Chronic obstructive pulmonary disease MedDRA version: 20.0 Level: LLT Classification code 10010952 Term: COPD System Organ Class: 100000015472
Conditions
Interventions
Product Name: Danirixin HBr
Product Code: GSK1325756
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: Danirixin
Other descri
Sponsors
GlaxoSmithKline Research & Development Ltd
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: Participants are eligible to be included in the study only if all of the following criteria apply: Age 1. Participant must be 50 to 75 years of age inclusive, at the time of signing the informed consent. Type of Participant and Disease Characteristics 2. Diagnosis of COPD with mild to moderate airflow obstruction (post-bronchodilator FEV1/ Forced Vital Capacity (FVC) ratio 0.5 units/ml sputum. Two further screening samples can be submitted for analysis within 30day screening period if previous samples do not pass criteria. 4. Able to produce at least 1ml of sputum sample at the screening visit with nebulised saline induction 5. Current smokers and former smokers with a cigarette smoking history of =10 pack years (1 pack year = 20 cigarettes smoked per day for 1 year or equivalent). Former smokers are defined as those who have stopped smoking for at least 6 months prior to Visit 1. Weight 6. Body weight = 45 kg Sex 7. Male or female a. Male participants: A male participant must agree to use contraception as detailed in protocol during the treatment period and for at least [60 hours, corresponding to approximately 6 half-lives which is the time needed to eliminate any teratogenic treatments after the last dose of study treatment and refrain from donating sperm during this period] b. Female participants: A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies: (i) Not a woman of childbearing potential (WOCBP) as defined in the protocol OR (ii) A WOCBP who agrees to follow the contraceptive guidance in protocol during the treatment period and for at least 60 hours after the last dose of study treatment. Informed Consent 8. Capable of giving signed informed consent as described in protocol which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol. Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 12 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 12
Exclusion criteria
Exclusion criteria: Participants are excluded from the study if any of the following criteria apply: Medical Conditions 1. Primary clinical diagnoses of any of the following relevant lung diseases; asthma, sarcoidosis, tuberculosis, pulmonary fibrosis, severe bronchiectasis or lung cancer 2. Known alpha-1-antitrypsin deficiency 3. Pulse oximetry 15 hours/day of oxygen use) 5. Unstable co-morbidities (eg cardiovascular disease, active malignancy) which in the opinion of the Investigator would make the participant unsuitable to be enrolled in the study. This includes any abnormality identified on screening bloods or screening ECG which in the opinion of the Investigator would make the participant unsuitable for the study 6. 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 of GSK medical monitor, contraindicates their participation. 7. Current or chronic history of liver disease, or know hepatic or biliary abnormalities (with the exception of Gilbert’s syndrome or asymptomatic gallstones). 8. Participants with a known or suspected history of alcohol or drug abuse within the last 2 years Prior/Concomitant Therapy 9. Antibiotic use concurrently or within 28 days preceding the screening visit, including current or planned chronic use of macrolide antibiotics during the study period for the prevention of COPD exacerbations. Examples of chronic use include daily or two-three times per week for at least 3 months 10. Systemic immunosuppressive medication, including current oral corticosteroids at a dose >5mg, concurrently or within 28 days preceding the screening visit. 11. Oral or injectable Cytochrome P450 (CYP) 3A4 or Breast Cancer Resistance Protein (BCRP) substrates with narrow therapeutic index (CYP3A4 substrates include, but are not limited to, alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, tacrolimus, and theophylline; BCRP substrates include: Methotrexate, mitoxantrone, imatinib, irinotecan, lapatinib, rosuvastatin, sulfasalazine, topotecan.. 12. Current use of phosphodiesterase-4 inhibitors: Roflumilast, Crisaborole and Apremilast 13. Current use of Raloxifene 14. Current use of low molecular weight heparin Prior/Concurrent Clinical Study Experience 15. The participant 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). 16. Exposure to more than four investigational products within 12 months prior to the first dosing day. Diagnostic assessments 17. Participants with a peripheral blood neutrophil count < 1.0 x 109/L at screening 18. Diagnosis of pneumonia (chest X-ray or computed tomography [CT]
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To assess the change from baseline in NETs formation in participants with COPD following 14 days treatment with danirixin HBr 35mg twice daily; Secondary Objective: -To assess the change from baseline in NETs formation in participants with COPD following 14 days treatment with danirixin HBr 35mg twice daily -To further characterize the safety of danirixin HBr 35mg twice daily compared with placebo in participants with COPD. -To assess the effects of danirixin HBr 35mg twice daily on NET osis- associated biomarkers in sputum and peripheral blood -Characterise the population pharmacokinetic (PK) profile of approximately 14 days of dosing of danirixin HBr 35mg twice daily in participants with COPD ;Primary end point(s): - Reduction in sputum NETs (quantified by Histone-elastase complexes);Timepoint(s) of evaluation of this end point: Screening, baseline, day 7 and day 14(end of treatment) | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): -Reduction in sputum NETS (quantified by Deoxyribonucleic acid [DNA]-elastase complexes) -Reduction in sputum NET area quantification by microscopy -Adverse events -Vital Signs -ECG - Spirometry -Clinical Laboratory Assessments (hematology, clinical chemistry, urinalysis) -Change from baseline in sputum resistin levels -Change from baseline in the ratio of sputum NETs to sputum neutrophils -Change from baseline in sputum elastase activity -Change from baseline in peripheral blood neutrophil NET formation (DNA release, microscopy) -Model specific PK parameters of danirixin (e.g., oral clearance, oral steady state volume of distribution). ;Timepoint(s) of evaluation of this end point: Screening, baseline, day 7 and day 14(end of treatment) | — |
Countries
United Kingdom
Contacts
Public ContactGSK Clinical Support Help Desk
GlaxoSmithKline Research and Development Ltd
Outcome results
None listed