Study to Evaluate the Efficacy and Safety of Danirixin Co-administered With Oseltamivir in the Treatment of Adults Hospitalized With Influenza

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Virus Diseases

Intervention / Treatment
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* Drug: Danirixin 15 mg FBE
* Drug: Danirixin 50 mg FBE
* Drug: Placebo
* Drug: Oseltamivir 75 mg


Participation Criteria
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Eligibility Criteria
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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: ALT is <=5 times the upper limit of normal (ULN) and bilirubin is <=2 times the ULN 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: ALT >8 times the ULN 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).

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Danirixin 15 mg FBE IV plus 75 mg oseltamivir<br>Subjects will receive double blind 15 mg FBE IV danirixin twice daily with open label 75 mg oral oseltamivir twice daily for 5 days. If a subject is discharged from the hospital in less than 5 days, treatment with IV DNX will be discontinued. | Drug: Danirixin 15 mg FBE<br>* 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.<br>Drug: Oseltamivir 75 mg<br>* 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.<br>|
| Experimental: Danirixin 50 mg FBE IV plus 75 mg oseltamivir<br>Subjects will receive double blind 50 mg FBE IV danirixin twice daily with 75 mg oral oseltamivir twice daily for 5 days. If a subject is discharged from the hospital in less than 5 days, treatment with IV DNX will be discontinued. | Drug: Danirixin 50 mg FBE<br>* 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.<br>Drug: Oseltamivir 75 mg<br>* 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.<br>|
| Placebo Comparator: Placebo of danirixin IV plus 75 mg oseltamivir<br>Subjects will receive double blind IV placebo of DNX twice daily with 75 mg oral oseltamivir twice daily for 5 days. If a subject is discharged from the hospital in less than 5 days, treatment with IV DNX will be discontinued. | Drug: Placebo<br>* 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.<br>Drug: Oseltamivir 75 mg<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Clinical Response (TTCR) | The clinical response was defined as Hospital discharge due to clinical improvement OR normalization of temperature; and oxygen saturation; and respiratory status/heart rate/systolic blood pressure (normalization of 2 out of these 3 parameters). The clinical response based on vital signs/ventilation status required 24-hour confirmation. Considering 2-hour assessment window, the response confirmation period was 22 hours. Kaplan Meier estimates for the median of TTCR was provided. One participant had vital sign resolution at Baseline and was counted as having a clinical response but was not included in the Kaplan Meier Estimates. Influenza Positive Population (IPP) Population comprised of all participants in the Intent to Treat Exposed (ITT-E) Population with influenza infection (positive influenza Polymerase Chain Reaction [PCR] or culture at any time point) confirmed by central lab testing. Only those participants with data available at the indicated time point were analyzed. | Up to 45 Days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Respiratory Response (TTRR) | Time to Respiratory Response was defined as meeting at least one of the following criteria, and maintained for 24 hours: return to pre-morbid oxygen requirement (participants with chronic oxygen use or ventilator support), or return to no requirement of supplemental oxygen, or respiratory rate <=24 per minute (without supplemental oxygen). Kaplan Meier estimates for the median of TTRR for each treatment group was provided. NA indicates data is not available. Due to limited data, no TTRR estimate could be calculated for any of the treatment groups. | Up to 45 Days | 
| Time to Absence of Fever | Time from first dose of treatment to time to afebrile status (<=36.6 degree celsius-axilla/temporal or <=37.2 degree celsius- oral, or <=37.7 degree celsius-rectal/core, tympanic) was to be evaluated. | Up to 45 Days | 
| Time to Improved Oxygen Saturation | Time from first dose of treatment to time of improved oxygen saturation was to be calculated. A participant with a history of chronic hypoxia (without supplemental oxygen) satisfied normalization criteria for oxygen saturation if the value (without supplemental oxygen) is <=2 percent from participant's historical oxygen saturation Baseline as recorded within 12 months prior to enrollment as documented in the participant's medical records. This requirement was to be waived for participants with a history of chronic supplemental oxygen requirement who had a Baseline oxygen saturation <95 percent with supplemental oxygen, within 12 months prior to enrollment as documented in the participant's medical records. | Up to 45 Days | 
| Time to Improved Heart Rate | Time from first dose of treatment to time of heart rate <=100 beats per minute was to be evaluated. | Up to 45 Days | 
| Time to Improved Systolic Blood Pressure (SBP) | Time from first dose of treatment to time of SBP at >=90 millimeters of mercury (mmHg) was to be evaluated. | Up to 45 Days | 
| Percentage of Participants With Clinical Response Over Time | The clinical response was defined as Hospital discharge due to clinical improvement OR normalization of temperature; and oxygen saturation; and respiratory status/heart rate/systolic blood pressure (normalization of 2 out of these 3 parameters). The clinical response based on vital signs/ventilation status required 24-hour confirmation. Considering 2-hour assessment window, the response confirmation period was 22 hours. Percentage of participants with positive clinical response are presented. | Up to 45 Days | 
| Percentage of Participants With Improved Respiratory Status Over Time | The Respiratory Response was defined as meeting at least one of the following criteria, and maintained for 24 hours: return to pre-morbid oxygen requirement (participants with chronic oxygen use or ventilator support), or return to no requirement of supplemental oxygen, or respiratory rate <=24 per minute (without supplemental oxygen). Percentage of participants with improved respiratory status has been presented. | Up to 45 Days | 
| Time to Improvement of Ventilation Status | Time to improvement of ventilation status was assessed by modality, frequencies and durations of invasive and non-invasive ventilator support, duration of oxygen supplementation. | Up to 45 Days | 
| Number of Days of Stay in the Intensive Care Unit (ICU) | Number of days of stay in the ICU over the treatment period and post treatment period was to be recorded. | Up to 45 Days | 
| Number of Participants Requiring ICU Admission and Readmission | Number of participants requiring ICU admission during treatment period and after post treatment was to be recorded. | Up to 45 Days | 
| Number of Days of Stay in the Hospital | Number of days of stay in the hospital over treatment period and post treatment period was to be recorded. | Up to 45 Days | 
| Number of Participants With Development of Septic Shock | Development of septic shock was to be assessed by occurrence of hypotension requiring vasopressive therapy and serum lactate level >2 millimeter (mm) after adequate fluid resuscitation. Number of participants with development of septic shock were planned to be presented. | Up to 45 Days | 
| Number of Participants Used Antibiotics for Complications of Influenza | Complications of influenza such as bacterial pneumonia, pneumothorax, pleural effusion, acute respiratory distress syndrome (ARDS), myositis, encephalitis, myocarditis, and associated antibiotic use was recorded. Number of participants who reqruied use of associated antibiotics for complications of influenza is presented. | Up to 45 Days | 
| Number of Participants With Improvement in Ordinal Scale of Clinical Efficacy Over Time | Number of participants with improvement in ordinal scale of clinical efficacy over time was to be assessed by: death, mechanical vent, in the ICU, non-ICU hospitalization, and hospital discharge. | Up to 45 Days | 
| Number of Participants With Any Non-serious Adverse Event (AE); Any Serious AE (SAE); Any AEs of Special Interest (AESIs) | An AE is any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. Any untoward event resulting in death, life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, congenital anomaly/birth defect, any other situation according to medical or scientific judgment that may not be immediately life-threatening or result in death or hospitalization but may jeopardize the participant or may require medical or surgical intervention or event associated with liver injury and impaired liver function were categorized as SAE. Participants who received any of the study treatment and had any AE or SAE or AESI were considered for analysis. Safety Population comprised of all participants who received at least 1 dose of study treatment. | Up to 45 Days | 
| Change From Baseline in Albumin and Total Protein | Blood samples were collected to evaluate albumin and total protein at indicated time points. Values at Day 1 were considered as Baseline values. Change from Baseline at each visit was calculated by subtracting Baseline value from post-dose visit value. Only those participants with data available at the specified time points were analyzed (represented by n=X in the category titles). NA indicates data is not available. | Baseline and up to 45 days | 
| Change From Baseline in White Blood Cell Count (WBC) and Absolute Neutrophil Count (ANC) | Blood samples were collected to evaluate WBC and ANC at indicated time points. Values at Day 1 were considered as Baseline values. Change from Baseline at each visit was calculated by subtracting Baseline value from post-dose visit value. Only those participants with data available at the specified time points were analyzed (represented by n=X in the category titles). NA indicates data is not available. | Baseline and up to 45 days | 
| Change From Baseline in Total Bilirubin (T. Bilirubin), Creatinine and Direct Bilirubin (D. Bilirubin) | Blood samples were collected to evaluate T. Bilirubin, creatinine and D. Bilirubin at indicated time points. Values at Day 1 were considered as Baseline values. Change from Baseline at each visit was calculated by subtracting Baseline value from post-dose visit value. Only those participants with data available at the specified time points were analyzed (represented by n=X in the category titles). NA indicates data is not available. | Baseline and up to 45 days | 
| Change From Baseline in Alanine Amino Transferase (ALT), Aspartate Amino Transferase (AST) and Alkaline Phosphatase (ALP) | Blood samples were collected to evaluate ALT, AST and ALP at indicated time points. Values at Day 1 were considered as Baseline values. Change from Baseline at each visit was calculated by subtracting Baseline value from post-dose visit value. Only those participants with data available at the specified time points were analyzed (represented by n=X in the category titles). NA indicates data is not available. | Baseline and up to 45 days | 
| Number of Participants With Clinically Significant Abnormality in Electrocardiogram (ECG) | Single 12-lead ECGs were obtained at Baseline and on the day of last dose during the study using an ECG machine that automatically calculates the heart rate (HR) and measures PR, QRS, QT, and QT duration corrected for heart rate (QTc). Number of participants with clinically significant abnormality in ECG are presented. | Up to 6 days | 
| Maximum Observed Plasma Concentration (Cmax) of Intravenous (IV) DNX | Cmax of IV DNX was to be derived from the Pharmacokinetics (PK) samples collected at Day 1 pre-dose, Day 3 at pre-dose and 0.5, 1, 1.5, 2, 3, 4, 8 and 12 hours post-dose and Day 5 pre-dose. PK Population comprised of all participants who underwent blood PK sampling during the study and from whom one or more blood concentration was determined. | Day 1 pre-dose, Day 3 at pre-dose and 0.5, 1, 1.5, 2, 3, 4, 8 and 12 hours post-dose and Day 5 pre-dose | 
| Area Under the Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUC [0-t]) of IV DNX | AUC (0-t) of IV DNX was to be derived from the PK samples collected at Day 1 pre-dose, Day 3 at pre-dose and 0.5, 1, 1.5, 2, 3, 4, 8 and 12 hours post-dose and Day 5 pre-dose. | Day 1 pre-dose, Day 3 at pre-dose and 0.5, 1, 1.5, 2, 3, 4, 8 and 12 hours post-dose and Day 5 pre-dose | 
| Time to Reach Cmax (Tmax) of IV DNX | Tmax of IV DNX was to be derived from the PK samples collected at Day 1 pre-dose, Day 3 at pre-dose and 0.5, 1, 1.5, 2, 3, 4, 8 and 12 hours post-dose and Day 5 pre-dose. | Day 1 pre-dose, Day 3 at pre-dose and 0.5, 1, 1.5, 2, 3, 4, 8 and 12 hours post-dose and Day 5 pre-dose | 
| Average Concentration (Cavg) of IV DNX | Cavg of IV DNX was to be derived from the PK samples collected at Day 1 pre-dose, Day 3 at pre-dose and 0.5, 1, 1.5, 2, 3, 4, 8 and 12 hours post-dose and Day 5 pre-dose. | Day 1 pre-dose, Day 3 at pre-dose and 0.5, 1, 1.5, 2, 3, 4, 8 and 12 hours post-dose and Day 5 pre-dose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Danirixin, Anti-inflammatory, Influenza, Hospitalized patients