Study to Evaluate Tezepelumab in Adults With Severe Uncontrolled Asthma (DIRECTION)

A Regional, Multicentre, Randomized, Double-Blind, Placebo Controlled, Parallel Group, Phase 3 Study to Evaluate the Efficacy and Safety of Tezepelumab in Adults With Severe Uncontrolled Asthma

A Regional, Multicentre, Randomized, Double-Blind, Placebo Controlled, Parallel Group, Phase 3 Study to Evaluate the Efficacy and Safety of Tezepelumab in Adults with Severe Uncontrolled Asthma

Study Overview

• Status: Active, not recruiting
• Conditions: Asthma
• Intervention / Treatment: Biological: Experimental: Tezepelumab; Other: Placebo

Detailed Description

This is a regional, multicentre, randomized, double-blind, placebo controlled, parallel group, phase 3 study designed to evaluate the efficacy and safety of 210 mg Q4W (SC) of tezepelumab in adults with severe, uncontrolled asthma on medium to high-dose ICS and at least one additional asthma controller medication with or without OCS. Approximately 396 participants will be randomized regionally (China/non-China). Participants 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

• Study Type: Interventional
• Enrollment (Actual): 405
• Phase: Phase 3

Contacts and Locations

Study Locations

• China
  • Baotou, China, 14010
    • Research Site
  • Beijing, China, 100070
    • Research Site
  • Beijing, China, 100020
    • Research Site
  • Beijing, China, 100730
    • Research Site
  • Beijing, China, 100853
    • Research Site
  • Beijing, China, 100029
    • Research Site
  • Beijing, China, 1000096
    • Research Site
  • Changchun, China, 130021
    • Research Site
  • Changsha, China, 410011
    • Research Site
  • Changsha, China, 410008
    • Research Site
  • Chengdu, China, 610041
    • Research Site
  • Chongqing, China
    • Research Site
  • Chongqing, China, 400038
    • Research Site
  • Chongqing, China, 400016
    • Research Site
  • Fuzhou, China, 350001
    • Research Site
  • Guangzhou, China, 510120
    • Research Site
  • Guangzhou, China
    • Research Site
  • Guangzhou, China, 510080
    • Research Site
  • Guiyang, China, 550004
    • Research Site
  • Haikou, China, 570311
    • Research Site
  • Hangzhou, China, 310020
    • Research Site
  • Hefei, China, 133500
    • Research Site
  • Hengyang, China, 50012
    • Research Site
  • Hohhot, China, 010017
    • Research Site
  • Hohhot, China, 10050
    • Research Site
  • Huzhou, China, 313003
    • Research Site
  • Jinan, China, 250013
    • Research Site
  • Jinhua, China, 321000
    • Research Site
  • Kunming, China, 650032
    • Research Site
  • Lanzhou, China, 730000
    • Research Site
  • Linhai, China, 317000
    • Research Site
  • Linyi, China, CN-276003
    • Research Site
  • Nanchang, China, 330006
    • Research Site
  • Nanjing, China, 2100008
    • Research Site
  • Nanjing, China, 210009
    • Research Site
  • Nanjing, China, 210029
    • Research Site
  • Nanning, China, 530007
    • Research Site
  • Quanzhou, China, 362000
    • Research Site
  • Shanghai, China, 200032
    • Research Site
  • Shanghai, China, 200025
    • Research Site
  • Shanghai, China, 200050
    • Research Site
  • Shengyang, China, 110004
    • Research Site
  • Shenyang, China, 110015
    • Research Site
  • Shenzhen, China, 518035
    • Research Site
  • Shijiazhuang, China, 050000
    • Research Site
  • Tianjin, China, 300192
    • Research Site
  • Urumchi, China, 830054
    • Research Site
  • Weifang, China, 261041
    • Research Site
  • Wenzhou, China, 325027
    • Research Site
  • Wuhan, China, 430022
    • Research Site
  • Wuhan, China, 430030
    • Research Site
  • Wuhan, China, 430033
    • Research Site
  • Xi'an, China, 710004
    • Research Site
  • Xining, China, 810007
    • Research Site
  • Xuzhou, China, 221009
    • Research Site
  • Xuzhou, China, 221000
    • Research Site
  • Yangzhou, China, 225001
    • Research Site
  • Zhengzhou, China, 450000
    • Research Site
  • Zhuhai, China, 519099
    • Research Site
  • Zibo, China, 255036
    • Research Site
  • Zunyi, China, 563100
    • Research Site
• Korea, Republic of
  • Cheongju-si, Korea, Republic of, 28644
    • Research Site
  • Daegu, Korea, Republic of, 42415
    • Research Site
  • Jeonju-si, Korea, Republic of, 54907
    • Research Site
  • Seoul, Korea, Republic of, 03722
    • Research Site
  • Seoul, Korea, Republic of, 05505
    • Research Site
  • Seoul, Korea, Republic of, 06591
    • Research Site
  • Seoul, Korea, Republic of, 03312
    • Research Site
  • Suwon-si, Korea, Republic of, 16499
    • Research Site
• Philippines
  • Iloilo City, Philippines, 5000
    • Research Site
  • Quezon City, Philippines, 1100
    • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Age. 18-80
• Documented physician-diagnosed asthma for at least 12 months
• Participants who have received a physician-prescribed asthma controller medication with medium or high dose ICS for at least 6 months.
• Documented treatment with a total daily dose of either medium or high dose ICS (≥ 500 µg fluticasone propionate dry powder formulation equivalent total daily dose) for at least 3 months.
• At least one additional maintenance asthma controller medication is required according to standard practice of care and must be documented for at least 3 months.
• Morning pre-BD FEV1 <80% predicted normal
• Evidence of asthma as documented by either: Documented historical reversibility of FEV1 ≥12% and ≥200 mL in the previous 12 months OR Post-BD (albuterol/salbutamol) reversibility of FEV1 ≥12% and ≥200 mL during screening.
• Documented history of at least 2 asthma exacerbation events within 12 months, and at least one of the exacerbations should occur during the treatment of medium-to-high dose ICS.
• ACQ-6 score ≥1.5 at screening and on day of randomization

Exclusion Criteria:

• Pulmonary disease other than asthma.
• History of cancer.
• History of a clinically significant infection.
• Current smokers or participants with smoking history ≥10 pack-yrs.
• History of chronic alcohol or drug abuse within 12 months.
• Hepatitis B, C or HIV.
• Pregnant or breastfeeding.
• History of anaphylaxis following any biologic therapy.
• participant randomized in the current study or previous tezepelumab studies.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Tezepelumab; Tezepelumab: Tezepelumab subcutaneous injection	Biological: Experimental: Tezepelumab; Tezepelumab subcutaneous injection; Other Names: Tezepelumab
Placebo Comparator: Placebo; Placebo: Placebo subcutaneous injection	Other: Placebo; Placebo subcutaneous injection

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Annualized asthma exacerbation rate (AERR)	The annualized exacerbation rate is based on exacerbations reported by the investigator in the eCRF over 52 weeks.	Randomization to Week 52

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change from baseline in pre-dose/pre-bronchodilator (pre-BD) forced expiratory volume in 1 second (FEV1)	Mean change from baseline in FEV1 as compared to placebo at Week 52. FEV1 is defined as the volume of air exhaled from the lungs in the first second of a forced expiration.	Randomization, Week 52
Change from baseline in Standardized Asthma Quality of Life Questionnaire for 12 years and older (AQLQ(S)+12) total score	Mean change from baseline in AQLQ(S)+12 as compared to placebo at Week 52. The AQLQ(S)+12 is a questionnaire that measures the health-related quality of life experienced by asthma participants. The total score is defined as the average of all 32 questions in the AQLQ(S)+12 questionnaire. AQLQ(S)+12 is a 7-point scale questionnaire, ranging from 7 (no impairment) to 1 (severe impairment).	Randomization， Week 52
Change from baseline in Asthma Control Questionnaire-6 (ACQ-6) Score	Mean change from baseline in ACQ-6 as compared to placebo at Week 52. The ACQ-6 captures asthma symptoms and short-acting β2-agonist use via subject-report. Questions are weighted equally and scored from 0 (totally controlled) to 6 (severely uncontrolled). The ACQ-6 score is the mean of the responses.	Randomization, Week 52
Change from baseline in weekly mean daily Asthma Symptom Diary score	Mean change from baseline in Asthma Symptom Diary score as compared to placebo at Week 52. The Asthma Symptom Diary comprises of 10 items (5 items in the morning; 5 items in the evening). Asthma symptoms during night time and daytime are recorded by the patient each morning and evening in the daily diary. A daily ASD score is the mean of the 10 items. Responses for all 10 items are required to calculate the daily ASD score; otherwise, it is treated as missing. For the 7-day average asthma symptom score, scoring is done with no imputation using the mean of at least 4 of the 7 daily ASD scores as a mean weekly item score. The 7-day average ASD score ranges from 0 to 4.	Randomization, Week 52
Time to first asthma exacerbation	Time to the first occurrence of asthma exacerbation post randomization, presented as number of participants with at least one asthma exacerbation reported in the eCRF	Randomization to Week 52
Change from baseline in fractional exhaled nitric oxide	Mean change from baseline in FENO (ppb) at week 52 to assess the effect of 210 mg of tezepelumab SC Q4W on biomarkers	Randomization, Week 52
Change from baseline in weekly mean rescue medication use	Mean change from baseline in weekly mean rescue medication use at Week 52 to assess the effect of 210 mg of tezepelumab SC Q4W on other asthma control metrics. The number of rescue medication inhalations (puffs) and nebulizer treatments taken will be recorded by the participant in the Asthma Symptom Diary twice daily (i.e., in the morning and evening). Each timepoint is calculated as weekly means based on daily diary data.	Randomization, Week 52
Number of participants with asthma specific resource utilization (e.g.,eg, unscheduled physician visits, unscheduled phone calls to physicians, use of other asthma medications)	Number of participants with asthma specific resource utilization (e.g. unscheduled physician visits, unscheduled phone calls to physicians, use of other asthma medications) over 52 weeks.	Randomization to Week 52
Serum trough concentrations	Serum trough concentrations (pre-dose samples) at each scheduled visit to evaluate the pharmacokinetics (PK) of tezepelumab	Baseline to Week 64
European Quality of Life - 5 Dimensions 5 Levels Questionnaire (EQ-5D-5L) score	Mean change from baseline in EQ-5D-5L at week 52. EQ-5D-5L has two sections. The first section assesses five dimensions (mobility, self-care, usual activity, pain/discomfort, and anxiety/depression). Patients rate each of these items from "no problem," "slight problem" "moderate problem", "severe problem" and "unable". A composite health index is defined by combining the levels for each dimension. The second section measures self-rated (global) health status using a vertically oriented visual analogue scale where 100 represents the "best possible health state" and 0 represents the "worst possible health state". EQ-5D-5L assesses health status in terms of a single index value or health utility score. It allows "weighting" by the patient of particular health states and the generation of patient utilities. Overall scores range from 0 to 1,with lower scores representing a higher level of dysfunction.	Randomization, Week 52
Change from baseline in peripheral blood eosinophils	Mean change from baseline in blood eosinophil counts at week 52 to assess the effect of 210 mg of tezepelumab SC Q4W on biomarkers.	Randomization, Week 52
Change from baseline in total serum IgE	Mean change from baseline in IgE at week 52 to assess the effect of 210 mg of tezepelumab SC Q4W on biomarkers.	Randomization, Week 52
Change from baseline in weekly mean morning and evening peak expiratory flow (PEF)	Mean change from baseline in weekly mean morning and evening peak expiratory flow (PEF) at Week 52 to assess the effect of 210 mg of tezepelumab SC Q4W on other asthma control metrics. Home PEF testing will be performed by the participant in the morning upon awakening and in the evening at bedtime using an electronic, hand-held spirometer. Each timepoint is calculated as weekly means.	Randomization, Week 52
Change from baseline in weekly mean number of night time awakenings	Mean change from baseline in weekly mean number of night time awakenings at Week 52 to assess the effect of 210 mg of tezepelumab SC Q4W on other asthma control metrics. Each timepoint is calculated as weekly mean number of awakenings due to asthma based on daily diary data. Weekly mean number of night time awakenings is defined as the number of nights with awakenings due to asthma and requiring rescue medication divided by number of nights with data and multiplied by 100%.	Randomization, Week 52
Immunogenicity anti-drug antibodies	Anti-drug antibodies (ADA) responses at baseline and post baseline. Persistently positive is defined as positive at >=2 post baseline assessments (with >=16 weeks between the first and the last positive) or positive at last post baseline assessment. Transiently positive is defined as having at least one post baseline ADA positive assessment and not fulfilling the conditions of persistently positive. Treatment boosted ADA defined as baseline positive ADA that was boosted to a 4 fold or higher level following treatment. Treatment emergent ADA defined as sum of treatment induced ADA and treatment boosted ADA.	Baseline to Week 64
Proportion of participants who did not experience an asthma exacerbation	Percentage of participants who did not experience an asthma exacerbation as compared to placebo at Week 52	Week 52
Annualized rate of exacerbations associated with emergency room (ER) visit or hospitalizations	Annualized rate of exacerbations associated with ER visit or hospitalization as compared to placebo over 52 weeks	Randomization to Week 52

Collaborators and Investigators

• Sponsor: AstraZeneca
• Collaborators: Amgen
• Investigators: Principal Investigator: Nanshan Zhong, Bachelor, Guangzhou institute of Respiratory Disease, China

Study record dates

Study Major Dates

• Study Start (Actual): June 14, 2019
• Primary Completion (Estimated): May 29, 2024
• Study Completion (Estimated): August 19, 2024

Study Registration Dates

• First Submitted: April 23, 2019
• First Submitted That Met QC Criteria: April 23, 2019
• First Posted (Actual): April 25, 2019

Study Record Updates

• Last Update Posted (Actual): April 26, 2024
• Last Update Submitted That Met QC Criteria: April 25, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Keywords: Asthma; Uncontrolled Asthma; Severe Uncontrolled Asthma
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Immune System Diseases; Lung Diseases; Hypersensitivity, Immediate; Bronchial Diseases; Lung Diseases, Obstructive; Respiratory Hypersensitivity; Hypersensitivity; Asthma; Physiological Effects of Drugs; Immunologic Factors; Antibodies, Monoclonal
• Other Study ID Numbers: D5180C00021

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal.

All request will be evaluated as per the AZ disclosure commitment:

https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure. Yes, indicates that AZ are accepting requests for IPD, but this does not mean all requests will be shared.

• IPD Sharing Time Frame: AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please rerefer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
• IPD Sharing Access Criteria: When a request has been approved AstraZeneca will provide access to the deidentified individual patient-level data in an approved sponsored tool . Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes