A Phase IIa Study to Investigate the Efficacy and Safety of AZD7624 in Chronic Obstructive Pulmonary Disease (COPD) Patients While on Maintenance Therapy

Study Overview
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Brief Summary
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The purpose of this study is to determine whether AZD7624 can reduce acute Chronic Obstructive Pulmonary Disease (COPD) exacerbations in patients on COPD maintenance therapy with a history of frequent acute exacerbations.

Official Title
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A 12-week Phase IIa, Double-blind, Placebo-controlled, Randomized Study to Investigate the Efficacy and Safety of AZD7624 in COPD Patients With a History of Frequent Acute Exacerbations While on Maintenance Therapy

Conditions
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Chronic Obstructive Pulmonary Disease COPD

Intervention / Treatment
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* Drug: AZD7624 1.0 mg
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Provision of signed and dated written informed consent prior to any study specific procedures. Male and females aged 40-85 years. Females must have a negative pregnancy test at Visit 1, must not be lactating and must be of non-childbearing potential. Males must be surgically sterile or agree to use an acceptable method of contraception for the duration of the study and for 3 months after the last dose of investigational product to prevent pregnancy in a partner. A weight of ≥50 kg. Diagnosis of COPD for more than 1 year at Visit 1, according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2014 guidelines. COPD maintenance treatment with at least ICS/LABA for at least 2 months prior to enrolment to be continued unchanged during the study. A post-bronchodilator FEV1/FVC <0.70 and a post-bronchodilator FEV1 ≤70% of the predicted normal value. Documented history of 2 or more moderate to severe COPD exacerbations within 12 months of randomisation, but not within the last 6 weeks before randomisation. Current or ex-smokers with a smoking history of at least 10 pack-years. Exclusion Criteria: Involvement in the planning and conduct of the study. Previous randomisation in the present study. Participation in another clinical study with any investigational medicinal product within 3 months of randomisation. Previously intake of any p38 inhibitor. Participation in, or scheduled for an intensive COPD rehabilitation programme at any time during the study. Planned in-patient surgery or hospitalisation during the study. Significant disease or disorder other than COPD which, may either put the patient at risk because of participation in the study, or influence the results of the study, or the patient's ability to participate in the study. Asthma as a primary or main diagnosis according to the Global Initiative for Asthma (GINA) guidelines (GINA 2013) or other accepted guidelines. A clinically relevant abnormal findings in clinical chemistry, haematology and urinalysis. Plasma myoglobin and CK above the upper reference range of the analysing laboratory at randomization. A clinically relevant abnormal findings in physical examination, pulse or blood pressure. A positive result on screening for serum hepatitis B hepatitis C and Human Immunodeficiency Virus (HIV). History or family history of muscle diseases. Abnormal vital signs, defined as Systolic Blood Pressure (SBP) above 140 mmHg if <60 years of age and above 150 mmHg if ≥60 years of age; Diastolic Blood Pressure (DBP) above 90 mmHg; Pulse <50 or >100 bpm. Prolonged QTcF >450 ms or family history of long QT syndrome or sudden death at young age. PR(PQ) interval of clinical significance, PR(PQ) > 250 ms. Intermittent AV block of 2nd and 3rd degree or AV dissociation. Patients with a QRS duration >120 ms. Patients with persistent, and/or recurrent symptomatic tachyarrhythmias, as well as patients with an implantable cardioverter-defibrillator (ICD) or a permanent pacemaker. Patients with recent Cardiovascular (CV) events or unstable CV disease or a myocardial infarction or stroke within 6 months of screening. History of hospitalization within 12 months caused by heart failure or a diagnosis of heart failure higher than New York Heart Association (NYHA) class II. History of severe allergy/hypersensitivity or ongoing clinically important allergy/hypersensitivity or history of hypersensitivity to drugs with a similar chemical structure or class to AZD7624. Any exacerbation or respiratory infection within 6 weeks of randomization. Plasma donation within one month of Visit 1, or any blood donation/blood loss >500 mL during the 3 months prior to Visit 1. History of, or current alcohol or drug abuse. Treatment with any GCS (apart from prescribed steroids at run-in) within 6 weeks of Visit 3 regardless of indication. Treatment with strong CYP3A inhibitors within 4 weeks prior to randomisation.

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: AZD7624<br>Active treatment | Drug: AZD7624 1.0 mg<br>* Inhaled AZD7624 solution, 11 mg/mL<br>|
| Placebo Comparator: Placebo<br>Placebo Comparator | Drug: Placebo<br>* Inhaled placebo solution<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to First Moderate to Severe COPD Exacerbation or Early Drop-out Related to Worsening of COPD Symptoms |  | Up to Week 12 treatment discontinuation visit (in some patients this visit was delayed beyond the planned Day 84, up to maximum of 118 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Annual Event Rate of Moderate and Severe COPD Exacerbations and Early Drop-outs Related to Worsening of COPD Symptoms (i.e. Composite Endpoint, ExDo) | For the production of summary statistics, the annual event rate per subject is calculated, and standardized per a 52-week period according to the formula described below. Annual Event Rate = No. of Events*365.25 / (Follow-up date - Date of randomization + 1). | Up to Week 12 treatment discontinuation visit (in some patients this visit was delayed beyond the planned Day 84, up to maximum of 118 days) | 
| Time to First Event of Moderate or Severe COPD Exacerbations or Early Drop-out (Including Drop-outs Due to Any Cause) |  | Up to Week 12 treatment discontinuation visit (in some patients this visit was delayed beyond the planned Day 84, up to maximum of 118 days) | 
| Annual Event Rate of Moderate and Severe COPD Exacerbations and Early Drop-outs (Including Drop-outs Due to Any Cause) | For the production of summary statistics, the annual event rate per subject is calculated, and standardized per a 52-week period according to the formula described below. Annual Event Rate = No. of Events*365.25 / (Follow-up date - Date of randomization + 1). | Up to Week 12 treatment discontinuation visit (in some patients this visit was delayed beyond the planned Day 84, up to maximum of 118 days) | 
| Time to First Moderate or Severe Exacerbation |  | Up to Week 12 treatment discontinuation visit (in some patients this visit was delayed beyond the planned Day 84, up to maximum of 118 days) | 
| Annual Exacerbation Rate of Moderate and Severe Exacerbations | For the production of summary statistics, the annual exacerbation rate per subject is calculated, and standardized per a 52-week period according to the formula described below. Annual Exacerbation Rate = No. of Exacerbations*365.25 / (Follow-up date - Date of randomization + 1). | Up to Week 12 treatment discontinuation visit (in some patients this visit was delayed beyond the planned Day 84, up to maximum of 118 days) | 
| Time to First Moderate or Severe Exacerbation (Where Worsening of COPD Symptoms is Defined as Anthonisens Criteria Fulfilled) |  | Up to Week 12 treatment discontinuation visit (in some patients this visit was delayed beyond the planned Day 84, up to maximum of 118 days) | 
| Annual Exacerbation Rate of Moderate and Severe Exacerbations (Where Worsening of COPD Symptoms is Defined as Anthonisens Criteria Fulfilled) | For the production of summary statistics, the annual exacerbation rate per subject is calculated, and standardized per a 52-week period according to the formula described below. Annual Exacerbation Rate = No. of Exacerbations*365.25 / (Follow-up date - Date of randomization + 1). | Up to Week 12 treatment discontinuation visit (in some patients this visit was delayed beyond the planned Day 84, up to maximum of 118 days) | 
| Time to First Symptom Defined Exacerbation (as Defined by the Exacerbation of Chronic Pulmonary Disease Tool [EXACT] Daily Diary) |  | Up to Week 12 treatment discontinuation visit (in some patients this visit was delayed beyond the planned Day 84, up to maximum of 118 days) | 
| Annual Exacerbation Rate of Symptom Defined Exacerbations (as Defined by the EXACT Daily Diary) | For the production of summary statistics, the annual exacerbation rate per subject is calculated, and standardized per a 52-week period according to the formula described below. Annual Exacerbation Rate = No. of Exacerbations*365.25 / (Follow-up date - Date of randomization + 1). | Up to Week 12 treatment discontinuation visit (in some patients this visit was delayed beyond the planned Day 84, up to maximum of 118 days) | 
| Symptoms of COPD (Using the EXACT for Respiratory Symptoms [E-RS] Total Score, a Subset of Items From the EXACT Diary) | The EXACT for Respiratory Symptoms (E-RS) scale is a derivative instrument comprising a subset of 11 of the EXACT items to evaluate the severity of respiratory symptoms of COPD. Summation of E-RS item responses produces a total score ranging from 0 to 40, with higher scores indicating greater severity. | Up to Week 12 treatment discontinuation visit (in some patients this visit was delayed beyond the planned Day 84, up to maximum of 118 days) | 
| Health Related Quality of Life (as Assessed by St Georges Respiratory Questionnaire for COPD Patients [SGRQ-C]) | The SGRQ-C is a modified version of the St. George's Respiratory Questionnaire, which has been developed to measure the impact of respiratory disease on health status. The SGRQ-C includes 14 questions in 3 domains: symptoms; activity; and impacts. Scores range from 0 to 100 with higher scores indicating benefit. Change in total score from pre study-treatment baseline to Week 12 end of treatment visit are reported. | Up to Week 12 treatment discontinuation visit (in some patients this visit was delayed beyond the planned Day 84, up to maximum of 118 days) | 
| Dyspnea (Transitional Dyspnea Index (TDI) Score) | The Baseline/Transitional Dyspnea Index (BDI/TDI) provides a multidimensional measure of dyspnea in relation to activities of daily living. The BDI provides a measure of dyspnoea at a single state, the baseline, and the TDI evaluates changes in dyspnoea from the baseline state. The instrument consists of three components: functional impairment, magnitude of task, and magnitude of effort. For the BDI, each of these three components are rated in five grades from 0 (severe) to 4 (unimpaired), and are summed to form a baseline total score from 0 to 12. For the TDI, changes in dyspnea are rated for each component by seven grades from -3 (major deterioration) to +3 (major improvement), and are added to form a total TDI score from -9 to +9. Positive scores indicate an improvement, and a change from the BDI or a difference between treatments of 1 point has been estimated to constitute the minimum clinically important difference. | Up to Week 12 treatment discontinuation visit (in some patients this visit was delayed beyond the planned Day 84, up to maximum of 118 days) | 
| Pulmonary Function Measured as Changes From Baseline (Post-bronchodilator at Visit 3) in Trough Forced Expiratory Volume in 1 Second (FEV1) |  | Up to Week 12 treatment discontinuation visit (in some patients this visit was delayed beyond the planned Day 84, up to maximum of 118 days) | 
| Pulmonary Function Measured as Changes From Baseline (Post-bronchodilator at Visit 3) in Trough Forced Vital Capacity (FVC) |  | Up to Week 12 treatment discontinuation visit (in some patients this visit was delayed beyond the planned Day 84, up to maximum of 118 days) | 
| Pulmonary Function Measured as Changes From Baseline (Post-bronchodilator at Visit 3) in Trough FEV1/FVC Ratio |  | Up to Week 12 treatment discontinuation visit (in some patients this visit was delayed beyond the planned Day 84, up to maximum of 118 days) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Chronic Obstructive Pulmonary Disease, COPD patients, Exacerbations, ICS, LABA