A Phase II, Randomized, Double-blind, Placebo-controlled Study to Assess MEDI3506 in Participants With COPD and Chronic Bronchitis

Phase 2

Completed

Conditions: Chronic Bronchitis
Chronic Obstructive Pulmonary Disease (COPD)

Interventions: Biological: MEDI3506
Other: Placebo
Drug: Tozorakimab

Registration Number: NCT04631016

Lead Sponsor: AstraZeneca

Brief Summary: This is a research study to determine the efficacy and safety of investigational drug MEDI3506 for the treatment of adult participants with Chronic Obstructive Pulmonary Disease and Chronic Bronchitis.

Detailed Description: Study D9180C00002 is a Phase II, randomised, double-blind, placebo-controlled, parallel group, proof of concept study to evaluate the efficacy and safety of MEDI3506 in adult participants with moderate to severe Chronic Obstructive Pulmonary Disease and Chronic Bronchitis.

Approximately 85 sites globally will participate in this study. Approximately 144 participants will be randomized to 2 treatment groups in a 1:1 ratio to receive MEDI3506 or placebo.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 137

Inclusion Criteria

Provision of informed consent.
Participant must be 40 to 80 years of age inclusive, at the time of signing the informed consent form (ICF).
Participants who are current or ex-smokers with a tobacco history of >= 10 pack-years.
Participants who have a documented history of COPD for at least 1 year.
Participants who have a post-BD FEV1/FVC < 0.70 and a post-BD FEV1 >= 20% and < 80% predicted normal value at screening. Centralized spirometry will be used for this criteria assessment.
Participants who have a physician confirmed participant history of chronic bronchitis as defined as presence of cough and sputum on most days for >= 3 months/year in at least the 2 year period immediately prior to study visit 1 (SV1) (Screening).
Participants who have an average BCSS score of >= 2 in cough and >= 2 in sputum domains assessed over 14 days preceding SV3.
Participants who have a documented stable regimen of dual therapy or triple therapy for >= 3 months prior to enrolment; there should have been no change in treatment after the previous exacerbation prior to entering into the study. Where dual therapy consists of inhaled corticosteroids (ICS) + long-acting beta 2 agonist (LABA) or LABA + long-acting muscarinic receptor antagonist (LAMA), and triple therapy consists of ICS + LABA + LAMA.
Participants who have a documented history of >= 1 moderate or severe AECOPD requiring systemic corticosteroids and/or antibiotics for at least 3 days duration (or 1 injection of depot formulation), or hospitalization for reason of AECOPD in the previous 24 months.
Body mass index within the range 18 to 40 kg/m^2 (inclusive).
Female participants of childbearing potential, must have negative pregnancy tests.
Male and female participants must follow protocol contraceptive guidance.

Exclusion Criteria

Participants with a positive diagnostic nucleic acid test for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) at screening. Participants with mild or asymptomatic disease could be rescreened.
Participants with a significant coronavirus disease 2019 (COVID-19) illness within 6 months of enrolment.
As judged by the investigator, any evidence of any active medical or psychiatric condition or other reason which in the investigator's opinion makes it undesirable for the participant to participate in the study.
Current or past diagnosis of asthma which persisted beyond age of 25 years.
Clinically important pulmonary disease other than COPD, radiological findings, and/or laboratory findings suggestive of a respiratory disease other than COPD that is contributing to the participant's respiratory symptoms.
Increased pre-BD FEV1 at randomization visit (SV3) compared to Screening SV1 of >= 400 mL or >= 25% of SV1 FEV1.
Any other clinically relevant abnormal findings on physical examination, laboratory testing; or chest CT scan, which in the opinion of the investigator or medical monitor may compromise the safety of the participant in the study or interfere with evaluation of the study intervention or reduce the participant's ability to participate in the study.

Chest CT scan findings requiring further investigation or repeat CT surveillance before SV14.

A family history of heart failure.
A LVEF < 45% measured by echocardiogram.
History of a clinically significant infection (viral, bacterial, or fungal) within 4 weeks.
History of, or a reason to believe a participant has a history of, drug or alcohol abuse within the past 2 years prior to screening.
Participants with a recent history of, or who have a positive test for, infective hepatitis or unexplained jaundice, or participants who have been treated for hepatitis B, hepatitis C, or human immunodeficiency virus (HIV).
Evidence of active or untreated latent tuberculosis (TB).
Change in smoking status in 12 weeks prior to enrolment or intention to change smoking status between enrolment and end of follow-up.
Participants currently receiving background therapy that is not approved by regulatory authorities in the country of study for COPD are not eligible for the study.
History of treatment with cardiotoxic medications (eg, as part of cancer therapy) including thiazolidinedione's.
Treatment with broad spectrum antibiotic within 4 weeks prior to randomization (Day 1).
Receiving any of the prohibited concomitant medications as specified in the clinical study protocol (CSP).
Inability to perform technically acceptable spirometry.

Additional inclusion and exclusion criteria's applies.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
MEDI3506	MEDI3506	Approximately 72 participants will be randomized to receive MEDI3506
Placebo	Placebo	Approximately 72 participants will be randomized to receive placebo
Placebo	Placebo	Participants received 7 doses of SC placebo injection matched to tozorakimab once Q4W.
Tozorakimab	Tozorakimab	Participants received 7 doses of subcutaneous (SC) tozorakimab Dose Level 1 injection once every 4 weeks (Q4W).

Primary Outcome Measures

Name	Time	Method
Change From Baseline to Week 12 in Pre-bronchodilator Forced Expiratory Volume in 1 Second (Pre-BD FEV1) as Measured in Clinic	Baseline (Day -35 to Day -28) through Week 12	The mean change from baseline in Pre-BD FEV1 at Week 12 (tozorakimab - placebo) estimated using a repeated measures mixed effects analysis of covariance measures was estimated. Data available from all visits up to and including Week 12, irrespective of whether the participant discontinued study drug or received reliever therapy was considered. FEV1 was measured by spirometry at clinic.

Secondary Outcome Measures

Name	Time	Method
Serum Tozorakimab Concentration	Post-dose at Study Weeks 2, 4, 12, 20, 24, 28, 32, and 36	Serum concentration of tozorakimab collected over time are reported. The lower limit of quantification (LLOQ) for tozorakimab was considered to be 10 μg/L.
Number of Participants With Positive Anti-drug Antibodies (ADA) to Tozorakimab	Pre-dose at Study Weeks 0 (baseline) and post-dose at Study Weeks 2, 4, 12, 20, 24, 28, 32, and 36	Number of participants with positive ADA to tozorakimab are reported. Treatment-induced ADA positive is defined as ADA negative at baseline and positive at post-baseline assessment. Treatment-boosted ADA positive is defined as ADA positive at baseline and boosted (\>= 4 fold) the pre-existing titre during the study period. Persistent positive is defined as ADA negative at baseline and positive at \>= 2 post-baseline assessments (with \>= 16 weeks between first and last positive) or ADA positive at last post-baseline assessment. Transiently positive is defined as ADA negative at baseline and at least one post-baseline ADA positive measurement and not fulfilling the conditions for persistently positive.
Number of Participants Experiencing First Chronic Obstructive Pulmonary Disease Composite Exacerbations (COPDCompEx) Event	Baseline (Day -35 to Day -28) through Week 28	The COPDCompEx combines exacerbations with events defined from participant e-Diaries and peak expiratory flow (PEF). COPDCompEx defined exacerbations included episodes leading to one or more of the following: hospitalization, emergency room visit, treatment with systemic corticosteroids (injected and/or oral), or treatment with antibiotics. Diary COPDCompEx events are defined by threshold and slope criteria being met for \>= 2 consecutive days using the following diary and home spirometry variables: overall symptom rating, night-time awakenings due to symptoms, reliever medication use, PEF.
Change From Baseline to Week 12 in 4-weekly Mean Evaluating Respiratory Symptoms of COPD (E-RS:COPD) Total Score	Baseline (from evening of Study Day -14 to the morning of Study Day 1) through Week 12	Change from baseline to Week 12 in 4-weekly mean E-RS:COPD total score is reported. The E-RS™:COPD is an 11-item electronic patient reported outcome (ePRO) questionnaires developed to evaluate the severity of respiratory symptoms of COPD including breathlessness (5 items; score range: 0 to 17), cough and sputum (3 items; score range: 0 to 11), and chest symptoms (3 items; score range: 0 to 12). The ePRO was completed every day at home and at site visits. Summation of E-RS:COPD item responses produced a total score ranging from 0 to 40, with higher scores indicating greater severity. The 4-weekly mean will be calculated as the sum of all non-missing daily scores over the 28-day evaluation period, divided by the number of non-missing daily scores.
Change From Baseline to Week 12 in Mean Breathlessness, Cough and Sputum Scale (BCSS) Score (Over the Previous 4 Weeks)	Baseline (from evening of Study Day -14 to the morning of Study Day 1) through Week 12	Change from baseline to Week 12 in mean BCSS score (over the previous 4 weeks) is reported. The BCSS was a 3-item daily diary that assesses the severity of the 3 symptoms: breathlessness, sputum, and cough, each on a 5-point Likert scale ranging from 0 (no symptoms) to 4 (severe symptoms). Item scores were summed to yield a total score ranging from 0 to 12; wherein higher total score indicated more severe symptoms. The BCSS was captured each evening via eDiary. The 4-weekly mean BCSS score was calculated as the sum of all non-missing daily scores over the 28-dayevaluation period, divided by the number of non-missing daily scores.
Change From Baseline to Week 12 in Cough Visual Analogue Scale (VAS) Score	Baseline (from evening of Study Day -14 to the morning of Study Day 1) through Week 12	Change from baseline to Week 12 in cough VAS score is reported. Participants were asked to complete a cough severity VAS (100 mm linear scale marked with a horizontal line by the participant, with 0 mm representing ''no cough'' and 100 mm representing "worst cough") that measured subjective assessment by the participant of the prior 24 hrs for severity of cough symptoms. It was completed each evening in the eDiary. The 4-weekly mean cough VAS score was calculated as the sum of all non-missing daily scores over the 28-day evaluation period, divided by the number of non-missing daily scores.
Change From Baseline to Week 12 in Saint George's Respiratory Questionnaire (SGRQ) Total Score	Baseline (from evening of Study Day -14 to the morning of Study Day 1) through Week 12	Change from baseline to Week 12 in SGRQ total score is reported. The SGRQ was a 50-item electronic PRO instrument developed to measure the health status of participants with airway obstruction diseases and is divided into 2 parts. Part 1 consisted 8 items pertaining to the severity of respiratory symptoms in the preceding 4 weeks; Part 2 consisted 42 items related to the daily activity and psychosocial impacts of the individual's respiratory condition. The SGRQ yielded a total score and three domain scores (symptoms, activity, and impacts). The total score indicated the impact of disease on overall health status, which was expressed as a percentage of overall impairment, in which 100 represents the worst possible health status and 0 indicates the best possible health status. The domain scores range from 0 to 100, with higher scores indicative of greater impairment.
Change From Baseline to Week 12 in AO Parameter-Area Under the Reactance Curve (AX)	Baseline (Study Day 1) and Week 12	Change from baseline to Week 12 in AO Parameter-Area Under the Reactance Curve (AX) is reported. AO is a non-invasive lung function test assessed using an AO device. It is assessed during quiet, tidal breathing with no participant effort required, by superimposing a multi-frequency oscillation onto the participant's natural breathing.
Percentage of Participants With a Decrease in SGRQ Total Score of >= 4 Points From Baseline to Week 12	Baseline (from evening of Study Day -14 to the morning of Study Day 1) through Week 12	Percentage of participants with a decrease in SGRQ total score of \>= 4 points from baseline to Week 12 is reported. The SGRQ was a 50-item electronic PRO instrument developed to measure the health status of participants with airway obstruction diseases and is divided into 2 parts. Part 1 consisted 8 items pertaining to the severity of respiratory symptoms in the preceding 4 weeks; Part 2 consisted 42 items related to the daily activity and psychosocial impacts of individual's respiratory condition. SGRQ yielded a total score and three domain scores (symptoms, activity, and impacts). Total score indicated the impact of disease on overall health status, which was expressed as a percentage of overall impairment, in which 100 represents worst possible health status and 0 indicates best possible health status. The domain scores range from 0 to 100, with higher scores indicative of greater impairment. A change of 4 units/points is associated with a minimum clinically important difference.
Change From Baseline to Week 12 in Airwave Oscillometry (AO) Parameters	Baseline (Study Day 1) and Week 12	Change from baseline to Week 12 in AO parameters including frequency dependence of resistance at 5-20 Hz (R5-R20) and respiratory resistance at 5 Hz (R5; total airway resistance) and 20 Hz (R20; resistance of large airways) is reported. AO is a non-invasive lung function test assessed using an AO device. It is assessed during quiet, tidal breathing with no participant effort required, by superimposing a multi-frequency oscillation onto the participant's natural breathing. AO device uses a vibrating mesh to generate a multifrequency sinusoidal pseudorandom noise (PRN) signal. The AO markers; respiratory resistance at 5 Hz (R5) and 20 Hz (R20) and difference between resistance at 5 and 20Hz (R5-R20; resistance in small airways) are recorded. These markers measure peripheral airway resistance.
Ratio to Baseline in Daily, Night-time, and Awake Time Cough Frequency at Week 12	Baseline (Day -21 to Day -7) and Week 12	Ratio to baseline in daily, night-time, and awake time cough frequency at Week 12 is reported. Objective cough frequency was measured using an ambulatory cough monitoring (ACM) which was fitted and worn by the participants for approximately 24 hours after the visits. Daily cough frequency as full average hourly cough of the full duration of recording, night time cough frequency as sleep average hourly cough of the duration of recording at night, and awake time cough frequency as awake average hourly cough of the full duration of recording minus sleep recording will be derived from the recording.
Change From Baseline in Pre-BD FEV1 and Post-BD FEV1 Through Week 28 in Participants With Extent of Emphysema < 10%	Baseline (Week -5 to -4) through Week 28 post-dose	Change from baseline in pre-BD FEV1 and post-BD FEV1 through Week 28 in participants with extent of emphysema \< 10% is reported.
Number of Participants With Abnormal Vital Signs Reported as TEAEs	Day 1 through 253 days (maximum observed duration)	Number of participants with abnormal vital signs reported as TEAEs are reported. Abnormal vital signs are defined as any abnormal finding in the vital sign parameters (oral or tympanic temperature, diastolic blood pressure, systolic blood pressure, heart \[pulse\] rate, and respiratory rate).
Change From Baseline in Pre-BD FEV1 and Post-BD FEV1 Through Week 28 in Participants With Extent of Emphysema >= 10%	Baseline (Week -5 to -4) through Week 28 post-dose	Change from baseline in pre-BD FEV1 and post-BD FEV1 through Week 28 in participants with extent of emphysema \>= 10% is reported.
Change From Baseline in Pre-BD and Post-BD Forced Vital Capacity (FVC) Through Week 28 in Participants With Extent of Emphysema < 10%	Baseline (Week -5 to -4) through Week 28 post-dose	Change from baseline in pre-BD and post-BD FVC through Week 28 in participants with extent of emphysema \< 10% is reported.
Change From Baseline in Pre-BD and Post-BD FVC Through Week 28 in Participants With Extent of Emphysema >= 10%	Baseline (Week -5 to -4) through Week 28 post-dose	Change from baseline in pre-BD and post-BD FVC through Week 28 in participants with extent of emphysema \>= 10% is reported.
Number of Participants With Treatment Emergent Adverse Events (TEAEs), Treatment Emergent Serious Adverse Events (TESAEs), and TEAEs of Special Interest (TEAESIs)	Day 1 through 253 days (maximum observed duration)	An adverse event (AE) is any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. A serious adverse event (SAE) is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Adverse event of special interest (AESI) are AEs of scientific and medical interest specific to understanding of tozorakimab and requires close monitoring. The TEAEs are defined as events present at baseline that worsened in intensity after administration of study drug or events absent at baseline that emerged after administration of study drug.
Number of Participants With Abnormal Clinical Laboratory Parameters Reported as TEAEs	Day 1 through 253 days (maximum observed duration)	Number of participants with abnormal clinical laboratory parameters reported as TEAEs are reported. Abnormal clinical laboratory parameters defined as any abnormal finding during analysis of clinical chemistry, hematology, endocrinology, and urinalysis.
Number of Participants With Abnormal Electrocardiograms (ECGs) Reported as TEAEs	Day 1 through 253 days (maximum observed duration)	Number of participants with abnormal ECGs reported as TEAEs are reported.
Change From Baseline in Left Ventricular Ejection Fraction (LVEF) as Measured by Echocardiogram	Baseline (Week -3 to -1) through Week 28	Change from baseline in LVEF as measured by echocardiogram is reported.
Change From Baseline in N-terminal Pro-brain Natriuretic Peptide (NT-proBNP) Level	Baseline (Day -35 to Day -28) through Week 28	Change in NT-proBNP Level from baseline is reported.
Number of Participants With Coronavirus Disease 2019 (COVID-19) Related AEs and SAEs	Day 1 through 253 days (maximum observed duration)	The number of participants with COVID-19 related AEs and SAEs are reported.
Number of Participants Seropositive for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)	Baseline (Week 0) through Week 28	Number of participants who were seronegative at baseline and who had positive SARS-Cov-2 serology result at the end of study is reported.