Clinical trial NCT03034967: Danirixin Dose Ranging Study in Participants With Chronic Obstructive Pulmonary Disease (COPD)
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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Pulmonary Disease, Chronic Obstructive
Keywords: HCRU exacerbations
SGRQ
CXCR2 antagonist
GSK1325756
Danirixin
COPD
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2017-01-27
Enrollment: 614
Sex: ALL
Minimum age (years): 40
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility 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.

Primary outcomes:
measure: Change From Baseline in Respiratory Symptoms Measured by Evaluating Respiratory Symptoms (E-RS) in COPD. E-RS: COPD Total Score
timeFrame: Baseline and Month 6
measure: Change From Baseline in Respiratory Symptoms Measured by E-RS in COPD (E-RS: COPD Breathlessness Score)
timeFrame: Baseline and Month 6
measure: Change From Baseline in Respiratory Symptoms Measured by E-RS in COPD (E-RS: COPD Cough and Sputum Score)
timeFrame: Baseline and Month 6
measure: Change From Baseline in Respiratory Symptoms Measured by E-RS in COPD (E-RS: COPD Chest Symptoms Score)
timeFrame: Baseline and Month 6
measure: Number of Participants With Adverse Events (AE) and Serious Adverse Events (SAE)
timeFrame: Up to Day 196
measure: Number of Participants With Worst Case Hematology Parameter Results by Potential Clinical Importance (PCI)
timeFrame: Up to Day 196
measure: Number of Participants With Worst Case Clinical Chemistry Parameter Results by PCI
timeFrame: Up to Day 196
measure: Number of Participants With Worst Case Vital Signs Parameter Results by PCI
timeFrame: Up to Day 168
measure: Number of Participants With Worst Case Post-Baseline Abnormal 12-lead Electrocardiogram (ECG) Findings
timeFrame: Baseline and Day 168
Secondary outcomes:
measure: Number of Moderate or Severe Healthcare Resource Utilization (HCRU) Exacerbations Per Participant
timeFrame: Up to Day 196
measure: Number of Responders E-RS in COPD (E-RS): COPD Total Score
timeFrame: Month 6
measure: Number of EXACT Events Per Participant
timeFrame: Up to Day 196
measure: Time to First EXACT Event
timeFrame: Up to Day 168
measure: Severity of EXACT Event
timeFrame: Up to Day 168
measure: EXACT Event Duration for All Events
timeFrame: Up to Day 168
measure: Time to First HCRU-defined COPD Exacerbation
timeFrame: Up to Day 196
measure: Time to First Severe HCRU-defined COPD Exacerbation
timeFrame: Up to Day 196
measure: HCRU-defined Exacerbation Duration
timeFrame: Up to Day 196
measure: Change From Baseline in St. George's Respiratory Questionnaire for COPD Patients (SGRQ-C) Total Score
timeFrame: Baseline, Days 84 and 168
measure: Number of SGRQ Responder
timeFrame: Day 84 and Day 168
measure: Change From Baseline COPD Assessment Test (CAT) Total Score
timeFrame: Baseline, Days 84 and 168
measure: Number of CAT Responder
timeFrame: Day 84 and Day 168
measure: Change From Baseline in Post-bronchodilator FEV1 as a Lung Function Assessment
timeFrame: Baseline, Days 84 and 168
measure: Percent Predicted Normal FEV1
timeFrame: At Screening
measure: Change From Baseline in Post-bronchodilator Forced Vital Capacity (FVC) as a Lung Function Assessment
timeFrame: Baseline, Days 84 and 168
measure: Change From Baseline in Post-bronchodilator FEV1/FVC Ratio as a Lung Function Assessment
timeFrame: Baseline, Days 84 and 168
measure: Change From Baseline Number of Puffs of Rescue Medication Per Day
timeFrame: Baseline, Months 1, 2, 3, 4, 5 and 6
measure: Participant Experience of Physical Activity Measured Using PROactive Physical Activity in COPD (C-PPAC) Questionnaire
timeFrame: Days 84 and 168
measure: Danirixin Whole Blood Pharmacokinetic Concentration-Time Data
timeFrame: Pre-dose on Days 1, 56, 84 and 168; 0.5, 1, 2, 4, 6, 8, 10, 12 hours post-dose on Days 1 and 168
measure: Area Under the Plasma Concentration-time Curve From Time Zero to Last Time of Quantifiable Concentration [AUC(0-t)] of Danirixin in Whole Blood Using Dried Blood Spot
timeFrame: Days 1 and 168
measure: Concentration Maximum (Cmax) of Danirixin in Whole Blood Using Dried Blood Spots
timeFrame: Days 1 and 168
measure: Time to Reach Maximum Plasma Concentration (Tmax) of Danirixin in Whole Blood Using Dried Blood Spots
timeFrame: Days 1 and 168
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: GSK Investigational Site
state: Alabama
city: Birmingham
country: United States
facility: GSK Investigational Site
state: Alabama
city: Topeka
country: United States
facility: GSK Investigational Site
state: Kansas
city: Saint Louis
country: United States
facility: GSK Investigational Site
state: Missouri
city: Greensboro
country: United States
facility: GSK Investigational Site
state: North Carolina
city: Medford
country: United States
facility: GSK Investigational Site
state: Oregon
city: Orangeburg
country: United States
facility: GSK Investigational Site
state: South Carolina
city: Spartanburg
country: United States
facility: GSK Investigational Site
state: South Carolina
city: Morgantown
country: United States
facility: GSK Investigational Site
state: West Virginia
city: Randwick
country: Australia
facility: GSK Investigational Site
state: New South Wales
city: Westmead
country: Australia
facility: GSK Investigational Site
state: New South Wales
city: Clayton
country: Australia
facility: GSK Investigational Site
state: Victoria
city: Footscray
country: Australia
facility: GSK Investigational Site
state: Victoria
city: Murdoch
country: Australia
facility: GSK Investigational Site
state: Western Australia
city: Winnipeg
country: Canada
facility: GSK Investigational Site
state: Manitoba
city: Truro
country: Canada
facility: GSK Investigational Site
state: Nova Scotia
city: Toronto
country: Canada
facility: GSK Investigational Site
state: Ontario
city: Gatineau
country: Canada
facility: GSK Investigational Site
state: Quebec
city: St. Charles-Borromee
country: Canada
facility: GSK Investigational Site
state: Quebec
city: Quebec
country: Canada
facility: GSK Investigational Site
city: Darmstadt
country: Germany
facility: GSK Investigational Site
state: Hessen
city: Frankfurt
country: Germany
facility: GSK Investigational Site
state: Hessen
city: Frankfurt
country: Germany
facility: GSK Investigational Site
state: Hessen
city: Hannover
country: Germany
facility: GSK Investigational Site
state: Niedersachsen
city: Koblenz
country: Germany
facility: GSK Investigational Site
state: Rheinland-Pfalz
city: Leipzg
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
city: Berlin
country: Germany
facility: GSK Investigational Site
city: Bucheon-Si, Gyeonggi-Do
country: Korea, Republic of
facility: GSK Investigational Site
city: Incheon
country: Korea, Republic of
facility: GSK Investigational Site
city: Seoul
country: Korea, Republic of
facility: GSK Investigational Site
city: Seoul
country: Korea, Republic of
facility: GSK Investigational Site
city: Seoul
country: Korea, Republic of
facility: GSK Investigational Site
city: Seoul
country: Korea, Republic of
facility: GSK Investigational Site
city: Seoul
country: Korea, Republic of
facility: GSK Investigational Site
city: Wonju-si, Gangwon-do
country: Korea, Republic of
facility: GSK Investigational Site
city: Alkmaar
country: Netherlands
facility: GSK Investigational Site
city: Breda
country: Netherlands
facility: GSK Investigational Site
city: Eindhoven
country: Netherlands
facility: GSK Investigational Site
city: Hengelo
country: Netherlands
facility: GSK Investigational Site
city: Hoorn
country: Netherlands
facility: GSK Investigational Site
city: Ksawerow
country: Poland
facility: GSK Investigational Site
city: Lubin
country: Poland
facility: GSK Investigational Site
city: Ostrowiec Swietokrzyski
country: Poland
facility: GSK Investigational Site
city: Szczecin
country: Poland
facility: GSK Investigational Site
city: Wroclaw
country: Poland
facility: GSK Investigational Site
city: Bacau
country: Romania
facility: GSK Investigational Site
city: Bucharest
country: Romania
facility: GSK Investigational Site
city: Cluj Napoca
country: Romania
facility: GSK Investigational Site
city: Cluj Napoca
country: Romania
facility: GSK Investigational Site
city: Constanta
country: Romania
facility: GSK Investigational Site
city: Focsani
country: Romania
facility: GSK Investigational Site
city: Iasi
country: Romania
facility: GSK Investigational Site
city: Ramnicu Valcea
country: Romania
facility: GSK Investigational Site
city: Slobozia
country: Romania
facility: GSK Investigational Site
city: Suceava
country: Romania
facility: GSK Investigational Site
city: Barcelona
country: Spain
facility: GSK Investigational Site
city: Madrid
country: Spain
facility: GSK Investigational Site
city: Pozuelo De Alarcón/Madrid
country: Spain
facility: GSK Investigational Site
city: Salamanca
country: Spain
facility: GSK Investigational Site
city: Santander
country: Spain
facility: GSK Investigational Site
city: Zaragoza
country: Spain
facility: GSK Investigational Site
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Lazaar AL, Miller BE, Donald AC, Keeley T, Ambery C, Russell J, Watz H, Tal-Singer R; for 205724 Investigators. CXCR2 antagonist for patients with chronic obstructive pulmonary disease with chronic mucus hypersecretion: a phase 2b trial. Respir Res. 2020 Jun 12;21(1):149. doi: 10.1186/s12931-020-01401-4.