Investigation of Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Clinical Efficacy of Oral Danirixin in Symptomatic COPD Subjects With Mild to Moderate Airflow Limitation at Risk for Exacerbations

GlaxoSmithKline (GSK)

Status and phase: Completed; Phase 2

Conditions: Pulmonary Disease, Chronic Obstructive

Treatments: Drug: Placebo; Drug: Danirixin

Study type: Interventional

Funder types: Industry

Identifiers

NCT02130193

200163

Details and patient eligibility

About

The aim of this First Time in Patient study is to obtain initial information on the safety, tolerability, pharmacokinetics, pharmacodynamics and clinical efficacy of repeat daily administration of danirixin in subjects with symptomatic chronic obstructive pulmonary disease (COPD) having mild to moderate airflow limitation and are at high risk for future COPD exacerbations.

The study will be conducted in two parts. Part A will be a two week open label, single arm study in patients with COPD to obtain pharmacokinetic data and safety information of repeat dosing of danirixin in the population of interest. Approximately 10 subjects will be enrolled in Part A of the study. Progression to and dose selection for Part B will occur following review of the data collected in Part A. Part B will be a 52-week, randomized, double-blind (sponsor unblind), placebo-controlled on top of standard of care, parallel group study. Part B will evaluate several clinical efficacy assessments related to exacerbations and respiratory symptoms. Approximately 100 subjects will be enrolled with a target of 80 subjects completing 52 weeks of danirixin administration.

Enrollment: 102 patients

Sex: All

Ages: 40 to 70 years old

Volunteers: No Healthy Volunteers

Inclusion criteria

• Male or female aged between 40 and 70 years of age inclusive, at the time of signing the informed consent
• Subjects with a documented history of COPD exacerbation(s) in the 12 months prior to study participation meeting at least one of the following criteria: >=2 COPD exacerbations resulting in prescription for antibiotics and/or oral corticosteroids or hospitalization or extended observation in a hospital emergency room or outpatient center; 1 COPD exacerbation resulting in prescription for antibiotics and/or oral corticosteroids or hospitalization or extended observation in a hospital emergency room or outpatient center and a plasma fibrinogen concentration at screening >=3.5 milligram/milliliter (mg/mL)
• Diagnosis of symptomatic chronic obstructive pulmonary disease with mild to moderate airflow obstruction (COPD-GOLD I or II) for at least 2 years based on American Thoracic Society (ATS)/ European Respiratory Society (ERS) current guidelines or symptoms consistent with COPD for at least 2 years
• Subjects with a post-bronchodilator FEV1/FVC ratio of < 0.7 and FEV1 >=50% of predicted normal value calculated using National Health and Nutrition Examination Survey (NHANES) III reference equation at Visit 1
• A female subject is eligible to participate if she is of: Non-childbearing potential defined as pre-menopausal females with a documented tubal ligation or hysterectomy [for this definition, "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]; or postmenopausal defined as 12 months of spontaneous amenorrhea [in questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH) >40 milli international units/mL (MIU/mL) and estradiol < 40 picogram (pg)/mL (<147 picomole/Liter [pmol/L]) is confirmatory]. Females on hormone replacement therapy (HRT) will not be enrolled in the study.
• Body weight >=45 kilogram (kg)
• 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
• Subjects with a history of respiratory symptoms, including chronic cough and/or mucus hypersecretion on most days for at least the previous 3 months prior to Visit 1
• Aspartate aminotransferase (AST) and Alanine aminotransferase (ALT) <2x upper limit of normal (ULN); alkaline phosphatase and bilirubin <=1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%)
• Able to perform lung function tests reliably
• Based on single or averaged corrected QT (QTc) values of triplicate ECGs obtained over a brief recording period: Fridericia-corrected QTc (QTcF) < 450 milliseconds (msec); or QTc < 480 msec in subjects with Bundle Branch Block
• Subjects must have the ability to use an electronic diary on a daily basis [Part B only]
• Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form

Exclusion criteria

• Diagnosis of asthma, or other clinically relevant lung disease (other than COPD), e.g. sarcoidosis, tuberculosis, pulmonary fibrosis, severe bronchiectasis or lung cancer; Subject with alpha-1-antitrypsin deficiency as the underlying cause of COPD
• Pulse Oximetry levels <88% (at rest on room air) at screening
• Less than 14 days have elapsed from completion of a course of antibiotics or oral corticosteroids for a recent COPD exacerbation.
• Diagnosis of Pneumonia (chest X-Ray or computed tomography [CT] confirmed) within the last 3 months prior to screening
• History or current evidence of clinically significant renal disease, diabetes mellitus/metabolic syndrome, hypertension or any other clinically significant cardiovascular, neurological, endocrine, or hematological abnormalities that are uncontrolled on permitted therapy. Significant is defined as any disease that, in the opinion of the Investigator, would put the safety of the subjects at risk through study participation, or which would affect the safety analysis or other analysis if the disease/condition exacerbated during the study.
• A positive pre-study drug/alcohol screen
• A positive test for human immunodeficiency virus (HIV) antibody
• A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody result within 3 months of screening
• 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 GSK Medical Monitor, contraindicates their participation
• Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
• History of regular alcohol consumption within 6 months of the study defined as: For non United States of America (US) sites: an average weekly intake of >21 units for males or >14 units for females. One unit is equivalent to 8 g of alcohol: a half-pint (approximately 240 mL) of beer, 1 glass (125 mL) of wine or 1 (25 mL) measure of spirits; For US sites: an average weekly intake of >14 drinks for males or >7 drinks for females. One drink is equivalent to 12 g of alcohol: 12 ounces (360 mL) of beer, 5 ounces (150 mL) of wine or 1.5 ounces (45 mL) of 80 proof distilled spirits.
• Current or expected use of proton pump inhibitors or histamine H2-receptor antagonists during the study period
• Chest X-ray (posteroanterior with lateral) or CT scan reveals evidence of pneumonia or a clinically significant abnormality not believed to be due to the presence of COPD (historic data up to 1 yr may be used).
• Subjects with peripheral blood neutrophil count (PBN) <2x10^9/Liter
• Subject with history of previous lung surgery (e.g. lobectomy, pneumonectomy, or lung volume reduction)
• Requiring the use of oral or injectable Cytochrome P450 3A4 (CYP3A4) or breast cancer resistance protein (BCRP) substrates with a narrow therapeutic index

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Single Group Assignment

Masking: None (Open label)

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102 participants in 2 patient groups

Part A

Experimental group

Description:

Subjects will receive 50 mg danirixin twice daily (BID) orally for 14 days. If the exposure to danirixin is lower than expected, after 14 days of dosing, then the dose may be increased to 75 mg BID for Part B.

Treatment:

Drug: Danirixin

Part B

Experimental group

Description:

Subjects will be randomized to receive either danirixin BID or placebo BID treatment along with standard care of treatment for 52 weeks. Subjects completing Part A and meeting the eligibility criteria for Part B could also be randomized in Part B.

Treatment:

Drug: Danirixin

Drug: Placebo