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Study to Evaluate Tezepelumab in Adults & Adolescents With Severe Uncontrolled Asthma (NAVIGATOR)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03347279
Recruitment Status : Completed
First Posted : November 20, 2017
Results First Posted : November 26, 2021
Last Update Posted : November 26, 2021
Sponsor:
Collaborator:
Amgen
Information provided by (Responsible Party):
AstraZeneca

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

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

Detailed Description:
This is a multicentre, randomized, double-blind, placebo controlled, parallel group study designed to evaluate the efficacy and safety of tezepelumab in adults and adolescents with severe, uncontrolled asthma on medium to high-dose ICS and at least one additional asthma controller medication with or without OCS. Approximately 1060 subjects will be randomized globally. 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.
Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 1061 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 Multicentre, Randomized, Double-Blind, Placebo Controlled, Parallel Group, Phase 3 Study to Evaluate the Efficacy and Safety of Tezepelumab in Adults and Adolescents With Severe Uncontrolled Asthma (NAVIGATOR)
Actual Study Start Date : November 23, 2017
Actual Primary Completion Date : September 8, 2020
Actual Study Completion Date : November 12, 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Asthma
Drug Information available for: Tezepelumab

Arms and Interventions
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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


Outcome Measures
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Primary Outcome Measures :
  1. Annual Asthma Exacerbation Rate in Adult and Adolescent Patients With Uncontrolled Asthma [ Time Frame: From randomisation to Study Week 52. ]
    The annual exacerbation rate is based on unadjudicated exacerbations reported by the investigator in the eCRF. The analysis is based on the primary population (Full Analysis Set)

  2. Annual Asthma Exacerbation Rate in Adult and Adolescent Patients With Uncontrolled Asthma in Subjects With Baseline Eosinophils < 300 Cells/uL [ Time Frame: From randomisation to Study Week 52. ]
    The annual exacerbation rate is based on unadjudicated exacerbations reported by the investigator in the eCRF. This analysis is based on subjects with baseline eosinophils < 300 cells/uL


Secondary Outcome Measures :
  1. Mean Change From Baseline at Week 52 in Pre-dose/Pre-bronchodilator (Pre-BD) Forced Expiratory Volume in 1 Second (FEV1) (L) (Key Secondary Endpoint) [ Time Frame: From randomisation to Study Week 52 ]
    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.

  2. Mean Change From Baseline at Week 52 in Standardized Asthma Quality of Life Questionnaire for 12 Years and Older (AQLQ(S)+12) Total Score (Key Secondary Endpoint) [ Time Frame: From randomisation to Study Week 52 ]
    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 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. Mean Change From Baseline at Week 52 in Asthma Control Questionnaire-6(ACQ-6) (Key Secondary Endpoint) [ Time Frame: From randomisation to Study 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. Mean Change From Baseline at Week 52 in Asthma Symptom Diary (Key Secondary Endpoint) [ Time Frame: From randomisation to Study Week 52 ]
    Mean change from baseline at Week 52 in Asthma Symptom Diary. 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, where 0 indicates no asthma symptoms.

  5. Time to First Asthma Exacerbation [ Time Frame: From randomisation to Study Week 52 ]
    Time to first occurrence of asthma exacerbation post-randomisation, presented as number of subjects with at least one asthma exacerbation as reported by the investigator in the eCRF.

  6. Mean Change From Baseline at Week 52 in Clinic Fractional Exhaled Nitric Oxide (FeNO) (Ppb) [ Time Frame: From randomisation to Study Week 52 ]
    Mean change from baseline at Study Week 52 in FeNO (ppb) measured at site

  7. Mean Change From Baseline in Daily Rescue Medication Use (Weekly Means) at Week 52 [ Time Frame: From randomisation to Study Week 52 ]
    Daily rescue medication use is defined as: Number of night inhaler puffs + 2 x [number of night nebulizer times] + number of daytime inhaler puffs + 2 x [number of day nebulizer times]. Weekly means are calculated using at least 4 of 7 days of daily rescue medication use.

  8. Mean Change From Baseline in Work Productivity Loss Due to Asthma at Week 52 [ Time Frame: From randomisation to Study Week 52 ]
    WPAI+CIQ (Work Productivity and Activity Impairment plus Classroom Impairment Questionnaire) contains 10 questions. Work productivity loss is derived by sum of percentage of missed work due to asthma and product of percentage of actual working hours times degree of asthma affecting work productivity while working. Percentage of missed work due to asthma is calculated by number of hours missed work due to asthma divided by total number of hours missed work plus number of hours actually worked.

  9. Mean Change From Baseline in Class Productivity Loss Due to Asthma at Week 52 [ Time Frame: From randomisation to Study Week 52 ]
    WPAI+CIQ (Work Productivity and Activity Impairment plus Classroom Impairment Questionnaire) contains 10 questions. Class productivity loss is derived by sum of percentage of missed class hours due to asthma and product of percentage of actual hours in class times degree of asthma affecting productivity while in class. Percentage of missed hours in class due to asthma is calculated by number of hours in class missed due to asthma divided by total number of hours in class missed plus number of hours actually in class.

  10. Activity Impairment at Week 52 [ Time Frame: From randomisation to Study Week 52 ]
    WPAI+CIQ (Work Productivity and Activity Impairment plus Classroom Impairment Questionnaire) contains 10 questions. Activity impairment is the degree health affected regular activities (other than work or class) rated from 0 to 10, with 0 meaning no effect, divided by 10, and then expressed as a percentage.

  11. Pharmacokinetics of Tezepelumab [ Time Frame: Pre-dose samples at Baseline, Week 4, Week 12, Week 24, Week 36, Week 52, Week 64 ]
    Mean serum trough PK concentrations taken pre-dose at each visit

  12. Mean Change From Baseline at Week 52 in EQ-5D-5L VAS [ Time Frame: At Study Week 52 ]
    Mean change from baseline at Study Week 52 in EQ-5D-5L VAS. EQ-5D-5L visual analogue scale (VAS) allows subjects to rate current health status on a scale of 0-100, with 0 being the worst imaginable health state.

  13. Clinicians Global Impression of Change at Week 52 [ Time Frame: From randomisation to Study Week 52 ]
    CGIC (Clinical global impression of change) is an overall evaluation of response to treatment, conducted by investigator using 7-point rating scale, ranging from 1 (very much improved), to 7 (very much worse)

  14. Patients Global Impression of Change at Week 52 [ Time Frame: From randomisation to Study Week 52 ]
    PGIC (Patient global impression of change) is an overall evaluation of response to treatment, conducted by the patient using 7-point rating scale, ranging from 1 (very much improved), to 7 (very much worse).

  15. Patients Global Impression of Severity at Week 52 [ Time Frame: At Study Week 52 ]
    PGI-S (Patient global impression of severity) is an overall evaluation of patient's perception of overall symptom severity using a 6-point rating scale, ranging from 0 = No symptoms, 1=Very mild symptoms, 2=Mild symptoms, 3=Moderate symptoms, 4=Severe symptoms, 5=Very severe symptoms

  16. Mean Change From Baseline at Week 52 in Blood Eosinophils (Cells/uL) [ Time Frame: From randomisation to Study Week 52 ]
    Mean change from baseline at Study Week 52 in blood eosinophils (cells/uL)

  17. Mean Change From Baseline at Week 52 in Total Serum IgE (IU/mL) [ Time Frame: From randomisation to Study Week 52 ]
    Mean change from baseline at Study Week 52 in total serum IgE (IU/mL)

  18. Number of Participants With Asthma Specific Healthcare Utilization Over 52 Weeks [ Time Frame: From randomisation to Study Week 52 ]
    Number of participants with asthma specific healthcare utilizations (e.g. unscheduled physician visits, unscheduled phone calls to physicians, use of other asthma medications) over 52 weeks

  19. Mean Change From Baseline in Home Based Morning Peak Expiratory Flow (PEF) at Week 52 (Weekly Means) [ Time Frame: From randomisation to Study Week 52 ]
    Mean change from baseline in home based morning PEF (L/min) at Study Week 52. 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. Weekly means are calculated using at least 4 of the 7 days of PEF data.

  20. Mean Change From Baseline in Home Based Evening Peak Expiratory Flow (PEF) at Week 52 (Weekly Means) [ Time Frame: From randomisation to Study Week 52 ]
    Mean change from baseline in home based evening PEF (L/min) at Study Week 52. 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. Weekly means are calculated using at least 4 of the 7 days of PEF data.

  21. Mean Change From Baseline in Night Time Awakenings (Weekly Means) at Week 52 [ Time Frame: From randomisation to Study Week 52 ]
    Mean change from baseline in night time awakenings due to asthma at Study Week 52. Night-time awakenings percentage defined as number of nights with awakenings due to asthma and requiring rescue medication divided by number of nights with data and multiplied by 100%. At least 4 out of 7 days of data is required to calculate a weekly mean.

  22. Immunogenecity of Tezepelumab [ Time Frame: Baseline, and from time of first dose at Week 0 to end of study at Week 64. ]
    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.

  23. Proportion of Subjects Who Had no Asthma Exacerbations [ Time Frame: From randomisation to Study Week 52 ]
    The proportion of subjects who have no exacerbations is presented as the percentage of subjects with no exacerbations. This is defined as subjects who meet both the following criteria: (1) completed the 52 week treatment period and (2) did not report an exacerbation during this period.

  24. Annual Asthma Exacerbation Rate Resulting in Emergency Room Visit or Hospitalisation [ Time Frame: From randomisation to Study Week 52 ]
    The annualized exacerbation rate is based on exacerbations reported by the investigator that are associated with an emergency room visit, urgent care visit, or a hospitalization (where urgent care visit was captured as an emergency room visit on the eCRF)

  25. Proportion of Subjects With at Least One Asthma Exacerbation Associated With Emergency Room Visit or Hospitalisation [ Time Frame: From randomisation to Study Week 52 ]
    Proportion of subjects with at least one asthma exacerbation associated with emergency room visit or hospitalisation as recorded by the investigator in the CRF. This is presented as percentage of subjects with at least one asthma exacerbation associated with emergency room visit or hospitalisation.

  26. Proportion of Subjects Who Had no Asthma Exacerbations Associated With Emergency Room or Hospitalisation [ Time Frame: From randomisation to Study Week 52 ]
    The proportion of subjects with no exacerbations is presented as percentage of subjects who meet both the following criteria: (1) completed the 52 week treatment period and (2) did not report an exacerbation associated with emergency room or hospitalisation during this period.


Other Outcome Measures:
  1. Annual Asthma Exacerbation Rate Associated With Hospitalisations [ Time Frame: From randomisation to Study Week 52 ]
    The annualized exacerbation rate is based on exacerbations reported by the investigator that are associated with hospitalization

  2. Annual Asthma Exacerbation Rate Using Adjudicated Data [ Time Frame: From randomisation to Study Week 52 ]
    The annualized exacerbation rate is based on exacerbations as defined for the primary endpoint, but any hospitalisation and ER visits which are adjudicated to be asthma related are added, and those adjudicated to not be asthma related are removed from analyses.

  3. Annual Asthma Exacerbation Rate Associated With Emergency Room (ER) Visit or Hospitalisation Using Adjudicated Data [ Time Frame: From randomisation to Study Week 52 ]
    The annualized exacerbation rate is based on exacerbations associated with hospitalisations or ER visits, where hospitalisation and ER visits adjudicated to be asthma related are added, and those adjudicated to not be asthma related are removed from analyses.


Eligibility Criteria
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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:   12 Years to 80 Years   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Age. 12-80
  • 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 12 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 (<90% for subjects 12-17 yrs)
  • 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.
  • 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-years and subjects using vaping products, including electronic cigarettes.
  • 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.
Contacts and Locations
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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): NCT03347279


Locations
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Sponsors and Collaborators
AstraZeneca
Amgen
Investigators
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Principal Investigator: Andrew Menzies-Gow, MD Royal Brompton Hospital, United Kingdom
  Study Documents (Full-Text)

Documents provided by AstraZeneca:
Study Protocol  [PDF] May 14, 2020
Statistical Analysis Plan  [PDF] October 22, 2020

More Information
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Additional Information:

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: AstraZeneca
ClinicalTrials.gov Identifier: NCT03347279    
Other Study ID Numbers: D5180C00007
First Posted: November 20, 2017    Key Record Dates
Results First Posted: November 26, 2021
Last Update Posted: November 26, 2021
Last Verified: October 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
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.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
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.
Access Criteria: When a request has been approved AstraZeneca will provide access to the de-identified 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.
URL: https://astrazenecagroup-dt.pharmacm.com/DT/Home

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
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