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

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ClinicalTrials.gov Identifier: NCT03927157
Recruitment Status : Active, not recruiting
First Posted : April 25, 2019
Last Update Posted : August 7, 2020
Sponsor:
Collaborator:
Amgen
Information provided by (Responsible Party):
AstraZeneca

Brief Summary:
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

Condition or disease Intervention/treatment Phase
Asthma Biological: Experimental: Tezepelumab Other: Placebo Phase 3

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 subjects will be randomized regionally (China/non-China). 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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 396 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Subjects will be randomized in a 1:1 ratio to either tezepelumab or matching placebo both administered subcutaneously.
Masking: Triple (Participant, Care Provider, Investigator)
Masking Description: Double-Blind
Primary Purpose: Treatment
Official Title: 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
Actual Study Start Date : June 14, 2019
Estimated Primary Completion Date : December 25, 2023
Estimated Study Completion Date : December 25, 2023

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Asthma

Arm Intervention/treatment
Experimental: Tezepelumab
Tezepelumab: Tezepelumab subcutaneous injection
Biological: Experimental: Tezepelumab
Tezepelumab subcutaneous injection
Other Name: Tezepelumab

Placebo Comparator: Placebo
Placebo: Placebo subcutaneous injection
Other: Placebo
Placebo subcutaneous injection




Primary Outcome Measures :
  1. Annualized asthma exacerbation rate (AERR) [ Time Frame: Baseline to Week 52 ]
    The annualized exacerbation rate is based on exacerbations reported by the investigator in the eCRF over 52 weeks.


Secondary Outcome Measures :
  1. Change from baseline in pre-dose/pre-bronchodilator (pre-BD) forced expiratory volume in 1 second (FEV1) [ Time Frame: Baseline, Week 52 ]
    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.

  2. Change from baseline in Standardized Asthma Quality of Life Questionnaire for 12 years and older (AQLQ(S)+12) total score [ Time Frame: Baseline, Week 52 ]
    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 subjects. 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).

  3. Change from baseline in Asthma Control Questionnaire-6 (ACQ-6) Score [ Time Frame: Baseline, Week 52 ]
    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.

  4. Change from baseline in weekly mean daily Asthma Symptom Diary score [ Time Frame: Baseline, Week 52 ]
    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.

  5. Time to first asthma exacerbation [ Time Frame: Baseline to Week 52 ]
    Time to the first occurrence of asthma exacerbation post randomisation

  6. Change from baseline in fractional exhaled nitric oxide FENO (ppb) [ Time Frame: Baseline, Week 52 ]
    Change from baseline in fractional exhaled nitric oxide FENO (ppb) at week 52 to assess the effect of 210 mg of tezepelumab SC Q4W on biomarkers

  7. Change from baseline in weekly mean rescue medication use [ Time Frame: Baseline, Week 52 ]
    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 subject 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.

  8. Asthma specific resource utilization (e.g.,eg, unscheduled physician visits, unscheduled phone calls to physicians, use of other asthma medications) [ Time Frame: Baseline, Week 52 ]
    Number of asthma specific resource utilizations (e.g. unscheduled physician visits, unscheduled phone calls to physicians, use of other asthma medications) over 52 weeks.

  9. Serum trough concentrations [ Time Frame: Baseline to Week 52 ]
    Serum trough concentrations at each scheduled visit to evaluate the pharmacokinetics (PK) of tezepelumab

  10. European Quality of Life - 5 Dimensions 5 Levels Questionnaire (EQ-5D-5L) score [ Time Frame: Week 52 ]
    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. Published weights are available for the creation of a single summary health utility score. Overall scores range from 0 to 1, with lower scores representing a higher level of dysfunction.

  11. Change from baseline in peripheral blood eosinophils [ Time Frame: Baseline, Week 52 ]
    Change from baseline in blood eosinophil counts at week 52 to assess the effect of 210 mg of tezepelumab SC Q4W on biomarkers.

  12. Change from baseline in total serum IgE [ Time Frame: Baseline, Week 52 ]
    Change from baseline in IgE at week 52 to assess the effect of 210 mg of tezepelumab SC Q4W on biomarkers.

  13. Change from baseline in weekly mean morning and evening peak expiratory flow (PEF) [ Time Frame: Baseline, Week 52 ]
    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 subject in the morning upon awakening and in the evening at bedtime using an electronic, hand-held spirometer. Each timepoint is calculated as weekly means.

  14. Change from baseline in weekly mean number of night time awakenings [ Time Frame: Baseline, Week 52 ]
    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.

  15. Immunogenicity anti-drug antibodies [ Time Frame: Baseline to Week 52 ]
    Incidence of anti-drug antibodies over 52 weeks to evaluate immunogenicity of tezepelumab.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Age. 18-80
  • Documented physician-diagnosed asthma for at least 12 months
  • Subjects 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 subjects 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.
  • Subject randomized in the current study or previous tezepelumab studies.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03927157


Locations
Show Show 51 study locations
Sponsors and Collaborators
AstraZeneca
Amgen
Investigators
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Principal Investigator: Nanshan Zhong, Bachelor Guangzhou institute of Respiratory Disease, China
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Responsible Party: AstraZeneca
ClinicalTrials.gov Identifier: NCT03927157    
Other Study ID Numbers: D5180C00021
First Posted: April 25, 2019    Key Record Dates
Last Update Posted: August 7, 2020
Last Verified: August 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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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
Keywords provided by AstraZeneca:
Asthma
Uncontrolled Asthma
Severe Uncontrolled Asthma
Additional relevant MeSH terms:
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Asthma
Bronchial Diseases
Respiratory Tract Diseases
Lung Diseases, Obstructive
Lung Diseases
Respiratory Hypersensitivity
Hypersensitivity, Immediate
Hypersensitivity
Immune System Diseases
Antibodies, Monoclonal
Immunologic Factors
Physiological Effects of Drugs