Danirixin Dose Ranging Study in Participants With Chronic Obstructive Pulmonary Disease (COPD)

GlaxoSmithKline (GSK)

Status and phase: Completed; Phase 2

Conditions: Pulmonary Disease, Chronic Obstructive

Treatments: Drug: Danirixin matching placebo; Drug: Standard of care; Drug: Rescue medication; Drug: Danirixin

Study type: Interventional

Funder types: Industry

Identifiers

NCT03034967

2016-003675-21 (EudraCT Number)

205724

Details and patient eligibility

About

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.

Enrollment: 614 patients

Sex: All

Ages: 40 to 80 years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion 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 design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Double Blind

---

614 participants in 6 patient groups, including a placebo group

Danirixin 5 mg

Experimental group

Description:

Eligible participants will receive danirixin 5 mg tablet with food twice daily along with standard care of treatment for 24 weeks.

Treatment:

Drug: Rescue medication

Drug: Standard of care

Drug: Danirixin

Danirixin 10 mg

Experimental group

Description:

Eligible participants will receive danirixin 10 mg tablet with food twice daily along with standard care of treatment for 24 weeks.

Treatment:

Drug: Rescue medication

Drug: Standard of care

Drug: Danirixin

Danirixin 25 mg

Experimental group

Description:

Eligible participants will receive danirixin 25 mg tablet with food twice daily along with standard care of treatment for 24 weeks.

Treatment:

Drug: Rescue medication

Drug: Standard of care

Drug: Danirixin

Danirixin 35 mg

Experimental group

Description:

Eligible participants will receive danirixin 35 mg tablet with food twice daily along with standard care of treatment for 24 weeks.

Treatment:

Drug: Rescue medication

Drug: Standard of care

Drug: Danirixin

Danirixin 50 mg

Experimental group

Description:

Eligible participants will receive danirixin 50 mg tablet with food twice daily along with standard care of treatment for 24 weeks.

Treatment:

Drug: Rescue medication

Drug: Standard of care

Drug: Danirixin

Placebo

Placebo Comparator group

Description:

Eligible participants will receive placebo tablet with food twice daily along with standard care of treatment for 24 weeks.

Treatment:

Drug: Rescue medication

Drug: Standard of care

Drug: Danirixin matching placebo