enrollment: 45
Sex: ALL
Minimum age (years): 18
Maximum age (years): 64
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

Primary outcomes:
measure: Number of Participants With Adverse Events (AE) and Serious Adverse Events (SAE)
timeFrame: Up to Day 28/withdrawal
measure: Change From Baseline in Hematology Parameters-Basophils, Eosinophils, Lymphocytes, Monocytes, Total Neutrophils (Total Absolute Neutrophil Count [Total ANC]), Platelet Count and White Blood Cell (WBC) Count
timeFrame: Baseline (Day 1) and up to Day 28/withdrawal
measure: Change From Baseline in Hematology Parameters- Hemoglobin
timeFrame: Baseline (Day 1) and up to Day 28/withdrawal
measure: Change From Baseline in Hematology Parameters- Hematocrit
timeFrame: Baseline (Day 1) and up to Day 28/withdrawal
measure: Change From Baseline in Hematology Parameters- Mean Corpuscle Hemoglobin (MCH)
timeFrame: Baseline (Day 1) and up to Day 28/withdrawal
measure: Change From Baseline in Hematology Parameters- Mean Corpuscle Volume (MCV)
timeFrame: Baseline (Day 1) and up to Day 28/withdrawal
measure: Change From Baseline in Hematology Parameters- Red Blood Cell (RBC) Count and Reticulocytes Count
timeFrame: Baseline (Day 1) and up to Day 28/withdrawal
measure: Change From Baseline in Clinical Chemistry Parameters- Albumin and Total Protein
timeFrame: Baseline (Day 1) and up to Day 28/withdrawal
measure: Change From Baseline in Clinical Chemistry- Alkaline Phosphatase (ALP), Alanine Amino Transferase (ALT), Aspartate Amino Transferase (AST) and Gamma Glutamyl Transferase (GGT)
timeFrame: Baseline (Day 1) and up to Day 28/withdrawal
measure: Change From Baseline in Clinical Chemistry Parameters- Direct Bilirubin, Total Bilirubin, Creatinine and Uric Acid
timeFrame: Baseline (Day 1) and up to Day 28/withdrawal
measure: Change From Baseline in Clinical Chemistry Parameters- Calcium, Carbon Dioxide (CO2) Content/ Bicarbonate, Glucose, Potassium, Sodium and Urea/Blood Urea Nitrogen (BUN)
timeFrame: Baseline (Day 1) and up to Day 28/withdrawal
measure: Change From Baseline in Urinalysis Parameters- Urine pH
timeFrame: Baseline (Day 1), Day 5 and Day 28/withdrawal
measure: Change From Baseline in Urinalysis Parameters- Urine Specific Gravity
timeFrame: Baseline (Day 1), Day 5 and Day 28/withdrawal
measure: Number of Participants With Maximum Post-baseline Urine Dipstick Abnormalities- Urine Occult Blood (Dipstick)
timeFrame: Up to Day 28/withdrawal
measure: Number of Participants With Maximum Post-baseline Urine Dipstick Abnormalities- Urine Glucose (Dipstick)
timeFrame: Up to Day 28/withdrawal
measure: Number of Participants With Maximum Post-baseline Urine Dipstick Abnormalities- Urine Protein (Dipstick)
timeFrame: Up to Day 28/withdrawal
measure: Change From Baseline in Vital Signs- Diastolic Blood Pressure (DBP) and Systolic Blood Pressure (SBP)
timeFrame: Baseline (Day 1) and up to Day 28/withdrawal
measure: Change From Baseline in Vital Signs- Heart Rate (HR)
timeFrame: Baseline (Day 1) and up to Day 28/withdrawal
measure: Change From Baseline in Vital Signs- Respiration Rate (RR)
timeFrame: Baseline (Day 1) and up to Day 28/withdrawal
measure: Change From Baseline in Vital Signs- Temperature
timeFrame: Baseline (Day 1) and up to Day 28/withdrawal
measure: Change From Baseline in Vital Signs- Percent Oxygen in Blood (POB)
timeFrame: Baseline (Day 1) and up to Day 28/withdrawal
measure: Change From Baseline in Electrocardiogram (ECG) Parameters
timeFrame: Baseline (Day 1) and up to Day 28/withdrawal
measure: Number of Participants With Disease Related Events (DREs) of Interest
timeFrame: Up to Day 28/withdrawal
measure: Number of Participants With DRE of Interest-associated Antibiotic Use
timeFrame: Up to Day 28/withdrawal
Secondary outcomes:
measure: Time to Resolution of Fever Over Time Post Initiation of Treatment
timeFrame: Up to Day 28/withdrawal
measure: Number of Afebrile Participants Over Time Post Initiation of Treatment
timeFrame: Up to Day 28/withdrawal
measure: Number of Participants Who Used Relief Medication
timeFrame: Up to Day 28/withdrawal
measure: Number of Hospital Admissions Due to Influenza Infection
timeFrame: Up to Day 28/withdrawal
measure: Change From Baseline in Influenza Viral Load as Measured by Quantitative Reverse Transcription-polymerase Chain Reaction (qRT-PCR) From Nasopharyngeal Swabs on Day 3, Day 5, Day 8 and Day 14
timeFrame: Baseline (Day 1) and Day 3, Day 5, Day 8 and Day 14
measure: Number of Participants With no Detectable Influenza Viral RNA by qRT-PCR From Nasopharyngeal Swabs on Baseline (Day 1), Day 3, Day 5, Day 8 and Day 14
timeFrame: Up to Day 14
measure: Total Dose of Relief Medication
timeFrame: Up to Day 28/withdrawal
measure: Change From Baseline in Influenza Viral Load as Measured by Quantitative Virus Culture From Nasopharyngeal Swabs on Day 3, Day 5, Day 8 and Day 14
timeFrame: Baseline (Day 1) and Day 3, Day 5, Day 8 and Day 14
measure: Number of Participants With no Detectable Influenza Viral RNA by Quantitative Virus Culture From Nasopharyngeal Swabs on Baseline (Day 1), Day 3, Day 5, Day 8 and Day 14
timeFrame: Up to Day 14
Other outcomes:
Locations:
city: Palmetto Bay
country: United States
facility: GSK Investigational Site
state: Florida
city: Blackfoot
country: United States
facility: GSK Investigational Site
state: Idaho
city: Oklahoma City
country: United States
facility: GSK Investigational Site
state: Oklahoma
city: Medford
country: United States
facility: GSK Investigational Site
state: Oregon
city: Marshfield
country: United States
facility: GSK Investigational Site
state: Wisconsin
city: Baulkham Hills
country: Australia
facility: GSK Investigational Site
state: New South Wales
city: Brookvale
country: Australia
facility: GSK Investigational Site
state: New South Wales
city: Hinchinbrook
country: Australia
facility: GSK Investigational Site
state: New South Wales
city: Liverpool
country: Australia
facility: GSK Investigational Site
state: New South Wales
city: Browns Plains
country: Australia
facility: GSK Investigational Site
state: Queensland
city: Everton Plaza
country: Australia
facility: GSK Investigational Site
state: Queensland
city: Kedron
country: Australia
facility: GSK Investigational Site
state: Queensland
city: Springfield
country: Australia
facility: GSK Investigational Site
state: Queensland
city: Glenelg East
country: Australia
facility: GSK Investigational Site
state: South Australia
city: Happy Valley
country: Australia
facility: GSK Investigational Site
state: South Australia
city: Berwick
country: Australia
facility: GSK Investigational Site
state: Victoria
city: Lynbrook
country: Australia
facility: GSK Investigational Site
state: Victoria
city: Noble Park
country: Australia
facility: GSK Investigational Site
state: Victoria
city: Pakenham
country: Australia
facility: GSK Investigational Site
state: Victoria
city: Tarneit
country: Australia
facility: GSK Investigational Site
state: Victoria
city: Applecross
country: Australia
facility: GSK Investigational Site
state: Western Australia
city: Baldivis
country: Australia
facility: GSK Investigational Site
state: Western Australia
city: Claremont
country: Australia
facility: GSK Investigational Site
state: Western Australia
city: Morley
country: Australia
facility: GSK Investigational Site
state: Western Australia
city: Yokine
country: Australia
facility: GSK Investigational Site
state: Western Australia
city: Port Elizabeth
country: South Africa
facility: GSK Investigational Site
state: Eastern Cape
city: Johannesburg
country: South Africa
facility: GSK Investigational Site
state: Gauteng
city: Johannesburg
country: South Africa
facility: GSK Investigational Site
state: Gauteng
city: Moloto South
country: South Africa
facility: GSK Investigational Site
state: Gauteng
city: Pretoria
country: South Africa
facility: GSK Investigational Site
state: Gauteng
city: Middelburg
country: South Africa
facility: GSK Investigational Site
state: Mpumalanga
city: Western Cape
country: South Africa
facility: GSK Investigational Site
state: Western Province
city: Reiger Park
country: South Africa
facility: GSK Investigational Site
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Roberts G, Chen S, Yates P, Madan A, Walker J, Washburn ML, Peat AJ, Soucie G, Kerwin E, Roy-Ghanta S. Randomized, Double-Blind, Placebo-Controlled Study of the Safety, Tolerability, and Clinical Effect of Danirixin in Adults With Acute, Uncomplicated Influenza. Open Forum Infect Dis. 2019 Apr 22;6(4):ofz072. doi: 10.1093/ofid/ofz072. eCollection 2019 Apr.