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

NCT02927431 | Terminated Phase 2 Results DMC FDA Drug

• 2 other identifiers: 2010232016-002512-40
• Study Type: interventional
• Target: 10
• Locations: 4 countries
• Sites: 8

Brief 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.

Conditions

Virus Diseases

Keywords

Anti-inflammatory; Danirixin; Influenza; Hospitalized patients

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (24)

• Time to Respiratory Response (TTRR)

  Up to 45 Days

• Time to Absence of Fever

  Up to 45 Days

• Time to Improved Oxygen Saturation

  Up to 45 Days

• Time to Improved Heart Rate

  Up to 45 Days

• Time to Improved Systolic Blood Pressure (SBP)

  Up to 45 Days

Study Arms (3)

Danirixin 15 mg FBE IV plus 75 mg oseltamivir

EXPERIMENTAL

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; Drug: Oseltamivir 75 mg

Danirixin 50 mg FBE IV plus 75 mg oseltamivir

EXPERIMENTAL

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; Drug: Oseltamivir 75 mg

Placebo of danirixin IV plus 75 mg oseltamivir

PLACEBO COMPARATOR

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; Drug: Oseltamivir 75 mg

Interventions

Danirixin 15 mg FBE DRUG

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.

Danirixin 15 mg FBE IV plus 75 mg oseltamivir

Danirixin 50 mg FBE DRUG

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.

Danirixin 50 mg FBE IV plus 75 mg oseltamivir

Placebo DRUG

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.

Placebo of danirixin IV plus 75 mg oseltamivir

Oseltamivir 75 mg DRUG

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.

Danirixin 15 mg FBE IV plus 75 mg oseltamivir; Danirixin 50 mg FBE IV plus 75 mg oseltamivir; Placebo of danirixin IV plus 75 mg oseltamivir

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• GlaxoSmithKline: lead

Study Sites (8)

GSK Investigational Site

Stamford, Connecticut, 06902, United States

Location

GSK Investigational Site

Council Bluffs, Iowa, 51503, United States

Location

GSK Investigational Site

Natchitoches, Louisiana, 71457, United States

Location

GSK Investigational Site

Durham, North Carolina, 27710, United States

Location

GSK Investigational Site

Salem, Virginia, 24153, United States

Location

GSK Investigational Site

Bucharest, 030303, Romania

Location

GSK Investigational Site

Smolensk, 214006, Russia

Location

GSK Investigational Site

Lund, SE-221 85, Sweden

Location

Related Publications (1)

• Madan A, Chen S, Yates P, Washburn ML, Roberts G, Peat AJ, Tao Y, Parry MF, Barnum O, McClain MT, Roy-Ghanta S. Efficacy and Safety of Danirixin (GSK1325756) Co-administered With Standard-of-Care Antiviral (Oseltamivir): A Phase 2b, Global, Randomized Study of Adults Hospitalized With Influenza. Open Forum Infect Dis. 2019 Apr 3;6(4):ofz163. doi: 10.1093/ofid/ofz163. eCollection 2019 Apr.

  PMID: 31041358 BACKGROUND

MeSH Terms

Conditions

Virus Diseases; Influenza, Human

Interventions

danirixin; Oseltamivir

Condition Hierarchy (Ancestors)

Infections; Respiratory Tract Infections; Orthomyxoviridae Infections; RNA Virus Infections; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Acetamides; Amides; Organic Chemicals; Cyclohexenes; Cyclohexanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons

Limitations and Caveats

Interpretation of data is limited by the few participants enrolled prior to termination of the study due to poor recruitment.

Results Point of Contact

• Title: GSK Response Center
• Organization: GlaxoSmithKline

GSKClinicalSupportHD@gsk.com

866-435-7343

Study Officials

• GSK Clinical Trials

  GlaxoSmithKline

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 29, 2016
• First Posted: October 7, 2016
• Study Start: January 19, 2017
• Primary Completion: May 24, 2017
• Study Completion: May 24, 2017
• Last Updated: November 30, 2020
• Results First Posted: July 2, 2018

Record last verified: 2020-11

Locations

RO (1); RU (1); SE (1); US (5)