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

NCT03034967 | Completed Phase 2 Results FDA Drug

• 2 other identifiers: 2057242016-003675-21
• Study Type: interventional
• Target: 614
• Locations: 9 countries
• Sites: 64

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.

Conditions

Pulmonary Disease, Chronic Obstructive

Keywords

HCRU exacerbations; SGRQ; CXCR2 antagonist; GSK1325756; Danirixin; COPD

Outcome Measures

Primary Outcomes (9)

• Change From Baseline in Respiratory Symptoms Measured by Evaluating Respiratory Symptoms (E-RS) in COPD. E-RS: COPD Total Score

  E-RS: COPD is a subset of Exacerbations of Chronic pulmonary Disease Tool (EXACT). E-RS is a tool that consists of 11 items from the 14 item EXACT instrument. The domains include: respiratory symptoms (RS)-breathlessness (RS-BRL comprised of 5 items, score range \[0-17\]), RS-cough and sputum (RS-CSP comprised of 3 items, score range \[0-11\]), and RS-chest symptoms (RS-CSY comprised of 3 items, score range \[0-12\]). The total score ranged between 0-40 and higher values indicates severe respiratory symptoms. Day 1 was considered as Baseline. Change from Baseline was calculated by subtracting Baseline value from the specified time point value. Per protocol population included all participants from the mITT population who did not have a protocol deviation considered to impact efficacy. Posterior mean change and standard deviation has been presented.

  Baseline and Month 6

• Change From Baseline in Respiratory Symptoms Measured by E-RS in COPD (E-RS: COPD Breathlessness Score)

  E-RS: COPD is a subset of EXACT. E-RS is a tool that consists of 11 items from the 14 item EXACT instrument. The domains include: RS-BRL comprised of 5 items, score range (0-17), RS-CSP comprised of 3 items, score range (0-11), and RS-CSY comprised of 3 items, score range (0-12). The total score ranged between 0-40 and higher values indicates severe respiratory symptoms. Day 1 was considered as Baseline. Change from Baseline was calculated by subtracting Baseline value from the specified time point value. Posterior mean change and standard deviation has been presented.

  Baseline and Month 6

• Change From Baseline in Respiratory Symptoms Measured by E-RS in COPD (E-RS: COPD Cough and Sputum Score)

  E-RS: COPD is a subset of EXACT. E-RS is a tool that consists of 11 items from the 14 item EXACT instrument. The domains include: RS-BRL comprised of 5 items, score range (0-17), RS-CSP comprised of 3 items, score range (0-11), and RS-CSY comprised of 3 items, score range (0-12). The total score ranged between 0-40 and higher values indicates severe respiratory symptoms. Day 1 was considered as Baseline. Change from Baseline was calculated by subtracting Baseline value from the specified time point value. Posterior mean change and standard deviation has been presented.

  Baseline and Month 6

• Change From Baseline in Respiratory Symptoms Measured by E-RS in COPD (E-RS: COPD Chest Symptoms Score)

  E-RS: COPD is a subset of EXACT. E-RS is a tool that consists of 11 items from the 14 item EXACT instrument. The domains include: RS-BRL comprised of 5 items, score range (0-17), RS-CSP comprised of 3 items, score range (0-11), and RS-CSY comprised of 3 items, score range (0-12). The total score ranged between 0-40 and higher values indicates severe respiratory symptoms. Day 1 was considered as Baseline. Change from Baseline was calculated by subtracting Baseline value from the specified time point value. Posterior mean change and standard deviation has been presented.

  Baseline and Month 6

• Number of Participants With Adverse Events (AE) and Serious Adverse Events (SAE)

  AE is any untoward medical occurrence in a participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. SAE is any untoward event resulting in death, life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, congenital anomaly/birth defect or any other situation according to medical or scientific judgment is categorized as SAE.

  Up to Day 196

• Number of Participants With Worst Case Hematology Parameter Results by Potential Clinical Importance (PCI)

  Blood samples were collected from participants for analysis of following hematology parameters with PCI low and high values: Basophils % (High 5.00x), Eosinophils % (High 2.00x), Mean corpuscular hemoglobin concentration (MCHC) gram per deciliter (g/dL) (Low 0.85x, high 1.10x), Mean corpuscular hemoglobin (MCH) picograms (pg) (Low 0.85x, high 1.20x), Mean corpuscular volume (MCV) femtoliter (fL) (low 0.25x, high 2.00x), Erythrocytes (Ery.)(10\^12cells/L) (Low 0.93x, high 1.07x), Hematocrit (Ratio of 1) (Low 0.50x, high 0.50x), Hemoglobin gram per liter (g/L) (Low 0.85x, high 1.20x), Leukocytes (x10\^9/L) (Low 0.70x, high 1.60x), Lymphocytes % (Low 0.80x, high 1.20x), Monocytes % (Low 0.80x, high 1.60x), Neutrophils % (Low 0.65x, high 1.50x), Platelets (x10\^9cells/L) (Low 0.90x, high 1.10x). Multipliers are identified by "x", otherwise actual comparison values are provided with units. Values above and below this range were considered of PCI.

  Up to Day 196

• Number of Participants With Worst Case Clinical Chemistry Parameter Results by PCI

  Blood samples were collected from participants for analysis of following chemistry parameters with PCI low and high values: Alanine aminotransferase (ALT) International units per liter (IU/L) (High =\> 3x ULN), Alkaline phosphatase (ALP) (IU/L) (High ≥ 2x ULN); Aspartate aminotransferase (AST) (IU/L) (High=\> 3x ULN); Bilirubin micromole per liter (umol/L) (High ≥ 2x ULN); Calcium millimole per liter (mmol/L) (Low 0.85x, high 1.08x), Chloride (mmol/L) (Low 0.90x, high 1.10x), Creatinine (umol/L) (High 1.30x), Direct bilirubin (umol/L) (High ≥ 2x ULN), Glucose (mmol/L) (Low \<0.6x, high \>4x), Potassium (mmol/L) (Low 0.75x, high 1.30x); Protein (g/L) (High 1.25x), Sodium (mmol/L) (Low 0.80x, high 1.15x), Multipliers are identified by "x", otherwise actual comparison values are provided with units. Values above and below this range were considered of PCI.

  Up to Day 196

• Number of Participants With Worst Case Vital Signs Parameter Results by PCI

  Vital signs parameters includes systolic blood pressure (SBP) and diastolic blood pressure (DBP), pulse rate and respiration rate were measured in a semi-supine position after 5 minutes rest for the participants at indicated time points. PCI ranges for vital signs parameters were as follows: \<90 to \>160 millimeters of mercury (mmHg) for SBP and \<40 to \>110 mmHg for DBP, \<35 or \>120 beats per minute for heart rate and \<8 or \>30 breaths per minute for respiration rate. Values above and below this range were considered of PCI.

  Up to Day 168

• Number of Participants With Worst Case Post-Baseline Abnormal 12-lead Electrocardiogram (ECG) Findings

  Triplicate 12-lead ECG obtained to measure PR, QRS, QT, and Corrected QT intervals. Only those participants with worst case post-Baseline data have been represented for abnormal - not clinical significant and abnormal - clinical significant. Day 1 was considered as Baseline.

  Baseline and Day 168

Secondary Outcomes (23)

• Number of Moderate or Severe Healthcare Resource Utilization (HCRU) Exacerbations Per Participant

  Up to Day 196

• Number of Responders E-RS in COPD (E-RS): COPD Total Score

  Month 6

• Number of EXACT Events Per Participant

  Up to Day 196

• Time to First EXACT Event

  Up to Day 168

• Severity of EXACT Event

  Up to Day 168

Study Arms (6)

Danirixin 5 mg

EXPERIMENTAL

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

Drug: Danirixin; Drug: Standard of care; Drug: Rescue medication

Danirixin 10 mg

EXPERIMENTAL

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

Drug: Danirixin; Drug: Standard of care; Drug: Rescue medication

Danirixin 25 mg

EXPERIMENTAL

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

Drug: Danirixin; Drug: Standard of care; Drug: Rescue medication

Danirixin 35 mg

EXPERIMENTAL

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

Drug: Danirixin; Drug: Standard of care; Drug: Rescue medication

Danirixin 50 mg

EXPERIMENTAL

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

Drug: Danirixin; Drug: Standard of care; Drug: Rescue medication

Placebo

PLACEBO COMPARATOR

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

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

Interventions

Danirixin DRUG

Danirixin is available as 5, 10, 25, 35 and 50 mg white, film-coated, oval or round shaped tablets for oral administration.

Danirixin 10 mg; Danirixin 25 mg; Danirixin 35 mg; Danirixin 5 mg; Danirixin 50 mg

Danirixin matching placebo DRUG

Danirixin matching placebo will be available as white, film-coated, oval or round shaped tablets for oral administration.

Placebo

Standard of care DRUG

Participants will continue with their standard of care inhaled medications (i.e. long acting bronchodilators with or without inhaled corticosteroids) during the study treatment.

Danirixin 10 mg; Danirixin 25 mg; Danirixin 35 mg; Danirixin 5 mg; Danirixin 50 mg; Placebo

Rescue medication DRUG

Participants will continue to use rescue medication(s). The following rescue medications may be used: short acting beta agonists, short acting muscarinic antagonists, or short acting combination bronchodilators.

Danirixin 10 mg; Danirixin 25 mg; Danirixin 35 mg; Danirixin 5 mg; Danirixin 50 mg; Placebo

Eligibility Criteria

• Age: 40 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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).

Sponsors & Collaborators

• GlaxoSmithKline: lead

Study Sites (64)

GSK Investigational Site

Birmingham, Alabama, 35243, United States

Location

GSK Investigational Site

Birmingham, Alabama, 35294, United States

Location

GSK Investigational Site

Topeka, Kansas, 66606, United States

Location

GSK Investigational Site

St Louis, Missouri, 63141, United States

Location

GSK Investigational Site

Greensboro, North Carolina, 27403, United States

Location

GSK Investigational Site

Medford, Oregon, 97504, United States

Location

GSK Investigational Site

Orangeburg, South Carolina, 29118, United States

Location

GSK Investigational Site

Spartanburg, South Carolina, 29303, United States

Location

GSK Investigational Site

Morgantown, West Virginia, 26505, United States

Location

GSK Investigational Site

Randwick, New South Wales, 2031, Australia

Location

GSK Investigational Site

Westmead, New South Wales, 2145, Australia

Location

GSK Investigational Site

Clayton, Victoria, 3168, Australia

Location

GSK Investigational Site

Footscray, Victoria, 3011, Australia

Location

GSK Investigational Site

Murdoch, Western Australia, 6150, Australia

Location

GSK Investigational Site

Winnipeg, Manitoba, R2K 3S8, Canada

Location

GSK Investigational Site

Truro, Nova Scotia, B2N 1L2, Canada

Location

GSK Investigational Site

Toronto, Ontario, M5T 3A9, Canada

Location

GSK Investigational Site

Gatineau, Quebec, J8Y 6S8, Canada

Location

GSK Investigational Site

Québec, Quebec, G1V 4G5, Canada

Location

GSK Investigational Site

Saint-Charles-Borromée, Quebec, J6E 2B4, Canada

Location

GSK Investigational Site

Darmstadt, Hesse, 64283, Germany

Location

GSK Investigational Site

Frankfurt am Main, Hesse, 60389, Germany

Location

GSK Investigational Site

Frankfurt am Main, Hesse, 60596, Germany

Location

GSK Investigational Site

Hanover, Lower Saxony, 30173, Germany

Location

GSK Investigational Site

Koblenz, Rhineland-Palatinate, 56068, Germany

Location

GSK Investigational Site

Leipzg, Saxony, 04109, Germany

Location

GSK Investigational Site

Großhansdorf, Schleswig-Holstein, 22927, Germany

Location

GSK Investigational Site

Berlin, 10367, Germany

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GSK Investigational Site

Berlin, 10717, Germany

Location

GSK Investigational Site

Berlin, 10787, Germany

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GSK Investigational Site

Alkmaar, 1815 JD, Netherlands

Location

GSK Investigational Site

Breda, 4818 CK, Netherlands

Location

GSK Investigational Site

Eindhoven, 5623 EJ, Netherlands

Location

GSK Investigational Site

Hengelo, 7555 DL, Netherlands

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GSK Investigational Site

Hoorn, 1624 NP, Netherlands

Location

GSK Investigational Site

Ksawerów, 95-054, Poland

Location

GSK Investigational Site

Lubin, 59-300, Poland

Location

GSK Investigational Site

Ostrowiec Świętokrzyski, 27-400, Poland

Location

GSK Investigational Site

Szczecin, 71-124, Poland

Location

GSK Investigational Site

Wroclaw, 54-239, Poland

Location

GSK Investigational Site

Bacau, 600252, Romania

Location

GSK Investigational Site

Bucharest, 050159, Romania

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GSK Investigational Site

Cluj-Napoca, 400275, Romania

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GSK Investigational Site

Cluj-Napoca, 400371, Romania

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GSK Investigational Site

Constanța, 900002, Romania

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GSK Investigational Site

Focşani, 620043, Romania

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GSK Investigational Site

Iași, 700115, Romania

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GSK Investigational Site

Râmnicu Vâlcea, 240564, Romania

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GSK Investigational Site

Slobozia, 920013, Romania

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GSK Investigational Site

Suceava, 720237, Romania

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GSK Investigational Site

Bucheon-Si, Gyeonggi-Do, 420-021, South Korea

Location

GSK Investigational Site

Incheon, 403-720, South Korea

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GSK Investigational Site

Seoul, 130-709, South Korea

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GSK Investigational Site

Seoul, 130-872, South Korea

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GSK Investigational Site

Seoul, 138-736, South Korea

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GSK Investigational Site

Seoul, 156-707, South Korea

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GSK Investigational Site

Seoul, 156-755, South Korea

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GSK Investigational Site

Wonju-si, Gangwon-do, 220-701, South Korea

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GSK Investigational Site

Barcelona, 08003, Spain

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GSK Investigational Site

Madrid, 28040, Spain

Location

GSK Investigational Site

Pozuelo de Alarcón/Madrid, 28223, Spain

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GSK Investigational Site

Salamanca, 37007, Spain

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GSK Investigational Site

Santander, 39008, Spain

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GSK Investigational Site

Zaragoza, 50009, Spain

Location

Related Publications (1)

• 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.

  PMID: 32532258 BACKGROUND

MeSH Terms

Conditions

Pulmonary Disease, Chronic Obstructive

Interventions

danirixin; Standard of Care

Condition Hierarchy (Ancestors)

Lung Diseases, Obstructive; Lung Diseases; Respiratory Tract Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Quality Indicators, Health Care; Quality of Health Care; Health Services Administration; Health Care Quality, Access, and Evaluation

Results Point of Contact

• Title: GSK Response Center
• Organization: GlaxoSmithKline

GSKClinicalSupportHD@gsk.com

866-435-7343

Study Officials

• GSK Clinical Trials

  GlaxoSmithKline

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 25, 2017
• First Posted: January 27, 2017
• Study Start: April 25, 2017
• Primary Completion: October 5, 2018
• Study Completion: October 5, 2018
• Last Updated: October 28, 2020
• Results First Posted: November 29, 2019

Record last verified: 2020-10

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR
• Time Frame: IPD is available via the Clinical Study Data Request site (copy the URL below to your browser)
• Access Criteria: Access is provided after a research proposal is submitted and has received approval from the Independent Review Panel and after a Data Sharing Agreement is in place. Access is provided for an initial period of 12 months but an extension can be granted, when justified, for up to another 12 months.

Locations

AU (5); DE (10); PL (5); RO (10); NL (5); US (9); KR (8); CA (6); ES (6)