Last updated: 10/06/2020 19:20:07
Danirixin dose ranging study in participants with Chronic Obstructive Pulmonary Disease (COPD)
EudraCT ID
EU CT Number
Not applicable
Trial status
Completed
Completed
Trial overview
Official title: Randomised, Double-Blind (Sponsor Open), Placebo-Controlled, Multicentre, Dose Ranging Study to Evaluate the Efficacy and Safety of Danirixin Tablets Administered Twice Daily Compared With Placebo for 24 Weeks in Adult Participants With Chronic Obstructive Pulmonary Disease (COPD)
Trial description: Danirixin (DNX) is a selective CXC chemokine receptor (CXCR2) antagonist being developed as a potential anti-inflammatory agent for the treatment of COPD. This is a Phase 2, randomized, double-blind (Sponsor Open) study. The primary objective of the study is to evaluate the clinical activity and safety of danirixin compared with placebo in participants with COPD. Following baseline assessments collected over a 7 day period participants will be randomized (1:1:1:1:1:1) to receive one of five dose strengths of danirixin (5 milligram [mg], 10 mg, 25 mg, 35 mg and 50 mg) or placebo. Study treatment will be administered orally twice daily for 24 weeks. Participants will continue with their standard of care inhaled medications (i.e. long acting bronchodilators with or without inhaled corticosteroids) while receiving study treatment. Follow up will continue up to 28 days post last dose. Approximately 700 participants will be screened with a target of 540 participants completing 24 weeks of treatment and key study assessments.
Primary purpose:
Treatment
Trial design:
Parallel Assignment
Masking:
Double (Participant, Investigator)
Allocation:
Randomized
Primary outcomes:
Change from baseline in respiratory symptoms measured by Evaluating Respiratory Symptoms in COPD (E-RS)
Timeframe: Baseline and Day 168
Number of participants with any adverse events (AEs) and serious adverse events (SAEs)
Timeframe: Up to Day 196
Number of participants with abnormal clinical chemistry as a measure of safety
Timeframe: Up to Day 196
Number of participants with abnormal hematological parameters as a measure of safety
Timeframe: Up to Day 196
Number of participants with abnormal electrocardiogram (ECG) assessment
Timeframe: Up to Day 168
Number of participants with abnormal blood pressure assessment
Timeframe: Up to Day 168
Number of participants with abnormal pulse rate measurement
Timeframe: Up to Day 168
Number of participants with abnormal body temperature
Timeframe: Up to Day 168
Number of participants with abnormal respiratory rate
Timeframe: Up to Day 168
Secondary outcomes:
Number of participants with Healthcare Resource Utilization (HCRU)-defined COPD exacerbations
Timeframe: Up to Day 196
Responder analysis of E-RS
Timeframe: Up to Day 168
Number of Exacerbations of Chronic Pulmonary Disease tool (EXACT) defined events
Timeframe: Up to Day 196
Time to first EXACT event
Timeframe: Up to Day 168
EXACT event severity
Timeframe: Up to Day 168
EXACT event duration for all events
Timeframe: Up to Day 168
Time to first HCRU-defined COPD exacerbation
Timeframe: Up to Day 196
Time to first severe HCRU-defined COPD exacerbation
Timeframe: Up to Day 196
HCRU-defined exacerbation duration
Timeframe: Up to Day 196
Change From Baseline in St. George's Respiratory Questionnaire for COPD Patients (SGRQ-C) Total Score
Timeframe: Baseline and Day 168
SGRQ responder analysis
Timeframe: Up to Day 168
Change for baseline COPD Assessment Test (CAT) total score
Timeframe: Baseline and Day 168
CAT responder analysis
Timeframe: Up to Day 168
Forced Expiratory Volume in one second (FEV1) as a lung function assessment
Timeframe: Up to Day 168
Percent Predicted FEV1 as a lung function assessment
Timeframe: Up to Day 168
Forced Vital Capacity (FVC) as a lung function assessment
Timeframe: Up to Day 168
FEV1/FVC ratio as a lung function assessment
Timeframe: Up to Day 168
Use of rescue medication
Timeframe: Up to Day 168
Participant experience of physical activity measured using PROactive physical activity in COPD (C-PPAC) questionnaire
Timeframe: Up to Day 168
Area under the curve (AUC) from time zero to 12 hours of Danirixin in whole blood
Timeframe: Pre-dose, and post-dose at 0.5, 1, 2, 4, 6, 8, 10, 12 hours
Concentration maximum (Cmax) of Danirixin in whole blood
Timeframe: Pre-dose, and post-dose at 0.5, 1, 2, 4, 6, 8, 10, 12 hours
Time to reach maximum plasma concentration (tmax) of Danirixin in whole blood
Timeframe: Pre-dose, and post-dose at 0.5, 1, 2, 4, 6, 8, 10, 12 hours
Interventions:
Drug: Danirixin
Drug: Danirixin matching placebo
Drug: Standard of care
Drug: Rescue medication
Enrollment:
614
Observational study model:
Not applicable
Primary completion date:
2018-05-10
Time perspective:
Not applicable
Clinical publications:
Aili Lazaar, Bruce Miller Alison Donald Tom Keeley Claire Ambery John Russell Henrik Watz Ruth Tal-Singer. CXCR2 antagonist for patients with chronic obstructive pulmonary disease with chronic mucus hypersecretion: a phase 2b trial. Respir Res. 2020;21(49)
DOI: 10.1186/s12931-020-01401-4
Medical condition
Pulmonary Disease, Chronic Obstructive
Product
danirixin
Collaborators
Not applicable
Study date(s)
April 2017 to October 2018
Type
Interventional
Phase
2
Participation criteria
Sex
Female & Male
Age
40 - 80 years
Accepts healthy volunteers
No
- Inclusion Criteria
- Participants must be aged between 40 to 80 years of age inclusive, at the time of signing the informed consent.
Inclusion and exclusion criteria
Inclusion criteria:
- Inclusion Criteria
- Participants must be aged between 40 to 80 years of age inclusive, at the time of signing the informed consent.
- Participants who have COPD (post bronchodilator FEV1/FVC ratio <0.7 and FEV1% predicted >=40%) based on American Thoracic Society (ATS)/European Respiratory Society (ERS) current guidelines. Participants with a historical diagnosis of asthma may be included so long as they have a current diagnosis of COPD.
- History of respiratory symptoms including chronic cough, mucus hypersecretion, and dyspnea on most days for at least the previous 3 months prior to screening.
- Participants with a documented history of COPD exacerbation(s) in the 12 months prior to study participation (screening) 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 of hospitalization or extended observation in a hospital emergency room or outpatient center and a plasma fibrinogen concentration at screening >=3 grams/liter (300 milligram/deciliter)
- Current 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). Current smokers are defined as those who are currently smoking cigarettes (i.e. have smoked at least one cigarette daily or most days for the month prior to Visit 1). Former smokers are defined as those who have stopped smoking for at least 6 months prior to Visit 1.
- Participants must have the ability and willingness to use an electronic diary (log pad) on a daily basis.
- Body weight >=45 kilogram (kg)
- Male or female: A male participant must agree to use contraception during the treatment period and for at least 60 hours after the last dose of study treatment, corresponding to approximately 6 half-lives (which is the time needed to eliminate any teratogenic study treatment) and to refrain from donating sperm during this period; A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies: Not a woman of childbearing potential (WOCBP) OR A WOCBP who agrees to follow the contraceptive guidance during the treatment period and for at least 60 hours after the last dose of study treatment.
- Capable of giving signed informed consent. Exclusion Criteria
- Diagnosis of other clinically relevant lung diseases (other than COPD), e.g. sarcoidosis, tuberculosis, pulmonary fibrosis, severe bronchiectasis or lung cancer.
- Alpha-1-antitrypsin deficiency as the underlying cause of COPD
- Pulse oximetry <88% at rest at screening. Participants should be tested while breathing room air. However, participants living at high altitudes (above 5000 feet or 1500 meters above sea level) who are receiving supplemental oxygen can be included provided they are receiving the equivalent of <4 liter per minute (L/min) and screening pulse oximetry is measured while on their usual oxygen settings.
- Less than 14 days have elapsed from the completion of a course of antibiotics or oral corticosteroids for a recent COPD exacerbation.
- A peripheral blood neutrophil count <1.5 x 10^9/L.
- Diagnosis of pneumonia (chest X-ray or CT confirmed) within the 3 months prior to screening.
- Chest x-ray (posterior-anterior with lateral) or CT scan reveals evidence of a clinically significant abnormality not believed to be due to the presence of COPD (historic results up to 1 year prior to screening may be used). For sites in Germany: If a chest x-ray (or CT scan) within 1 year prior to screening is not available, approval to conduct a diagnostic chest x-ray will need to be obtained from the Federal Office of Radiation Protection (BfS).
- History or current evidence of other clinically significant medical condition that is uncontrolled on permitted therapies. Significant is defined as any disease that, in the opinion of the Investigator, would put the safety of the participant at risk through study participation, or that would affect the safety analysis or other analysis if the disease/condition worsened during the study.
- Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert’s syndrome or asymptomatic gallstones).
- Abnormal and clinically significant 12-lead ECG finding. The investigator will determine the clinical significance of each abnormal ECG finding in relation to the participant’s medical history and exclude participants who would be at undue risk by participating in the study. An abnormal and clinically significant finding that would preclude a participant from entering the study is defined as a 12-lead tracing that is interpreted as, but not limited to, any of the following: atrial fibrillation with rapid ventricular rate >120 beats per minute (bpm); sustained or non-sustained ventricular tachycardia; second degree heart block Mobitz type II and third degree heart block (unless pacemaker or defibrillator has been implanted); Corrected QT Interval using Fridericia formula (QTcF) >=500 millisecond (msec) in participants with QRS <120 msec and QTcF >=530 msec in participants with QRS >=120 msec.
- Previous lung surgery (e.g. lobectomy, pneumonectomy) or lung volume reduction procedure.
- Current or expected chronic use of macrolide antibiotics during the study period for the prevention of COPD exacerbations. Examples of chronic use include, but are not limited to, daily or two to three times per week use for at least 3 months.
- Oral or injectable CYP3A4 or breast cancer resistance protein (BRCP) substrates with a narrow therapeutic index (CYP3A4 substrates include, but are not limited to, alfenatil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, tacrolimus, and theophylline; BRCP substrates include, but are not limited to, topotecan.) The Investigator should consult with the Medical Monitor if necessary.
- Current or expected use of phosphodiesterase-4 inhibitors (e.g. roflumilast). Participants currently receiving roflumilast may be included if they are able to discontinue use from 30 days prior to screening through the completion of the follow up visit.
- Participation in a previous clinical trial and has received an investigational product within any of the following time periods 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).
- Participation in a previous clinical trial with danirixin within 1 year prior to the first dosing day in the current study
- Exposure to more than four investigational products within 1 year prior to the first dosing day in the current study.
- Alanine transferase (ALT) >2x upper limit of normal (ULN); bilirubin > 1.5xULN (isolated bilirubin > 1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%).
- 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 prior to screening.
- Pulmonary rehabilitation: Participants who have taken part in the acute phase of a pulmonary rehabilitation program within 4 weeks prior to screening or participants who plan to enter the acute phase of a pulmonary rehabilitation program during the study. Participants who are in the maintenance phase of a pulmonary rehabilitation program are not excluded.
- A history of allergy or hypersensitivity to any of the ingredients in the study treatment.
- A known or suspected history of alcohol or drug abuse within the 2 years prior to screening.
- Inability to read: in the opinion of the Investigator, any participant who is unable to read and/or would not be able to complete study related materials.
- Affiliation with the study site: study investigators, sub-investigators, study coordinators, employees of a study investigator, sub-investigator or study site, or immediate family member of any of the above that are involved with the study.
Trial location(s)
Location
GSK Investigational Site
Birmingham, Alabama, United States, 35243
Status
Study Complete
Location
GSK Investigational Site
Birmingham, Alabama, United States, 35294
Status
Study Complete
Location
GSK Investigational Site
Bucheon-Si, Gyeonggi-Do, South Korea, 420-021
Status
Study Complete
Location
GSK Investigational Site
Greensboro, North Carolina, United States, 27403
Status
Study Complete
Location
GSK Investigational Site
Grosshansdorf, Schleswig-Holstein, Germany, 22927
Status
Study Complete
Location
GSK Investigational Site
Hannover, Niedersachsen, Germany, 30173
Status
Study Complete
Location
GSK Investigational Site
Koblenz, Rheinland-Pfalz, Germany, 56068
Status
Study Complete
Location
GSK Investigational Site
MORGANTOWN, West Virginia, United States, 26505
Status
Study Complete
Location
GSK Investigational Site
Murdoch, Western Australia, Australia, 6150
Status
Study Complete
Location
GSK Investigational Site
Orangeburg, South Carolina, United States, 29118
Status
Study Complete
Location
GSK Investigational Site
Ostrowiec Swietokrzyski, Poland, 27-400
Status
Study Complete
Location
GSK Investigational Site
Pozuelo de Alarcón/Madrid, Spain, 28223
Status
Study Complete
Location
GSK Investigational Site
Randwick, New South Wales, Australia, 2031
Status
Study Complete
Location
GSK Investigational Site
Spartanburg, South Carolina, United States, 29303
Status
Study Complete
Location
GSK Investigational Site
St. Charles-Borromee, Québec, Canada, J6E 2B4
Status
Study Complete
Location
GSK Investigational Site
St. Louis, Missouri, United States, 63141
Status
Study Complete
Location
GSK Investigational Site
Westmead, New South Wales, Australia, 2145
Status
Study Complete
Location
GSK Investigational Site
Wonju-si, Gangwon-do, South Korea, 220-701
Status
Study Complete
Study documents
Clinical study report
Available language(s): English
Protocol
Available language(s): English
Statistical analysis plan
Available language(s): English
If you wish to request for full study report, please contact - [email protected]
Results overview
Results posted on ClinicalTrials.gov
Recruitment status
Completed
Actual primary completion date
2018-05-10
Actual study completion date
2018-05-10
Plain language summaries
Summary of results in plain language
Available language(s): English, German, Spanish, French (Canadian), Korean, Dutch, Polish, Romanian
To view plain language summaries on trialsummaries.com click here.
Additional information about the trial
Additional information
Not applicable
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