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
Overview
- Phase
- Phase 2
- Intervention
- Danirixin
- Conditions
- Pulmonary Disease, Chronic Obstructive
- Sponsor
- GlaxoSmithKline
- Enrollment
- 102
- Locations
- 1
- Primary Endpoint
- Number of Participants With Any Adverse Event (AE) and, Serious Adverse Event (SAE) in Part A
- Status
- Completed
- Last Updated
- 8 years ago
Overview
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.
Investigators
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
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).
Arms & Interventions
Part A
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.
Intervention: Danirixin
Part B
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.
Intervention: Danirixin
Part B
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.
Intervention: Placebo
Outcomes
Primary Outcomes
Number of Participants With Any Adverse Event (AE) and, Serious Adverse Event (SAE) in Part A
Time Frame: Up to Day 28 in Part A
An AE is any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. Any untoward event resulting in death, life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, congenital anomaly/birth defect, any other situation according to medical or scientific judgment that may not be immediately life-threatening or result in death or hospitalization but may jeopardize the participant or may require medical or surgical intervention, events associated with liver injury and impaired liver function were categorized as SAE. Participants with any AE or SAE were summarized. Participants with AE or SAE occurrences \>= 5 percent were summarized. All Subjects Population comprised of all participants who were screened and for whom a record existed on the study database.
Number of Participants With Any AE and SAE in Part B
Time Frame: Up to Day 392 in Part B
An AE is any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. Any untoward event resulting in death, life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, congenital anomaly/birth defect, any other situation according to medical or scientific judgment that may not be immediately life-threatening or result in death or hospitalization but may jeopardize the participant or may require medical or surgical intervention, events associated with liver injury and impaired liver function were categorized as SAE. Participants with AE or SAE occurrences \>= 5 percent were summarized.
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
Time Frame: Up to Day 28 in Part A
Vital signs including SBP, DBP, pulse rate, respiratory rate and body temperature were taken on Day 1 pre-dose and on Day 14 and at Follow-up (Day 21 to 28) in Part A. Measurements were obtained in a semi-supine/ supine position after 5 minutes rest. The mean of replicate assessments at any given time point was used as the value for that time point. SBP \<90 or \>160 millimeter of mercury (mmHg); DBP \<40 or \>110 mmHg, pulse rate \<35 or \>120 beats per minute (bpm) and respiratory rate \<8 or \>30 breaths per minute were considered as values of potential clinical importance and were presented as 'High' or 'Low' values. Intent-to-Treat (ITT) Population comprised of all randomized par. who received at least one dose of study medication.
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
Time Frame: Up to Day 392 in Part B
Vital signs including SBP, DBP, pulse rate and respiratory rate were taken on Day 1 pre-dose and on Day 28, 56, 112, 168, 280, 364 and at Follow-up (Day 378 to 392) in Part B. Measurements were obtained in a semi-supine/ supine position after 5 minutes rest. The mean of replicate assessments at any given time point was used as the value for that time point. SBP \<90 or \>160 mmHg, DBP \<40 or \>110 mmHg, pulse rate \<35 or \>120 bpm and respiratory rate \<8 or \>30 breaths per minute were considered as values of potential clinical importance and were presented as 'High' or 'Low' values. Only those participants with data available at the specified time points were analyzed (represented by n=X, X in the category titles).
Number of Participants With Abnormal 12-lead Electrocardiogram (ECG) in Part A
Time Frame: Up to Day 28 in Part A
12-lead ECG was taken on Day 1 pre-dose and on Follow-up visit (Day 21 to 28) in Part A using an ECG machine. Triplicate reading were taken on Day 1 pre-dose. Participants with abnormal-clinically not significant (NCS) and abnormal-clinically significant (CS) findings were sumarized.
Number of Participants With Abnormal 12-lead ECG in Part B
Time Frame: Up to Day 392 in Part B
12-lead ECG was taken on Day 1 pre-dose and on Day 28, 168 and at Follow-up (Day 378 to 392) in Part B using an ECG machine. Participants with abnormal-NCS and abnormal-CS findings were sumarized. Only those participants with data available at the specified time points were analyzed (represented by n=X, X in the category titles).
Number of Participants With Hematology Values of Potential Clinical Importance in Part A
Time Frame: Up to Day 28 in Part A
Blood samples were collected at Screening and Day 14 in Part A to evaluate hematology parameters which included hemoglobin, hematocrit, basophils, eosinophils, lymphocytes, monocytes, neutrophils, mean corpuscular hemoglobin concentration (MCHC), mean corpuscular hemoglobin (MCH), mean corpuscular volume (MCV), red blood cell (RBC) count, white blood cell (WBC) count, platelet count and reticulocyte count. Hematology values of potential clinical importance were presented as 'High' or 'Low' values based on the reference laboratory standards.
Number of Participants With Hematology Values of Potential Clinical Importance in Part B
Time Frame: Up to Day 392 in Part B
Blood samples were collected at Screening and on Day 28, 168, and 364 in Part B to evaluate hematology parameters which included hemoglobin, hematocrit, basophils, eosinophils, lymphocytes, monocytes, neutrophils, MCHC, MCH, MCV, RBC count, WBC count, platelet count and reticulocyte count. Hematology values of potential clinical importance were presented as 'High' or 'Low' values based on the reference laboratory standards. Only those participants with data available at the specified time points were analyzed (represented by n=X, X in the category titles).
Number of Participants With Clinical Chemistry Values of Potential Clinical Importance in Part A
Time Frame: Up to Day 28 in Part A
Blood samples were collected at Screening and Day 14 in Part A to evaluate clinical chemistry parameters which included alanine aminotransferase (ALT), albumin, alkaline phosphatase (ALP), aspartate aminotransferase (AST), total bilirubin, calcium, bicarbonate, chloride, creatinine, direct bilirubin, gamma glutamyl transferase (GGT), glucose, potassium, total protein, sodium, blood urea nitrogen (BUN) and uric acid. Additional liver monitoring chemistry (ALT, AST, ALP and total and direct bilirubin) was done on Day 1 pre-dose. Clinical chemistry values of potential clinical importance were presented as 'High' or 'Low' values based on the reference laboratory standards.
Number of Participants With Clinical Chemistry Values of Potential Clinical Importance in Part B
Time Frame: Up to Day 392 in Part B
Blood samples were collected at Screening and on Day 28, 168 and 364 in Part B to evaluate clinical chemistry parameters which included ALT, albumin, ALP, AST, total bilirubin, calcium, bicarbonate, chloride, creatinine, direct bilirubin, GGT, glucose, potassium, total protein, sodium, BUN and uric acid. Clinical chemistry values of potential clinical importance were presented as 'High' or 'Low' values based on the reference laboratory standards. Only those participants with data available at the specified time points were analyzed (represented by n=X, X in the category titles).
Number of Participants With Urinalysis Dipstick Results in Part A
Time Frame: Up to Day 28 in Part A
Test strip urinalysis was done for glucose, ketones, occult blood and protein at Screening and Day 14 in Part A. Results were presented as negative, trace, 1+, 2+ and 3+ for glucose, ketones, occult blood and protein. Only those participants with data available at the specified time points were analyzed (represented by n=X in the category titles).
Number of Participants With Urinalysis Dipstick Results in Part B
Time Frame: Up to Day 392 in Part B
Test strip urinalysis was done for glucose, ketones, occult blood and protein at Screening and on Day 28, 168, 224 and 364 in Part B. Results were presented as negative, trace, 1+, 2+ and 3+ for glucose, ketones, occult blood and protein. Only those participants with data available at the specified time points were analyzed (represented by n=X, X in the category titles).
Change From Baseline in Urine Power of Hydrogen (pH) at Day 14 in Part A
Time Frame: Up to Day 28 in Part A
Urinalysis including urine pH was done at Screening and Day 14 in Part A. Baseline was considered as the measurement obtained at Screening (Day -1). The change from Baseline was calculated by subtracting the Baseline values from the individual post-randomization values.
Change From Baseline in Urine pH in Part B
Time Frame: Up to Day 392 in Part B
Urinalysis including urine pH was done at Screening and on Day 28, 168 and 364 in Part B. Baseline was considered as the measurement obtained at Screening (Day -1). The change from Baseline was calculated by subtracting the Baseline values from the individual post-randomization values. Only those participants with data available at the specified time points were analyzed (represented by n=X, X in the category titles).
Change From Baseline in Urine Specific Gravity of Urine in Part A
Time Frame: Up to Day 28 in Part A
Urinalysis including urine specific gravity was done at Screening and Day 14 in Part A. Baseline was considered as the measurement obtained at Screening (Day -1). The change from Baseline was calculated by subtracting the Baseline values from the individual post-randomization values.
Change From Baseline in Urine Specific Gravity of Urine in Part B
Time Frame: Up to Day 392 in Part B
Urinalysis including urine specific gravity was done at Screening and on Day 28, 168 and 364 in Part B. Baseline was considered as the measurement obtained at Screening (Day -1). The change from Baseline was calculated by subtracting the Baseline values from the individual post-randomization values.
Change From Baseline in Forced Expiratory Volume in One Second (FEV1) and Forced Vital Capacity (FVC) at the Indicated Time Points in Part A
Time Frame: Up to Day 28 in Part A
FEV1 measures how much air a person can exhale during a forced breath in 1 second. FVC is the total amount of air exhaled during the FEV test. FEV1 and FVC were performed at Screening and on Day 1, 14 and at Follow-up visit (Day 21 to 28). FEV1 and FVC assessments at each time point (post-bronchodilator) were taken in triplicate. The maximum of the triplicate assessments were used. Baseline was considered as the measurement obtained at Day 1 pre-dose. The change from Baseline was calculated by subtracting the Baseline values from the individual post-randomization values.
Change From Baseline in FEV1 and FVC at the Indicated Time Points in Part B
Time Frame: Up to Day 392 in Part B
FEV1 and FVC were performed at Screening and on Day 1, 28, 56, 112, 168, 280, 364 and at Follow-up (Day 378 to 392) in Part B. FEV1 and FVC assessments at each time point (post-bronchodilator) were taken in triplicate. The maximum of the triplicate assessments were used. Baseline was considered as the measurement obtained at Day 1 pre-dose. The change from Baseline was calculated by subtracting the Baseline values from the individual post-randomization values. Statistical analysis was performed using a repeated measures mixed effects model in a Bayesian framework. The estimate of the treatment difference and corresponding 95 percent credible interval was constructed for the difference between danirixin and placebo for each visit. Only those participants available at the specified time points were analyzed (represented by n=X, X in the category titles).
Maximum Observed Plasma Concentration (Cmax) of Danirixin in Part A
Time Frame: 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
Cmax of danirixin was derived from the Pharmacokinetics (PK) samples collected at 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. PK analysis of danirixin was conducted by non-compartmental methods. PK Concenteration Population comprised of par. in the ITT Population and who had provided at least one on-treatment blood sample for determination of danirixin concentration.
Time of Occurrence of Cmax (Tmax) of Danirixin in Part A
Time Frame: 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
Tmax of danirixin was derived from the PK samples collected at 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. PK analysis of danirixin was conducted by non-compartmental methods.
Area Under the Blood Concentration-time Curve (AUC) Over Dosing Interval (AUC[0-12]) of Danirixin in Part A
Time Frame: 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
AUC (0-12) of danirixin was derived from the PK samples collected at 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. PK analysis of danirixin was conducted by non-compartmental methods. A Bayesian random effects model was performed adjusting for the trial as a random effect. A non-informative normal prior distribution was used. Point estimates and corresponding 90 percent credible intervals were constructed.
Number of Health Care Resource Utilization (HCRU) Defined COPD Exacerbations Per Year in Part B
Time Frame: Up to Day 392 in Part B
HCRU COPD exacerbations are defined as moderate or severe exacerbations based on requirement of new prescription antibiotics or oral corticosteroids, hospitalization or emergency room visits for management of COPD exacerbation. For par. with less than 364 days on-treatment, the annual exacerbation rate was imputed as the number of recorded on-treatment exacerbations, divided by the number of 4-week treatment period intervals for which the par. was in the study, multiplied by 13. For par. with 364 or more days on-treatment, the annual exacerbation rate was calculated as the number of recorded exacerbations between study days 1 and 364. Statistical analysis was done using a Bayesian Cox model, assuming a negative binomial distribution for the underlying exacerbation rate. The exacerbation rates along with the ratio (danirixin/placebo), were estimated and corresponding 95 percent credible intervals were produced using non-informative priors. 1 par. was excluded from the analysis.
Monthly Weighted Means of Exacerbations of Chronic Pulmonary Disease Tool-respiratory Symptoms (EXACT-RS) Total Score in Part B
Time Frame: Up to Day 392 in Part B
EXACT-RS is a tool which consists of 11 items from the 14 item EXACT- patient reported outcomes (EXACT-PRO) instrument, intended to capture information related to the respiratory symptoms of COPD, i.e. breathlessness, cough, sputum production, chest congestion and chest tightness. The EXACT-RS has a scoring range of 0-40, higher scores indicate more severe symptoms. A par. had at least 10 days of diary data in any month to contribute a non-missing weighted mean AUC of daily values; otherwise the weighted mean for that month were considered missing. A mixed effects model in a Bayesian framework with repeated measures were performed on the EXACT-RS monthly weighted mean AUC data. The posterior mean and corresponding 95 percent credible interval were calculated. Only those participants with data available at the specified time points were analyzed (represented by n=X, X in the category titles).
Secondary Outcomes
- Assessment of Severity of EXACT-PRO Events in Part B(Up to Day 392 in Part B)
- Number of Participants With Patient Global Impression of Change (PGIC)Score in Part B(Up to Day 392 in Part B)
- Change From Baseline for COPD Assessment Test (CAT) at the Indicated Time Points in Part B(Up to Day 392 in Part B)
- Cmax of Danirixin in Part B(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)
- Tmax of Danirixin in Part B(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)
- AUC(0-12) of Danirixin in Part B(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)
- Number of EXACT-PRO Exacerbations Per Year in Part B(Up to Day 392 in Part B)
- Monthly Weighted Means of Exacerbations of EXACT-PRO Total Score in Part B(Up to Day 392 in Part B)
- Time to First HCRU COPD Exacerbation in Part B(Up to Day 392 in Part B)
- Time to First EXACT-PRO Event in Part B(Up to Day 392 in Part B)
- Assessment of Duration of EXACT-PRO Events in Part B(Up to Day 392 in Part B)
- Monthly Weighted Means of EXACT-RS Domain Scores in Part B(Up to Day 392 in Part B)
- Number of Participants With Physician's Global Assessment (PGA) Readings in Part B(Up to Day 392 in Part B)
- Number of Participants With Patient Global Rating of Severity (PGRS) Score in Part B(Up to Day 392 in Part B)