The study listed may include approved and non-approved uses, formulations or treatment regimens. The results reported in any single study may not reflect the overall results obtained on studies of a product. Before prescribing any product mentioned in this Register, healthcare professionals should consult prescribing information for the product approved in their country. GSK Medicine: danirixin Study Number: 201682 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) Rationale: The aim of Study 201682 (DAISI) was 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. Phase: IIa Study Period: 01 JUN 2015 to 25 APR 2016 Study Design: This exploratory study was a Phase IIa, randomized, double blind, placebo-controlled four-arm outpatient study evaluating the safety, tolerability and clinical effect of DNX or DNX + OSV combination in comparison to placebo (PBO) or OSV. The randomization ratio was 2:2:1:1, respectively. The study consisted of a 5 day Treatment Period with follow-up through Day 28. Centres: This study was conducted at sites in Australia (20), South Africa (9) and the United States (12). Indication: uncomplicated influenza Treatment: Subjects received one of the four following treatments: 75 mg oral DNX twice daily with OSV matching PBO twice daily (DNX) DNX matching placebo twice daily with OSV matching PBO twice daily (PBO) 75 mg oral DNX twice daily with 75 mg OSV twice daily (DNX+OSV) DNX matching placebo twice daily with 75 mg OSV twice daily (OSV) Objectives: To characterize the safety and tolerability of danirixin with and without a neuraminidase inhibitor (NAI) in healthy adults with acute uncomplicated influenza. Primary Outcome (Endpoints)/Safety: The primary outcome/endpoints of the study was safety. Primary outcomes/endpoints included frequency of adverse events (AEs) and serious adverse events (SAEs), change from baseline of clinical laboratory evaluations (hematology, clinical chemistry, urinalysis), vital signs, and electrocardiogram (ECG) parameters, and frequency of pre-defined disease-related events (DREs) of interest and associated antibiotic use. Secondary Outcome (Endpoints)/Efficacy and Virology : Secondary endpoints were time to resolution of fever; proportion of afebrile subjects over time; total use of relief medications for symptom relief; incidence of hospital admissions due to influenza infection; change from baseline in influenza viral load as measured by quantitative reverse transcription - polymerase chain reaction (qrt-pcr) and quantitative virus culture (qvc); percentage of subjects with no detectable influenza viral RNA by qrt-pcr and qvc. Statistical Methods: No formal hypotheses were tested. This study explored the safety of DNX with and without OSV in otherwise healthy adult subjects with acute uncomplicated influenza. Descriptive statistics and corresponding 95% confidence intervals were provided as appropriate. Analysis Populations: Influenza Positive Population (IPP) - This population consisted of all randomized subjects who received at least one dose of study treatment with proven influenza infection (positive rapid antigen test and positive influenza by qrt-pcr or culture test at any time point). The IPP was used for clinical effect, virology analyses and selected safety analyses. Safety Population - The safety population consisted of all randomized subjects who received at least one dose of study treatment. Subjects were assessed according to their actual treatment received, regardless of the randomization assigned. This was the key population for safety analysis. Study Population: DNX PBO DNX+OSV OSV Number of Subjects: Planned, N 30 15 30 15 Randomised, N 15 7 16 7 Completed, n (%) 14 (93) 6 (86) 14 (88) 5 (71) Total Number Subjects Withdrawn, N (%) 1 (7) 1 (14) 2 (13) 2 (29) 1
Withdrawn due to Adverse Events n (%) 0 0 0 0 Withdrawn due to Lack of Efficacy n (%) 0 0 0 0 Withdrawn for other reasons n (%) 1 (7) 1 (14) 2 (13) 2 (29) Demographics N (Safety) 15 7 16 7 Females Males 6 (40) 9 (60) 1 (14) 6 (86) 7 (44) 9 (56) 2 (29) 5 (71) Mean Age, years (SD) 37.9 (13.4) 33.4 (11.6) 42.6 (11.5) 36.3 (12.0) White, n (%) 11 (73) 5 (71) 13 (81) 6 (86) Tobacco use, never smoked n (%) 10 (67) 5 (71) 11 (69) 5 (71) Primary Efficacy Results: The primary outcome of the study was safety. Safety data are included in the Safety Results section. Secondary Outcome Results: DNX PBO DNX+OSV OSV Secondary endpoint: Time to resolution of fever (IPP) N 9 6 13 7 Clinical resolution, n (%) Yes 6 (66.7) 6 (100.0) 11 (84.6) 5 (71.4) No 2 (22.2) 0 1 (7.7) 2 (28.6) Missing 1 (11.1) 0 1 (7.7) 0 Normal at baseline, n (%) Yes 1 (11.1) 0 0 2 (28.6) No 7 (77.8) 6 (100) 12 (92.3) 5 (71.4) Missing 1 (11.1) 0 1 (7.7) 0 Kaplan meier estimate, hours Median 119.833 98.092 54.425 76.167 95% CI 15.167 - ND 46.033-129.917 20.917-116.417 18.150 - ND Secondary endpoint: Proportion of afebrile subjects over time (IP Population) n 7 6 12 5 Screening/baseline 0% 0% 0% 0% Day 3 28.6% 33.3% 66.7% 40.0% Day 5 57.1% 66.7% 83.3% 60.0% Day 8 57.1% 100% 91.7% 60.0% Day 14 71.4% 100% 91.7% 60.0% Secondary endpoint: Use of medications for symptom relief (Safety Population) 2
Paracetamol, n (%) n 15 7 16 7 Yes 12 (80.0) 7 (100) 15 (93.8) 7 (100) No 3 (20.0) 0 1 (6.3) 0 Paracetamol total dose, mg n 12 7 15 7 Median 5000.00 9000.00 5500.00 3000.00 Min. 1000.0 500.0 500.0 1000.0 Max. 14000.0 71000.0 20000.0 12000.0 Dextromethorphan, n (%) n 15 7 16 7 Yes 12 (80.0) 5 (71.4) 13 (81.3) 7 (100) No 3 (20.0) 2 (28.6) 3 (18.8) 0 Dextromethorphan total dose, mg n 12 5 13 7 Median 150.00 390.00 120.00 60.00 Min. 15.0 120.0 30.0 15.0 Max. 360.0 2250.0 2250.0 300.0 Secondary endpoint: Incidence of hospital admissions due to influenza (Safety Population) N 15 7 16 7 Hospitalized subjects, n (%) 0 0 0 0 Secondary endpoint: Change from baseline in influenza viral load (qrt-pcr) (IP Population) Secondary endpoint: Change from baseline in influenza viral load (qvc) (IP Population) 3
DNX PBO DNX+OSV OSV Secondary endpoint: Proportion of subjects with no detectable influenza viral RNA (IPP), n (%) Screening/baseline n 9 6 13 7 Virus not detected 0 0 0 0 Day 3 n 9 6 12 5 Virus not detected 0 0 0 0 Day 5 n 9 6 12 5 Virus not detected 0 0 3 (25) 1 (20) Day 8 n 8 6 12 5 Virus not detected 3 (38) 1 (17) 6 (50) 5 (100) Day 14 n 9 5 12 5 Virus not detected 5 (56) 4 (80) 11 (92) 5 (100) Safety Results: DNX N=15 PBO DNX+OSV N=16 Most Frequent Adverse Events Subjects with any event, n (%) 3 (20) 4 (57) 7 (44) 0 Vomiting 0 0 2 (13) 0 Diarrhea 1 (7) 1 (14) 0 0 Epistaxis 0 1 (14) 1 (6) 0 Pre-defined Disease-related events Subjects with any event, n (%) 2 (13) 0 1 (6) 0 Otitis media 2 (13) 0 0 0 Sinusitis 1 (7) 0 1 (6) 0 Bronchitis 0 0 1 (6) 0 Pneumonia 0 0 0 0 Antibiotic Use for Pre-defined Disease Related Events DRE Subjects receiving any antibiotic 0 0 1 (6) 0 Roxithromycin 0 0 1 (6) 0 Serious Adverse Events - On-Therapy, n (%) [n considered by the investigator to be related to study medication] Subjects with any SAE (includes both fatal and non-fatal events) OSV 1 (7) [0] 0 0 0 T-wave abnormality 1 (7) [0] 0 0 0 Subjects with fatal SAEs, n (%) 0 0 0 0 4
Clinical Laboratory Evaluations Clinical chemistries : The incidences of any clinical chemistry assessments with post Baseline toxicity grades of 1 were low. There was no pattern of Grade 1 assessments in the DNX groups in the study. No significant changes in urine ph or specific gravity were observed. Hematology: The incidences of any clinical hematology assessments with post Baseline toxicity grades of 1 were low. Assessments of neutropenia were the most common hematology toxicity with Grade 1. Grades 1-3 neutropenia occurred in 1 (14%), 2 (14%) and 4 (25%) subjects in the PBO, DNX and DNX+OSV groups respectively. Median neutrophil counts decreased from baseline to Day 3 across all groups, followed by increases at Day 5 while on therapy with complete resolution by Day 8. Seven subjects had neutrophil counts bellow 1.5x10 9 /L; there was one in the PBO group, and the remainder were in DNX and DNX+OSV groups. None of the neutropenic subjects had a confirmed bacterial related AE. Only one subject receiving DNX+OSV with grade 2 (neutrophil 0.92 x10 9 /L) had an AE reported of upper respiratory infection. DNX N=15 PBO DNX+OSV N=16 Any Clinical Chemistry Parameter, n (%) n 15 7 15 5 Grade 0 2 (13%) 2 (29%) 9 (56%) 0 Grade 1 11 (73%) 4 (57%) 5 (31%) 4 (57%) Grade 2 2 (13%) 1 (14%) 0 1 (14%) Grade 3 0 0 1 (6%) 0 Grade 4 0 0 0 0 Any Clinical Hematology Parameter, n (%) n 15 7 15 5 Grade 0 11 (73%) 6 (86%) 11 (69%) 5 (71%) Grade 1 2 (13%) 0 2 (13%) 0 Grade 2 1 (7%) 1 (14%) 1 (6%) 0 Grade 3 1 (7%) 0 1 (6%) 0 Grade 4 0 0 0 0 Plot of Median Absolute Neutrophil Count by Visit (Safety Population) OSV Vital Signs, n (%) DNX N=15 PBO DNX+OSV N=16 OSV 5
Systolic blood pressure To low 0 0 0 0 To normal or no change 14 (93) 7 (100) 14 (88) 6 (86) To high 0 0 1 (6) 0 Missing 1 (7) 0 1 (6) 1 (14) Diastolic blood pressure To low 0 0 0 0 To normal or no change 15 (100) 6 (86) 14 (88) 6 (86) To high 0 1 (14) 0 0 Missing 0 0 2 (13) 1 (14) Heart rate To low 0 0 0 0 To normal or no change 15 (100) 6 (86) 15 (94) 6 (86) To high 0 0 0 0 Missing 0 1 (14) 1 (6) 1 (14) Electrocardiograms, n (%) Screening/baseline 15 (100) 7 (100) 16 (100) 7 (100) Normal 11 (73) 2 (29) 8 (50) 4 (57) Abnormal - not clinically significant 4 (27) 5 (71) 8 (50) 3 (43) Abnormal - clinically significant 0 0 0 0 Worst post-baseline result 15 (100) 7 (100) 15 (94) 5 (71) Normal 9 (60) 1 (14) 7 (44) 3 (43) Abnormal - not clinically significant 5 (33) 6 (86) 8 (50) 2 (29) Abnormal - clinically significant 1 (7) 0 0 0 Conclusion: AEs were reported by 3 subjects in the DNX group, 4 subjects in the PBO group, 7 subjects in the DNX+OSV group and no subjects in the OSV group. Two subjects in the DNX+OSV group had vomiting; all other AEs occurred in single subjects in each of the treatment groups. There was 1 SAE reported in the study, which was a T-wave abnormality in a DNX-treated subject, considered by the investigator to be unrelated to study medication. No deaths or fatal events occurred during the study. Assessments of clinical laboratory values, vital signs and ECGs did not indicate any safety concerns for DNX treatment. 6