Chronic Obstructive Pulmonary Disease
Conditions
Keywords
Chronic Obstructive Pulmonary Disease (COPD), MEDI8968
Brief summary
The purpose of this study is to evaluate the effect of MEDI8968 on the rate of moderate or severe acute exacerbations of chronic obstructive pulmonary disease (AECOPD) in adult subjects with symptomatic, moderate to very severe COPD (Global Initiative for Chronic Obstructive Lung Disease - GOLD stage II-IV) receiving standard maintenance therapy for the underlying disease condition.
Detailed description
A Phase 2 double-blind, placebo-controlled study to evaluate the efficacy of MEDI8968 in Chronic Obstructive Pulmonary Disease. The study will have a screening phase of 23 days, treatment phase from Week 1 to 53 and follow-up phase from Week 53 to 69. Participants will receive either MEDI8968 600 milligram (mg) as intravenous (IV) infusion on Day 1 followed by 300 mg injection subcutaneously (SC) every 4 weeks up to Week 53 or matching placebo in the same fashion. Participants will primarily be assessed for incidence rate of moderate or severe acute exacerbations of chronic obstructive pulmonary disease (AECOPD). Safety will be monitored throughout the study.
Interventions
BIOLOGICALMEDI8968 600 mg IV, 300 mg SC
MEDI8968 600 mg as IV infusion on Day 1 followed by 300 mg injection SC every 4 weeks up to Week 53.
OTHERPlacebo
Placebo matched to MEDI8968 as IV infusion on Day 1 followed by SC injection every 4 weeks up to Week 53.
Sponsors
MedImmune LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
45 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Age 45 through 75 years * Predicted (Global Initiative for Chronic Obstructive Lung Disease \[GOLD\] stage II, III, and IV) at Screening * History of previous acute exacerbations of chronic obstructive pulmonary disease (AECOPD) 12 months prior to Screening * Clinically stable and free from an AECOPD for 8 weeks prior to Day 1 * Current smoker or ex-smoker with a tobacco history of more than or equal to (\>=) 10 pack-years.
Exclusion criteria
* Past or present disease or disorder, * Significant or unstable ischemic heart disease etc * Known history of allergy or reaction to any component of the investigational manufacturing product (IMP) * Past or current malignancy within the past 5 years * Subjects have had a chest x-ray or Computed Tomography (CT) scan suggestive of malignancy or tuberculosis (TB). * Use of immunosuppressive medication receipt of any biologic agent.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Rate of Moderate or Severe Acute Exacerbations of Chronic Obstructive Pulmonary Disease (AECOPD) | Day 1 up to 393 | An AECOPD is defined as worsening of two or more major symptoms or one major and one minor symptom for two or more consecutive days. The severity of an AECOPD is defined as: Moderate exacerbations require treatment with systemic corticosteroids, and or antibiotics. Severe exacerbations require hospitalization. The AECOPD rate was analyzed using a Poisson Regression model adjusted for over dispersion with number of exacerbations as the outcome and the log of follow-up time as an offset variable, with covariates for treatment group (MEDI8986, placebo), background maintenance therapy and previous exacerbations. Mean exacerbations were presented as number of exacerbations/year. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to First Moderate or Severe Acute Exacerbations of Chronic Obstructive Pulmonary Disease (AECOPD) | Day 1 up to 393 | Time to first worsening of two or more major symptoms or one major and one minor symptom for two or more consecutive days. The severity of an AECOPD is defined as: Mild exacerbations require treatment with an increase in usual therapy, e.g., increase use of short acting bronchodilators. Moderate exacerbations require treatment with systemic corticosteroids, and or antibiotics. Severe exacerbations require hospitalization. |
| Change From Baseline in COPD-Specific Saint George's Respiratory Questionnaire (SGRQ-C) Total and Subscales Scores at Week 53 | Baseline and Week 53 | The SGRQ is a health related quality of life questionnaire consisting of 40 items in three domains: symptoms (respiratory symptoms and severity), activity (activities that cause or are limited by breathlessness) and impacts (social functioning and psychological disturbances due to airway disease). Each question's response has a unique empirically derived weight where lowest possible weight is zero and the highest is 100. The total score and domain score are derived from the relevant items and converted to a score of 0 to 100 with a higher score indicating poorer health status. |
| Percentage of Participants With Improvement in COPD-Specific Saint George's Respiratory Questionnaire (SGRQ-C) Total Score | Week 53 | The SGRQ is a health related quality of life questionnaire consisting of 40 items in three domains: symptoms (respiratory symptoms and severity), activity (activities that cause or are limited by breathlessness) and impacts (social functioning and psychological disturbances due to airway disease). Each question's response has a unique empirically derived weight where lowest possible weight is zero and the highest is 100. The total score and domain score are derived from the relevant items and converted to a score of 0 to 100 with a higher score indicating poorer health status. A 4-point change in total score demonstrates a clinically meaningful change, while an 8-point change and a 12-point change are interpreted as a moderate and large change in health status, respectively. |
| Change From Baseline in Body Mass Index, Airflow Obstruction, Dyspnea, and Exercise Capacity (BODE) Score at Week 53 | Baseline and Week 53 | The BODE index is a multi-dimension COPD grading system that incorporates body-mass index (B), degree of airflow obstruction (O), dyspnea (D), and exercise capacity (E) as measured by the modified medical research council (MMRC) dyspnea scale and the 6-minute walk test. The MMRC dyspnea scale is a 5-point scale that measures the level of dyspnea (trouble breathing) experienced by participants where score range is 0 (none) to 4 (very severe). BODE score is derived into a score range of 0 (healthy) to 10 (severe COPD). |
| Mean Rate of Severe Acute Exacerbations of Chronic Obstructive Pulmonary Disease (AECOPD) | Day 1 up to 393 | An AECOPD is defined as worsening of two or more major symptoms or one major and one minor symptom for two or more consecutive days. Severe exacerbations require hospitalization. The AECOPD rate was analyzed using a Poisson Regression model adjusted for over dispersion with number of exacerbations as the outcome and the log of follow-up time as an offset variable, with covariates for treatment group (MEDI8986, placebo), background maintenance therapy and previous exacerbations. Mean exacerbations were presented as number of exacerbations/year. |
| Number of Participants Reporting Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs) | Day 1 up to Week 69 | An adverse event (AE) was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. A serious adverse event (SAE) was 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. Treatment-emergent are events between administration of study drug and up to Week 69 that were absent before treatment or that worsened relative to pre-treatment state. TEAEs reported below included both SAEs and non-serious AEs. |
| Observed Serum Concentrations of MEDI8968 | Pre-dose (Baseline), Post-dose on Week 53 | — |
| Number of Participants Exhibiting Anti-Drug Antibodies for MEDI8968 at Any Visit | Day 1 up to Week 69 | Anti-drug antibodies for MEDI8968 were analyzed for participants who received placebo or MEDI8968 as per planned analysis. |
| Percentage of Participants With Improvement in Body Mass Index, Airflow Obstruction, Dyspnea, and Exercise Capacity (BODE) Score | Baseline and Week 53 | The BODE index is a multi-dimension COPD grading system that incorporates body-mass index (B), degree of airflow obstruction (O), dyspnea (D), and exercise capacity (E) as measured by the modified medical research council (MMRC) dyspnea scale and the 6-minute walk test. The MMRC dyspnea scale is a 5-point scale that measures the level of dyspnea (trouble breathing) experienced by participants where score range is 0 (none) to 4 (very severe). BODE score is derived into a score range of 0 (healthy) to 10 (severe COPD). Negative change score signifies improvement compared to baseline. Number of participants with improvement in BODE score compared to baseline were reported. |
Countries
Bulgaria, Czechia, Hungary, Latvia, Lithuania, Philippines, Poland, Ukraine, United Kingdom, United States
Participant flow
Pre-assignment details
A total of 464 participants were screened and 324 participants were randomized into the study.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Placebo matched to MEDI8968 as intravenous (IV) infusion on Day 1 followed by subcutaneous (SC) injection every 4 weeks up to Week 53. | 164 |
| MEDI8968 600 mg IV, 300 mg SC MEDI8968 600 milligram (mg) as IV infusion on Day 1 followed by 300 mg injection SC every 4 weeks up to Week 53. | 160 |
| Total | 324 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 3 | 6 |
| Overall Study | Lost to Follow-up | 3 | 1 |
| Overall Study | Other | 15 | 12 |
| Overall Study | Withdrawal by Subject | 13 | 21 |
Baseline characteristics
| Characteristic | Placebo | MEDI8968 600 mg IV, 300 mg SC | Total |
|---|---|---|---|
| Age, Continuous | 63.0 years STANDARD_DEVIATION 6.8 | 62.8 years STANDARD_DEVIATION 6.7 | 62.9 years STANDARD_DEVIATION 6.8 |
| Gender Female | 54 Participants | 50 Participants | 104 Participants |
| Gender Male | 110 Participants | 110 Participants | 220 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 127 / 164 | 122 / 160 |
| serious Total, serious adverse events | 35 / 164 | 41 / 160 |
Outcome results
Primary
Mean Rate of Moderate or Severe Acute Exacerbations of Chronic Obstructive Pulmonary Disease (AECOPD)
An AECOPD is defined as worsening of two or more major symptoms or one major and one minor symptom for two or more consecutive days. The severity of an AECOPD is defined as: Moderate exacerbations require treatment with systemic corticosteroids, and or antibiotics. Severe exacerbations require hospitalization. The AECOPD rate was analyzed using a Poisson Regression model adjusted for over dispersion with number of exacerbations as the outcome and the log of follow-up time as an offset variable, with covariates for treatment group (MEDI8986, placebo), background maintenance therapy and previous exacerbations. Mean exacerbations were presented as number of exacerbations/year.
Time frame: Day 1 up to 393
Population: Modified intent-to-treat (mITT) population included all participants who were randomized into the study and received any investigational product.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Placebo | Mean Rate of Moderate or Severe Acute Exacerbations of Chronic Obstructive Pulmonary Disease (AECOPD) | 0.78 AECOPD events/year |
| MEDI8968 600 mg IV, 300 mg SC | Mean Rate of Moderate or Severe Acute Exacerbations of Chronic Obstructive Pulmonary Disease (AECOPD) | 0.71 AECOPD events/year |
p-value: 0.64590% CI: [0.68, 1.25]Poisson regression
Secondary
Change From Baseline in Body Mass Index, Airflow Obstruction, Dyspnea, and Exercise Capacity (BODE) Score at Week 53
The BODE index is a multi-dimension COPD grading system that incorporates body-mass index (B), degree of airflow obstruction (O), dyspnea (D), and exercise capacity (E) as measured by the modified medical research council (MMRC) dyspnea scale and the 6-minute walk test. The MMRC dyspnea scale is a 5-point scale that measures the level of dyspnea (trouble breathing) experienced by participants where score range is 0 (none) to 4 (very severe). BODE score is derived into a score range of 0 (healthy) to 10 (severe COPD).
Time frame: Baseline and Week 53
Population: The mITT population included all participants who were randomized into the study and received any investigational product. Here, 'N' signifies those participants evaluable for this measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Body Mass Index, Airflow Obstruction, Dyspnea, and Exercise Capacity (BODE) Score at Week 53 | -0.27 units on a scale | Standard Error 0.107 |
| MEDI8968 600 mg IV, 300 mg SC | Change From Baseline in Body Mass Index, Airflow Obstruction, Dyspnea, and Exercise Capacity (BODE) Score at Week 53 | -0.08 units on a scale | Standard Error 0.11 |
Secondary
Change From Baseline in COPD-Specific Saint George's Respiratory Questionnaire (SGRQ-C) Total and Subscales Scores at Week 53
The SGRQ is a health related quality of life questionnaire consisting of 40 items in three domains: symptoms (respiratory symptoms and severity), activity (activities that cause or are limited by breathlessness) and impacts (social functioning and psychological disturbances due to airway disease). Each question's response has a unique empirically derived weight where lowest possible weight is zero and the highest is 100. The total score and domain score are derived from the relevant items and converted to a score of 0 to 100 with a higher score indicating poorer health status.
Time frame: Baseline and Week 53
Population: The mITT population included all participants who were randomized into the study and received any investigational product. Here, 'n' signifies those participants evaluable for this measure at specified time points for each group, respectively.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline in COPD-Specific Saint George's Respiratory Questionnaire (SGRQ-C) Total and Subscales Scores at Week 53 | Change at Week 53: Total Score (n=134, 123) | -2.76 units on scale | Standard Error 1.069 |
| Placebo | Change From Baseline in COPD-Specific Saint George's Respiratory Questionnaire (SGRQ-C) Total and Subscales Scores at Week 53 | Change at Week 53: Activity Score (n=134, 123) | -1.15 units on scale | Standard Error 1.306 |
| Placebo | Change From Baseline in COPD-Specific Saint George's Respiratory Questionnaire (SGRQ-C) Total and Subscales Scores at Week 53 | Change at Week 53: Impacts Score (n=134, 123) | -2.91 units on scale | Standard Error 1.326 |
| Placebo | Change From Baseline in COPD-Specific Saint George's Respiratory Questionnaire (SGRQ-C) Total and Subscales Scores at Week 53 | Change at Week 53: Symptoms Score (n=134, 123) | -5.60 units on scale | Standard Error 1.279 |
| MEDI8968 600 mg IV, 300 mg SC | Change From Baseline in COPD-Specific Saint George's Respiratory Questionnaire (SGRQ-C) Total and Subscales Scores at Week 53 | Change at Week 53: Symptoms Score (n=134, 123) | -6.81 units on scale | Standard Error 1.325 |
| MEDI8968 600 mg IV, 300 mg SC | Change From Baseline in COPD-Specific Saint George's Respiratory Questionnaire (SGRQ-C) Total and Subscales Scores at Week 53 | Change at Week 53: Total Score (n=134, 123) | -2.22 units on scale | Standard Error 1.101 |
| MEDI8968 600 mg IV, 300 mg SC | Change From Baseline in COPD-Specific Saint George's Respiratory Questionnaire (SGRQ-C) Total and Subscales Scores at Week 53 | Change at Week 53: Impacts Score (n=134, 123) | -1.08 units on scale | Standard Error 1.366 |
| MEDI8968 600 mg IV, 300 mg SC | Change From Baseline in COPD-Specific Saint George's Respiratory Questionnaire (SGRQ-C) Total and Subscales Scores at Week 53 | Change at Week 53: Activity Score (n=134, 123) | -1.38 units on scale | Standard Error 1.348 |
Secondary
Mean Rate of Severe Acute Exacerbations of Chronic Obstructive Pulmonary Disease (AECOPD)
An AECOPD is defined as worsening of two or more major symptoms or one major and one minor symptom for two or more consecutive days. Severe exacerbations require hospitalization. The AECOPD rate was analyzed using a Poisson Regression model adjusted for over dispersion with number of exacerbations as the outcome and the log of follow-up time as an offset variable, with covariates for treatment group (MEDI8986, placebo), background maintenance therapy and previous exacerbations. Mean exacerbations were presented as number of exacerbations/year.
Time frame: Day 1 up to 393
Population: The mITT population included all participants who were randomized into the study and received any investigational product.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Placebo | Mean Rate of Severe Acute Exacerbations of Chronic Obstructive Pulmonary Disease (AECOPD) | 0.14 AECOPD events/year |
| MEDI8968 600 mg IV, 300 mg SC | Mean Rate of Severe Acute Exacerbations of Chronic Obstructive Pulmonary Disease (AECOPD) | 0.10 AECOPD events/year |
Secondary
Number of Participants Exhibiting Anti-Drug Antibodies for MEDI8968 at Any Visit
Anti-drug antibodies for MEDI8968 were analyzed for participants who received placebo or MEDI8968 as per planned analysis.
Time frame: Day 1 up to Week 69
Population: Immunogenicity (IM) population included all participants who were randomized, received at least one dose of investigational product, and had at least one post-dose serum sample for IM testing.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Number of Participants Exhibiting Anti-Drug Antibodies for MEDI8968 at Any Visit | 10 participants |
| MEDI8968 600 mg IV, 300 mg SC | Number of Participants Exhibiting Anti-Drug Antibodies for MEDI8968 at Any Visit | 19 participants |
Secondary
Number of Participants Reporting Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs)
An adverse event (AE) was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. A serious adverse event (SAE) was 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. Treatment-emergent are events between administration of study drug and up to Week 69 that were absent before treatment or that worsened relative to pre-treatment state. TEAEs reported below included both SAEs and non-serious AEs.
Time frame: Day 1 up to Week 69
Population: Safety population included all participants who were randomized and received at least one dose of investigational product.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Number of Participants Reporting Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs) | TEAEs | 130 participants |
| Placebo | Number of Participants Reporting Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs) | TESAEs | 35 participants |
| MEDI8968 600 mg IV, 300 mg SC | Number of Participants Reporting Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs) | TEAEs | 130 participants |
| MEDI8968 600 mg IV, 300 mg SC | Number of Participants Reporting Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs) | TESAEs | 41 participants |
Secondary
Observed Serum Concentrations of MEDI8968
Time frame: Pre-dose (Baseline), Post-dose on Week 53
Population: PK population included all participants who were randomized, received at least one dose of investigational product, and had at least one post-dose serum concentration.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Observed Serum Concentrations of MEDI8968 | Baseline (n=145) | 1.7 nanogram per milliliters (ng/mL) | Standard Deviation 14.6 |
| Placebo | Observed Serum Concentrations of MEDI8968 | Week 53 (n=120) | 28555.7 nanogram per milliliters (ng/mL) | Standard Deviation 27545.6 |
Secondary
Percentage of Participants With Improvement in Body Mass Index, Airflow Obstruction, Dyspnea, and Exercise Capacity (BODE) Score
The BODE index is a multi-dimension COPD grading system that incorporates body-mass index (B), degree of airflow obstruction (O), dyspnea (D), and exercise capacity (E) as measured by the modified medical research council (MMRC) dyspnea scale and the 6-minute walk test. The MMRC dyspnea scale is a 5-point scale that measures the level of dyspnea (trouble breathing) experienced by participants where score range is 0 (none) to 4 (very severe). BODE score is derived into a score range of 0 (healthy) to 10 (severe COPD). Negative change score signifies improvement compared to baseline. Number of participants with improvement in BODE score compared to baseline were reported.
Time frame: Baseline and Week 53
Population: The mITT population included all participants who were randomized into the study and received any investigational product. Here, 'N' signifies those participants evaluable for this measure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants With Improvement in Body Mass Index, Airflow Obstruction, Dyspnea, and Exercise Capacity (BODE) Score | 39.0 percentage of participants |
| MEDI8968 600 mg IV, 300 mg SC | Percentage of Participants With Improvement in Body Mass Index, Airflow Obstruction, Dyspnea, and Exercise Capacity (BODE) Score | 33.6 percentage of participants |
Secondary
Percentage of Participants With Improvement in COPD-Specific Saint George's Respiratory Questionnaire (SGRQ-C) Total Score
The SGRQ is a health related quality of life questionnaire consisting of 40 items in three domains: symptoms (respiratory symptoms and severity), activity (activities that cause or are limited by breathlessness) and impacts (social functioning and psychological disturbances due to airway disease). Each question's response has a unique empirically derived weight where lowest possible weight is zero and the highest is 100. The total score and domain score are derived from the relevant items and converted to a score of 0 to 100 with a higher score indicating poorer health status. A 4-point change in total score demonstrates a clinically meaningful change, while an 8-point change and a 12-point change are interpreted as a moderate and large change in health status, respectively.
Time frame: Week 53
Population: The mITT population included all participants who were randomized into the study and received any investigational product. Here, 'n' signifies those participants evaluable for this measure at specified time points for each group, respectively.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Percentage of Participants With Improvement in COPD-Specific Saint George's Respiratory Questionnaire (SGRQ-C) Total Score | Week 53: 4-point improvement (n=134,123) | 45.5 percentage of participants |
| Placebo | Percentage of Participants With Improvement in COPD-Specific Saint George's Respiratory Questionnaire (SGRQ-C) Total Score | Week 53: 12-point improvement (n=134,123) | 17.9 percentage of participants |
| MEDI8968 600 mg IV, 300 mg SC | Percentage of Participants With Improvement in COPD-Specific Saint George's Respiratory Questionnaire (SGRQ-C) Total Score | Week 53: 4-point improvement (n=134,123) | 43.1 percentage of participants |
| MEDI8968 600 mg IV, 300 mg SC | Percentage of Participants With Improvement in COPD-Specific Saint George's Respiratory Questionnaire (SGRQ-C) Total Score | Week 53: 12-point improvement (n=134,123) | 17.1 percentage of participants |
Secondary
Time to First Moderate or Severe Acute Exacerbations of Chronic Obstructive Pulmonary Disease (AECOPD)
Time to first worsening of two or more major symptoms or one major and one minor symptom for two or more consecutive days. The severity of an AECOPD is defined as: Mild exacerbations require treatment with an increase in usual therapy, e.g., increase use of short acting bronchodilators. Moderate exacerbations require treatment with systemic corticosteroids, and or antibiotics. Severe exacerbations require hospitalization.
Time frame: Day 1 up to 393
Population: The mITT population included all participants who were randomized into the study and received any investigational product.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Time to First Moderate or Severe Acute Exacerbations of Chronic Obstructive Pulmonary Disease (AECOPD) | NA days |
| MEDI8968 600 mg IV, 300 mg SC | Time to First Moderate or Severe Acute Exacerbations of Chronic Obstructive Pulmonary Disease (AECOPD) | NA days |