Clinical trial NCT02130193: 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
Official title: A Two Part, Phase IIa, Randomized, Placebo-controlled Study To Investigate The Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Clinical Efficacy of Oral Danirixin (GSK1325756) in Symptomatic COPD Subjects With Mild to Moderate Airflow Limitation at Risk for Exacerbations
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Pulmonary Disease, Chronic Obstructive
Keywords: Efficacy
Danirixin
EXACT-PRO
COPD
Safety
RD
CXCR2 inhibitor
EXACT-RS
PK
HCRU exacerbations
PD
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2014-05-05
Enrollment: 102
Sex: ALL
Minimum age (years): 40
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: 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

Primary outcomes:
measure: Number of Participants With Any Adverse Event (AE) and, Serious Adverse Event (SAE) in Part A
timeFrame: Up to Day 28 in Part A
measure: Number of Participants With Any AE and SAE in Part B
timeFrame: Up to Day 392 in Part B
measure: Number of Participants With Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP), Pulse Rate, Respiratory Rate and Body Temperature Abnormalities of Potential Clinical Importance in Part A
timeFrame: Up to Day 28 in Part A
measure: Number of Participants With Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP), Pulse Rate and Respiratory Rate Abnormalities of Potential Clinical Importance in Part B
timeFrame: Up to Day 392 in Part B
measure: Number of Participants With Abnormal 12-lead Electrocardiogram (ECG) in Part A
timeFrame: Up to Day 28 in Part A
measure: Number of Participants With Abnormal 12-lead ECG in Part B
timeFrame: Up to Day 392 in Part B
measure: Number of Participants With Hematology Values of Potential Clinical Importance in Part A
timeFrame: Up to Day 28 in Part A
measure: Number of Participants With Hematology Values of Potential Clinical Importance in Part B
timeFrame: Up to Day 392 in Part B
measure: Number of Participants With Clinical Chemistry Values of Potential Clinical Importance in Part A
timeFrame: Up to Day 28 in Part A
measure: Number of Participants With Clinical Chemistry Values of Potential Clinical Importance in Part B
timeFrame: Up to Day 392 in Part B
measure: Number of Participants With Urinalysis Dipstick Results in Part A
timeFrame: Up to Day 28 in Part A
measure: Number of Participants With Urinalysis Dipstick Results in Part B
timeFrame: Up to Day 392 in Part B
measure: Change From Baseline in Urine Power of Hydrogen (pH) at Day 14 in Part A
timeFrame: Up to Day 28 in Part A
measure: Change From Baseline in Urine pH in Part B
timeFrame: Up to Day 392 in Part B
measure: Change From Baseline in Urine Specific Gravity of Urine in Part A
timeFrame: Up to Day 28 in Part A
measure: Change From Baseline in Urine Specific Gravity of Urine in Part B
timeFrame: Up to Day 392 in Part B
measure: Change From Baseline in Forced Expiratory Volume in One Second (FEV1) and Forced Vital Capacity (FVC) at the Indicated Time Points in Part A
timeFrame: Up to Day 28 in Part A
measure: Change From Baseline in FEV1 and FVC at the Indicated Time Points in Part B
timeFrame: Up to Day 392 in Part B
measure: Maximum Observed Plasma Concentration (Cmax) of Danirixin in Part A
timeFrame: Pre-dose and at 0.5, 1, 2, 4, 6, 8, 10 and 12 hour post-dose on Day 1 and Day 14 in Part A
measure: Time of Occurrence of Cmax (Tmax) of Danirixin in Part A
timeFrame: Pre-dose and at 0.5, 1, 2, 4, 6, 8, 10 and 12 hour post-dose on Day 1 and Day 14 in Part A
measure: Area Under the Blood Concentration-time Curve (AUC) Over Dosing Interval (AUC[0-12]) of Danirixin in Part A
timeFrame: Pre-dose and at 0.5, 1, 2, 4, 6, 8, 10 and 12 hour post-dose on Day 1 and Day 14 in Part A
measure: Number of Health Care Resource Utilization (HCRU) Defined COPD Exacerbations Per Year in Part B
timeFrame: Up to Day 392 in Part B
measure: Monthly Weighted Means of Exacerbations of Chronic Pulmonary Disease Tool-respiratory Symptoms (EXACT-RS) Total Score in Part B
timeFrame: Up to Day 392 in Part B
Secondary outcomes:
measure: Cmax of Danirixin in Part B
timeFrame: Pre-dose and at 0.5, 1, 2, 4, 6, 8, 10 and 12 hour post-dose on Day 1 and Day 364; and at pre-dose and 2 hours on Day 28, 56 and 168 in Part B
measure: Tmax of Danirixin in Part B
timeFrame: Pre-dose and at 0.5, 1, 2, 4, 6, 8, 10 and 12 hour post-dose on Day 1 and Day 364; and at pre-dose and 2 hours on Day 28, 56 and 168 in Part B
measure: AUC(0-12) of Danirixin in Part B
timeFrame: Pre-dose and at 0.5, 1, 2, 4, 6, 8, 10 and 12 hour post-dose on Day 1 and Day 364; and at pre-dose and 2 hours on Day 28, 56 and 168 in Part B
measure: Number of EXACT-PRO Exacerbations Per Year in Part B
timeFrame: Up to Day 392 in Part B
measure: Monthly Weighted Means of Exacerbations of EXACT-PRO Total Score in Part B
timeFrame: Up to Day 392 in Part B
measure: Time to First HCRU COPD Exacerbation in Part B
timeFrame: Up to Day 392 in Part B
measure: Time to First EXACT-PRO Event in Part B
timeFrame: Up to Day 392 in Part B
measure: Assessment of Duration of EXACT-PRO Events in Part B
timeFrame: Up to Day 392 in Part B
measure: Assessment of Severity of EXACT-PRO Events in Part B
timeFrame: Up to Day 392 in Part B
measure: Monthly Weighted Means of EXACT-RS Domain Scores in Part B
timeFrame: Up to Day 392 in Part B
measure: Change From Baseline for COPD Assessment Test (CAT) at the Indicated Time Points in Part B
timeFrame: Up to Day 392 in Part B
measure: Number of Participants With Physician's Global Assessment (PGA) Readings in Part B
timeFrame: Up to Day 392 in Part B
measure: Number of Participants With Patient Global Rating of Severity (PGRS) Score in Part B
timeFrame: Up to Day 392 in Part B
measure: Number of Participants With Patient Global Impression of Change (PGIC)Score in Part B
timeFrame: Up to Day 392 in Part B
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: GSK Investigational Site
state: Alabama
city: Denver
country: United States
facility: GSK Investigational Site
state: Colorado
city: Iowa City
country: United States
facility: GSK Investigational Site
state: Iowa
city: Oaks
country: United States
facility: GSK Investigational Site
state: Pennsylvania
city: Philadelphia
country: United States
facility: GSK Investigational Site
state: Pennsylvania
city: Spartanburg
country: United States
facility: GSK Investigational Site
state: South Carolina
city: Frankfurt
country: Germany
facility: GSK Investigational Site
state: Hessen
city: Neu isenburg
country: Germany
facility: GSK Investigational Site
state: Hessen
city: Dueren
country: Germany
facility: GSK Investigational Site
state: Nordrhein-Westfalen
city: Essen
country: Germany
facility: GSK Investigational Site
state: Nordrhein-Westfalen
city: Magdeburg
country: Germany
facility: GSK Investigational Site
state: Sachsen-Anhalt
city: Leipzig
country: Germany
facility: GSK Investigational Site
state: Sachsen
city: Leipzig
country: Germany
facility: GSK Investigational Site
state: Sachsen
city: Grosshansdorf
country: Germany
facility: GSK Investigational Site
state: Schleswig-Holstein
city: Berlin
country: Germany
facility: GSK Investigational Site
city: Berlin
country: Germany
facility: GSK Investigational Site
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Lazaar AL, Miller BE, Tabberer M, Yonchuk J, Leidy N, Ambery C, Bloomer J, Watz H, Tal-Singer R. Effect of the CXCR2 antagonist danirixin on symptoms and health status in COPD. Eur Respir J. 2018 Oct 4;52(4):1801020. doi: 10.1183/13993003.01020-2018. Print 2018 Oct. No abstract available.