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

Phase 2

Completed

Conditions: Pulmonary Disease, Chronic Obstructive

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

Registration Number: NCT03034967

Lead Sponsor: GlaxoSmithKline

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.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 614

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Danirixin 25 mg	Danirixin	Eligible participants will receive danirixin 25 mg tablet with food twice daily along with standard care of treatment for 24 weeks.
Danirixin 5 mg	Danirixin	Eligible participants will receive danirixin 5 mg tablet with food twice daily along with standard care of treatment for 24 weeks.
Danirixin 5 mg	Standard of care	Eligible participants will receive danirixin 5 mg tablet with food twice daily along with standard care of treatment for 24 weeks.
Danirixin 5 mg	Rescue medication	Eligible participants will receive danirixin 5 mg tablet with food twice daily along with standard care of treatment for 24 weeks.
Danirixin 10 mg	Danirixin	Eligible participants will receive danirixin 10 mg tablet with food twice daily along with standard care of treatment for 24 weeks.
Danirixin 10 mg	Standard of care	Eligible participants will receive danirixin 10 mg tablet with food twice daily along with standard care of treatment for 24 weeks.
Danirixin 10 mg	Rescue medication	Eligible participants will receive danirixin 10 mg tablet with food twice daily along with standard care of treatment for 24 weeks.
Danirixin 25 mg	Standard of care	Eligible participants will receive danirixin 25 mg tablet with food twice daily along with standard care of treatment for 24 weeks.
Danirixin 25 mg	Rescue medication	Eligible participants will receive danirixin 25 mg tablet with food twice daily along with standard care of treatment for 24 weeks.
Danirixin 35 mg	Danirixin	Eligible participants will receive danirixin 35 mg tablet with food twice daily along with standard care of treatment for 24 weeks.
Danirixin 35 mg	Standard of care	Eligible participants will receive danirixin 35 mg tablet with food twice daily along with standard care of treatment for 24 weeks.
Danirixin 35 mg	Rescue medication	Eligible participants will receive danirixin 35 mg tablet with food twice daily along with standard care of treatment for 24 weeks.
Danirixin 50 mg	Danirixin	Eligible participants will receive danirixin 50 mg tablet with food twice daily along with standard care of treatment for 24 weeks.
Danirixin 50 mg	Standard of care	Eligible participants will receive danirixin 50 mg tablet with food twice daily along with standard care of treatment for 24 weeks.
Danirixin 50 mg	Rescue medication	Eligible participants will receive danirixin 50 mg tablet with food twice daily along with standard care of treatment for 24 weeks.
Placebo	Standard of care	Eligible participants will receive placebo tablet with food twice daily along with standard care of treatment for 24 weeks.
Placebo	Rescue medication	Eligible participants will receive placebo tablet with food twice daily along with standard care of treatment for 24 weeks.
Placebo	Danirixin matching placebo	Eligible participants will receive placebo tablet with food twice daily along with standard care of treatment for 24 weeks.

Primary Outcome Measures

Name	Time	Method
Change From Baseline in Respiratory Symptoms Measured by Evaluating Respiratory Symptoms (E-RS) in COPD. E-RS: COPD Total Score	Baseline and Month 6	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.
Change From Baseline in Respiratory Symptoms Measured by E-RS in COPD (E-RS: COPD Breathlessness Score)	Baseline and Month 6	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.
Change From Baseline in Respiratory Symptoms Measured by E-RS in COPD (E-RS: COPD Cough and Sputum Score)	Baseline and Month 6	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.
Number of Participants With Worst Case Vital Signs Parameter Results by PCI	Up to Day 168	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.
Number of Participants With Worst Case Post-Baseline Abnormal 12-lead Electrocardiogram (ECG) Findings	Baseline and Day 168	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.
Change From Baseline in Respiratory Symptoms Measured by E-RS in COPD (E-RS: COPD Chest Symptoms Score)	Baseline and Month 6	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.
Number of Participants With Adverse Events (AE) and Serious Adverse Events (SAE)	Up to Day 196	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.
Number of Participants With Worst Case Hematology Parameter Results by Potential Clinical Importance (PCI)	Up to Day 196	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.
Number of Participants With Worst Case Clinical Chemistry Parameter Results by PCI	Up to Day 196	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.

Secondary Outcome Measures

Name	Time	Method
Number of Moderate or Severe Healthcare Resource Utilization (HCRU) Exacerbations Per Participant	Up to Day 196	Participants with moderate or severe COPD exacerbations, i.e. breathlessness, cough, sputum production, chest congestion and chest tightness analyzed. Mild exacerbations are defined as exacerbations that did not require treatment with oral/systemic corticosteroids and/or antibiotics (not involving hospitalization, Emergency Room \[ER\] visit or resulting in death). Moderate exacerbations are defined as exacerbations that required treatment with oral/systemic corticosteroids and/or antibiotics (not involving hospitalization, ER visit or resulting in death). Severe exacerbations are defined as exacerbations that required hospitalization, ER visit or resulted in death. Number of moderate or severe HCRU exacerbations per participant has been presented, where 0= participants in each treatment group who did not experience an event; 1= participants in each treatment group who experienced 1 event and \>=2= participants in each treatment group who experienced 2 or more events.
Number of EXACT Events Per Participant	Up to Day 196	EXACT is a 14 item patient reported outcome (PRO) instrument designed to capture information on the occurrence, frequency, severity, and duration of exacerbations of disease in participants with COPD. The total score for EXACT-PRO ranges from 0-100, higher scores indicate more severe symptoms. Events were categorized as recovered, censored, or persistent worsening. Number of EXACT events per participant has been presented, where 0= participants in each treatment group who did not experience an event; 1= participants in each treatment group who experienced 1 event and \>=2= participants in each treatment group who experienced 2 or more events.
Time to First EXACT Event	Up to Day 168	The time to first on-treatment EXACT event was calculated as the onset date of the first on-treatment EXACT event minus date of start of treatment plus 1.
Number of Responders E-RS in COPD (E-RS): COPD Total Score	Month 6	E-RS: COPD is a subset of EXACT. E-RS is a tool that consists of 11 items from the 14 item EXACT instrument. E-RS is intended to capture information related to the respiratory symptoms of COPD, i.e. breathlessness, cough, sputum production, chest congestion and chest tightness. The E-RS has a scoring range of 0-40; higher scores indicate more severe symptoms. Response is defined as an E-RS: COPD total score of 2 units below baseline or lower. Non-response is defined as an E-RS: COPD total score higher than 2 units below Baseline.
Severity of EXACT Event	Up to Day 168	EXACT is a 14 item PRO instrument designed to capture information on the occurrence, frequency, severity, and duration of exacerbations of disease in participants with COPD. The total score for EXACT-PRO ranges from 0-100, higher scores indicate more severe symptoms. Severity is the highest EXACT total score during the period from onset to recovery.
EXACT Event Duration for All Events	Up to Day 168	EXACT is a 14 item PRO instrument designed to capture information on the occurrence, frequency, severity, and duration of exacerbations of disease in participants with COPD. The total score for EXACT-PRO ranges from 0-100, higher scores indicate more severe symptoms. Severity is the highest EXACT total score during the period from onset to recovery. Duration of EXACT events has been reported.
Time to First HCRU-defined COPD Exacerbation	Up to Day 196	The time to first on-treatment Moderate/Severe HCRU exacerbation was calculated as exacerbation onset date of first on-treatment moderate or severe on-treatment exacerbation - date of start of treatment +1.
Time to First Severe HCRU-defined COPD Exacerbation	Up to Day 196	A COPD exacerbation defined as a severe exacerbation if it requires hospitalization or ER visit or extended observation. The time to first on-treatment Moderate/Severe HCRU exacerbation was calculated as exacerbation onset date of first on-treatment moderate or severe on-treatment exacerbation - date of start of treatment +1.
HCRU-defined Exacerbation Duration	Up to Day 196	The duration of HCRU exacerbation were determined. The duration of the exacerbation was calculated as (exacerbation resolution date or date of death - exacerbation onset date + 1). For exacerbations which were not resolved but where the participant later died from other causes, the duration was calculated using date of death as the end date of the event.
Change From Baseline in St. George's Respiratory Questionnaire for COPD Patients (SGRQ-C) Total Score	Baseline, Days 84 and 168	The SGRQ-C consists of 40 items aggregated into 3 component scores: Symptoms, Activity, Impacts, and a Total score. Each response to a question is assigned a weight. Component scores are calculated by summing the weights from all positive items in that component, dividing by the sum of weights for all items in that component, and multiplying this number by 100. Component scores could range from 0-100, with a higher component score indicating greater disease burden. 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.
Number of SGRQ Responder	Day 84 and Day 168	A participant was consider Responder according to SGRQ total score if their change from Baseline SGRQ total score of 4 units below Baseline or lower.
Change From Baseline COPD Assessment Test (CAT) Total Score	Baseline, Days 84 and 168	The CAT is an 8 item questionnaire (cough, sputum, chest tightness, breathlessness, going up hills/stairs, activity limitation at home, confidence leaving the home, and sleep and energy) that measures health status of participants with COPD. Participants were completed each question by rating their experience on a 6 point scale ranging from 0 (maximum impairment) to 5 (no impairment) with a total scoring range of 0-40; higher scores indicate worse health status. A CAT score was calculated by summing the non-missing scores on the eight items. Individual items are scored from 0 to 5 with a total score range from 0 - 40, higher scores indicate greater disease impact. 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.
Number of CAT Responder	Day 84 and Day 168	A participant was considered as a responder according to CAT score if their change from Baseline CAT score 2.0 units below Baseline or lower.
Change From Baseline in Post-bronchodilator FEV1 as a Lung Function Assessment	Baseline, Days 84 and 168	Spirometric analysis was done to determine FEV1. Day 1 was considered as Baseline. Change from Baseline was calculated by subtracting Baseline value from the specified time point value. Least square mean change from Baseline and standard error has been presented.
Percent Predicted Normal FEV1	At Screening	Spirometric analysis was done to determine percent predicted FEVI at screening. FEV1 is forced expiratory volume in one second. Percent predicted FEV1 is defined as the percent FEV1 of the participant is divided by average FEV1 percent in the population of any person similar age, sex and body composition.
Change From Baseline in Post-bronchodilator Forced Vital Capacity (FVC) as a Lung Function Assessment	Baseline, Days 84 and 168	Spirometric analysis was done to determine FVC. Day 1 was considered as Baseline. Change from Baseline was calculated by subtracting Baseline value from the specified time point value. Least square mean change from Baseline and standard error has been presented.
Change From Baseline in Post-bronchodilator FEV1/FVC Ratio as a Lung Function Assessment	Baseline, Days 84 and 168	Spirometric analysis was done to determine FEV1 and FVC. Day 1 was considered as Baseline. Change from Baseline was calculated by subtracting Baseline value from the specified time point value.
Change From Baseline Number of Puffs of Rescue Medication Per Day	Baseline, Months 1, 2, 3, 4, 5 and 6	The mean number of puffs of rescue per day was calculated over the same time periods and using the same assumptions as rescue use via diary. Day 1 was considered as Baseline. Change from Baseline was calculated by subtracting Baseline value from the specified time point value. Least square mean change from Baseline and standard error has been presented.
Participant Experience of Physical Activity Measured Using PROactive Physical Activity in COPD (C-PPAC) Questionnaire	Days 84 and 168	The Clinical Visit PROactive Physical Activity in COPD (C-PPAC) tool is a designed for intermittent use within a clinical study. PROactive Total Score and two domain scores (amount and difficulty) are derived using data from the C-PPAC questionnaire and a physical activity monitor worn for 7 days prior to the questionnaire.C-PPAC is a 12 item questionnaire. The PROactive tools are scored from 0 to 100 with higher scores indicating greater disease impact. It was implemented in a subset of approximately 50% of participants. The amount domain is calculated using 2 items from the C-PPAC questionnaire (amount of walking outside and chores outside) and 2 activity monitor outputs (vector magnitude units per minute (VMU/min) and steps/day). Each domain score is based on the addition of items (0-15 for amount and 0-40 for difficulty) and then scaled from 0-100. The total score is calculated as (amount+difficulty)/2.
Danirixin Whole Blood Pharmacokinetic Concentration-Time Data	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	Blood samples were collected from the participants for the analysis of blood pharmacokinetic concentration-time data. All participants in the mITT population who had at least 1 non-missing Pharmacokinetic assessment obtained and analyzed whilst on treatment with danirixin were included Pharmacokinetic population.
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	Days 1 and 168	Blood samples were collected at indicated timepoints for the analysis of phamacokinetic parameter. All participants in the PK population who had at least 1 non-missing PK assessment obtained and analyzed whilst on treatment with danirixin from a dry blood spot sample and corresponding wet whole blood sample were included in Pharmacokinetic population.
Concentration Maximum (Cmax) of Danirixin in Whole Blood Using Dried Blood Spots	Days 1 and 168	Blood samples were collected from the participants for the analysis of pharmacokinetic parameter.
Time to Reach Maximum Plasma Concentration (Tmax) of Danirixin in Whole Blood Using Dried Blood Spots	Days 1 and 168	Blood samples were collected from the participants for the analysis of pharmacokinetic parameter.