Tezepelumab COPD Exacerbation Study

Phase 2

Completed

Conditions: Chronic Obstructive Pulmonary Disease (COPD)

Interventions: Other: Placebo
Biological: Tezepelumab

Registration Number: NCT04039113

Lead Sponsor: AstraZeneca

Brief Summary: A Multicenter, Randomized, Double-blind, Placebo-controlled, Parallel Group, Phase 2a Study to Explore the Efficacy and Safety of Tezepelumab in Adults with Moderate to Very Severe Chronic Obstructive Pulmonary Disease (COPD)

Detailed Description: This is a Phase 2a, multicenter, randomized, double-blind, placebo-controlled, parallel group study to evaluate the safety and efficacy of tezepelumab in adults with moderate to very severe chronic obstructive pulmonary disease (COPD) receiving triple inhaled maintenance therapy, and having had 2 or more documented COPD exacerbations in the 12 months prior to Visit 1. Approximately, 338 subjects will be randomized globally. Subjects will be stratified by region and prior number of exacerbations (2 vs. 3 or more). Subjects will receive tezepelumab, or placebo, administered via subcutaneous injection at the study site, over a 52 week treatment period. The study also includes a post-treatment follow-up period of 12 weeks.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 337

Inclusion Criteria

History of moderate to very severe physician-diagnosed COPD for at least 12 months prior to enrolment with a post-bronchodilator FEV1/FVC<0.70 and a post-bronchodilator FEV1 ≥20% and ≤80% of predicted normal value.
History of at least 2 documented moderate to severe COPD exacerbations within 2 to 52 weeks prior to enrollment.
CAT score of ≥15 at enrollment and on day of randomization.
Documented treatment with triple therapy for COPD (medium or high dose ICS/LABA/LAMA) throughout the year prior to enrollment. The dose of ICS should be stable for 3 months prior to enrollment.

Exclusion Criteria

Clinically important pulmonary disease other than COPD, as judged by the Investigator (including current or historic asthma diagnosis).
Any disorder, including, but not limited to, cardiovascular, gastrointestinal, hepatic, renal, neurological, musculoskeletal, infectious (including risk factors for pneumonia), endocrine, metabolic, hematological, psychiatric, or major physical impairment that is not stable.
Major surgery within 8 weeks before enrollment.
History of clinically significant infection requiring antibiotics or antiviral medication within 14 days before enrollment.
Pregnant or breastfeeding.
The chest/lungs with pathology that precludes the patient's ability to complete the study
The patient has active COVID 19 infection during screening period.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Matching Placebo	Placebo	Matching placebo, SC, Q4W
Tezepelumab	Tezepelumab	Tezepelumab, SC, Q4W

Primary Outcome Measures

Name	Time	Method
Rate of Moderate or Severe COPD Exacerbations in Participants With Moderate to Very Severe COPD.	From randomisation up to Week 52	A COPD exacerbation was defined as a change in the participant's usual COPD symptoms that is beyond normal day-to-day variation, is acute in onset, lasts 2 or more days, and may warrant a change in regular medication and leads to any of the following: Use of systemic corticosteroids for at least 3 days, use of antibiotics for at least 3 days, an inpatient hospitalisation due to COPD, or results in death. Analysis was done using a negative binomial model with the response variable as the number of COPD exacerbations experienced during the follow-up for exacerbations. The model included covariates of treatment group, region, and number of exacerbations reported at randomisation as recorded in IWRS (2, \>=3). The logarithm of the time at risk (in years) for exacerbation in the study is used as an offset variable.

Secondary Outcome Measures

Name	Time	Method
Time to First Severe COPD Exacerbation	From randomisation up to Week 52	Time to first severe COPD exacerbation post-randomisation, presented as number of subjects with at least one severe COPD exacerbation.
Time to First Moderate/Severe COPD Exacerbation	From randomisation up to Week 52	Time to first moderate/severe COPD exacerbation post-randomisation, presented as number of subjects with at least one moderate/severe COPD exacerbation.
Proportion of Participants COPD Exacerbation Free at Week 52	From randomisation up to Week 52	An exacerbation event was defined as described in primary analysis. A participant was exacerbation free if they did not experience any moderate or severe exacerbations from randomisation to Week 52 (EOT).
Lease Square (LS) Mean Difference in Change From Baseline in St. George's Respiratory Questionnaire (SGRQ) Total Score at Week 52	Baseline and Week 52	The SGRQ is a 50-item PRO instrument to measure the health status of participants with airway obstruction diseases. The total score indicates the impact of disease on overall health status. This total score is expressed as a percentage of overall impairment, in which 100 represents the worst possible health status and 0 indicates the best possible health status. Baseline is the measurement recorded at Week 0 (Visit 3).
Serum Concentration of Tezepelumab	Pre-dose at weeks 0, 4, 12, 24, 36 and also at weeks 52 and 64 where no dosing was scheduled	Blood samples were collected to determine the serum concentration of Tezepelumab. With the exception of Week 0 and Week 64, only pre-dose data from samples collected between 21 and 35 days after previous dose of investigational product were included.
Comparison of Annual Severe COPD Exacerbation Rates Over 52 Weeks	From randomisation up to Week 52	An exacerbation was considered severe if it results in at least 1 of the following: Hospitalisation due to the COPD exacerbation (defined as a participant being admitted for ≥ 24 hours to an observation area, the emergency department, or other equivalent healthcare facility), or death related to COPD or COPD exacerbation.
Proportion of Participants With >=1 Severe COPD Exacerbations Over 52 Weeks	From randomisation up to Week 52	An exacerbation was considered severe if it results in at least 1 of the following: Hospitalisation due to the COPD exacerbation (defined as a participant being admitted for ≥ 24 hours to an observation area, the emergency department, or other equivalent healthcare facility), or death related to COPD or COPD exacerbation.
Least Square (LS) Mean Difference in Change From Baseline in Pre-bronchodilator Forced Expiratory Volume in 1 (FEV1) at Week 52	Baseline and Week 52	Pre-Bronchodilator FEV1 (L) was determined by spirometry at the clinic visit. FEV1 is defined as the volume of air exhaled from the lungs in the first second of a forced expiration. Change from baseline was obtained as an absolute difference between Week 52 measure and the baseline value. Baseline was defined as the last assessment recorded prior to the first dose of study treatment.
Proportion of Participants Achieving a Minimum Clinically Important Difference of 4 Units or More in St. George's Respiratory Questionnaire (SGRQ) Total Score at Week 52	Baseline and Week 52	The SGRQ is a 50-item PRO instrument to measure the health status of participants with airway obstruction diseases. The total score indicates the impact of disease on overall health status. This total score is expressed as a percentage of overall impairment, in which 100 represents the worst possible health status and 0 indicates the best possible health status. A responder was defined as an individual who had "improvement" at Week 52 (\>=4 point decrease in SGRQ total score).
Least Square (LS) Mean Difference in Change From Baseline in COPD Assessment Tool (CAT) Total Score at Week 52	Baseline and Week 52	The CAT is an 8-item PRO developed to measure the impact of COPD on health status. A CAT total score is the sum of item responses. Scores range from 0-40 with higher scores indicative of greater COPD impact on health status. Baseline was defined as the value at the randomisation visit (Visit 3). If the Visit 3 measurement was missing, the screening value was used as baseline instead.
Number of Participants With Anti-Drug Antibody (ADA) Response to Tezepelumab	Pre-dose at weeks 0, 4, 12, 24, 36 and also at weeks 52 and 64 where no dosing was scheduled	Blood samples were measured for the presence of ADAs for tezepelumab using validated assays. Treatment-induced ADA positive was defined as ADA negative at baseline and post-baseline ADA positive. Treatment-boosted ADA positive was defined as baseline positive ADA titre that was boosted to a 4 fold or higher level following IP administration. TE-ADA positive was defined as the sum of treatment-induced ADA positive and treatment-boosted ADA positive. ADA incidence is the proportion of TE-ADA positive subjects in a population. ADA persistently positive was defined as ADA positive at \>= 2 post-baseline assessments or ADA positive at last post-baseline assessment. ADA transiently positive was defined as having at least one post-baseline ADA positive assessment and not fulfilling the conditions of ADA persistently positive. Treatment-induced nAb positive was defined as nAb negative or ADA negative at baseline and nAb positive at any post-baseline visit.