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Efficacy and Safety of Tozorakimab in Symptomatic Chronic Obstructive Pulmonary Disease With a History of Exacerbations. (TITANIA)

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ClinicalTrials.gov Identifier: NCT05158387
Recruitment Status : Recruiting
First Posted : December 15, 2021
Last Update Posted : January 23, 2023
Sponsor:
Information provided by (Responsible Party):
AstraZeneca

Tracking Information
First Submitted Date  ICMJE December 2, 2021
First Posted Date  ICMJE December 15, 2021
Last Update Posted Date January 23, 2023
Actual Study Start Date  ICMJE February 7, 2022
Estimated Primary Completion Date June 5, 2025   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: August 10, 2022)
Annualized rate of moderate to severe COPD exacerbations in participants who are former smokers. [ Time Frame: over 52 weeks ]
The primary endpoint will be assessed first in the primary population (former smokers with symptomatic COPD and a history of exacerbations, on optimised treatment with maintenance inhaled therapy [triple therapy, or dual therapy if triple is not considered appropriate]) and then assessed in the overall population of participants.
Original Primary Outcome Measures  ICMJE
 (submitted: December 2, 2021)
Annualized rate of moderate to severe COPD exacerbations in participants who are former smokers. [ Time Frame: over 52 weeks ]
The primary endpoint will be assessed first in the primary population (former smokers with symptomatic COPD and a history of exacerbations, on optimised treatment with maintenance inhaled therapy [triple therapy, or dual therapy if triple is not indicated or contraindicated]) and then assessed in the overall population of participants.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: August 10, 2022)
  • Annualized rate of moderate to severe COPD exacerbations in former or current smokers. [ Time Frame: over 52 weeks ]
    The annualized rate will be assessed in the overall population of participants including current and former smokers with symptomatic COPD and history of exacerbations, on optimised treatment with maintenance inhaled therapy.
  • Time to first moderate to severe COPD exacerbation in former smokers. [ Time Frame: over 52 weeks ]
    To explore the extent to which treatment with each dose of tozorakimab delays the time to first exacerbation compared with placebo in former smokers.
  • Mean change from baseline in pre-BD, pre-dose trough FEV1 (mL) in former smokers. [ Time Frame: Week 52, or over 52 weeks ]
    Change from baseline in pre-bronchodilator, pre dose trough FEV1 (mL) in former smokers.
  • Mean change from baseline in pre-BD, pre-dose trough FEV1 (mL) in the overall population of current and former smokers. [ Time Frame: Week 52, or over 52 weeks ]
    Change from baseline in pre-bronchodilator, pre dose trough FEV1 (mL) in the overall population of current and former smokers.
  • Percentage of responders achieving MCID in E-RS:COPD total score in former smokers [ Time Frame: Week 52 ]
    Responder analyses for E-RS:COPD total score at Week 52 based upon a ≥ 2 point improvement (decrease) from baseline in former smokers.
  • Percentage of responders achieving MCID in E-RS:COPD total score in the overall population of current and former smokers. [ Time Frame: Week 52 ]
    Responder analyses for E-RS:COPD total score at Week 52 based upon a ≥ 2 point improvement (decrease) from baseline in the overall population of current and former smokers.
  • Mean change from baseline in E-RS:COPD total score in former smokers. [ Time Frame: over 52 weeks ]
    Difference in mean change in E-RS:COPD total score from baseline in former smokers.
  • Mean change from baseline in E-RS:COPD total score in the overall population of current and former smokers. [ Time Frame: over 52 weeks ]
    Difference in mean change in E-RS:COPD total score from baseline in the overall population of current and former smokers.
  • Percentage of responders achieving MCID in SGRQ total score in former smokers. [ Time Frame: Week 52 ]
    Percentage of participants with a decrease in SGRQ total score of ≥ 4 points from baseline in former smokers.
  • Percentage of responders achieving MCID in SGRQ total score in the overall population of current and former smokers. [ Time Frame: Week 52 ]
    Percentage of participants with a decrease in SGRQ total score of ≥ 4 points from baseline in the overall population of current and former smokers.
  • Mean change from baseline in SGRQ total score from in former smokers. [ Time Frame: over 52 weeks ]
    Difference in mean change from baseline in SGRQ total score in former smokers.
  • Mean change from baseline in SGRQ total score from in the overall population of current and former smokers. [ Time Frame: over 52 weeks ]
    Difference in mean change from baseline in SGRQ total score in the overall population of current and former smokers.
  • Time to first severe COPD exacerbation in former smokers. [ Time Frame: over 52 weeks ]
    To evaluate hazard ratio of first severe COPD exacerbation in former smokers.
  • Annualized rate of severe COPD exacerbations in former smokers. [ Time Frame: over 52 weeks ]
    The rate ratio of severe COPD exacerbations will be assessed in former smokers.
  • Change from baseline in CAT total score. [ Time Frame: Week 52 ]
    Analyses of change from baseline in CAT total score in former smokers.
  • Percentage of participants with a decrease in CAT total score in former smokers. [ Time Frame: Week 52 ]
    Proportion of participants achieving MCID in CAT total score, a decrease in CAT total score of ≥ 2 points from baseline in former smokers.
  • Proportion of participants having ≥ 1 healthcare resource utilization type in former smokers. [ Time Frame: over 52 weeks ]
    Proportion of participants having ≥ 1 healthcare resource utilization type in former smokers.
  • Annualized rate of healthcare resource utilization in former smokers. [ Time Frame: over 52 weeks ]
    Annualized rate of healthcare resource utilization in former smokers.
  • The change from baseline in mean number of puffs per day in rescue use in former smokers. [ Time Frame: over 52 weeks ]
    Difference in mean number of puffs per day from baseline.
  • Trough serum concentrations of tozorakimab. [ Time Frame: over 52 weeks ]
    Pharmacokinetics: concentrations of tozorakimab in trough serum.
  • Presence of anti-drug antibodies. [ Time Frame: over 60 weeks ]
    Immunogenicity: presence of tozorakimab anti-drug antibodies in blood serum.
Original Secondary Outcome Measures  ICMJE
 (submitted: December 2, 2021)
  • Annualized rate of moderate to severe COPD exacerbations in former or current smokers. [ Time Frame: over 52 weeks ]
    The annualized rate will be assessed in the overall population of participants including current and former smokers with symptomatic COPD and history of exacerbations, on optimised treatment with maintenance inhaled therapy.
  • Time to first moderate to severe COPD exacerbation in former smokers. [ Time Frame: over 52 weeks ]
    To explore the extent to which treatment with each dose of MEDI3506 delays the time to first exacerbation compared with placebo in former smokers.
  • Mean change from baseline in pre-BD, pre-dose trough FEV1 (mL) in former smokers. [ Time Frame: US - week 52; Ex-US - over 52 weeks ]
    Change from baseline in pre-bronchodilator, pre dose trough FEV1 (mL) in former smokers. US and EX-US testing approach.
  • Percentage of responders achieving MCID in E-RS:COPD total score in former smokers . [ Time Frame: Week 52 ]
    Responder analyses for E-RS:COPD total score at Week 52 based upon a ≥ 2 point improvement (decrease) from baseline in former smokers. US testing approach.
  • Mean change from baseline in E-RS:COPD total score in former smokers. [ Time Frame: over 52 weeks ]
    Difference in mean change in E-RS:COPD total score from baseline in former smokers. Ex-US testing approach.
  • Percentage of responders achieving MCID in SGRQ total score in former smokers. [ Time Frame: Week 52 ]
    Percentage of participants with a decrease in SGRQ total score of ≥ 4 points from baseline in former smokers. US testing approach.
  • Mean change from baseline in SGRQ total score from in former smokers. [ Time Frame: over 52 weeks ]
    Difference in mean change from baseline in SGRQ total score in former smokers. Ex-US testing approach.
  • Time to first severe COPD exacerbation in former smokers. [ Time Frame: over 52 weeks ]
    To evaluate hazard ratio of first severe COPD exacerbation in former smokers.
  • Annualized rate of severe COPD exacerbations in former smokers. [ Time Frame: over 52 weeks ]
    The rate ratio of severe COPD exacerbations will be assessed in former smokers.
  • Change from baseline in CAT total score. [ Time Frame: Week 52 ]
    Analyses of change from baseline in CAT total score in former smokers.
  • Percentage of participants with a decrease in CAT total score in former smokers. [ Time Frame: Week 52 ]
    Proportion of participants achieving MCID in CAT total score, a decrease in CAT total score of ≥ 2 points from baseline in former smokers.
  • Proportion of participants having ≥ 1 healthcare resource utilization type in former smokers. [ Time Frame: over 52 weeks ]
    Proportion of participants having ≥ 1 healthcare resource utilization type in former smokers.
  • Annualized rate of healthcare resource utilization in former smokers. [ Time Frame: over 52 weeks ]
    Annualized rate of healthcare resource utilization in former smokers.
  • The change from baseline in mean number of puffs per day in rescue use in former smokers. [ Time Frame: over 52 weeks ]
    Difference in mean number of puffs per day from baseline.
  • Trough serum concentrations of MEDI3506. [ Time Frame: over 52 weeks ]
    Pharmacokinetics: concentrations of MEDI3506 in trough serum.
  • Presence of anti-drug antibodies. [ Time Frame: over 60 weeks ]
    Immunogenicity: presence of MEDI3506 anti-drug antibodies in blood serum.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Efficacy and Safety of Tozorakimab in Symptomatic Chronic Obstructive Pulmonary Disease With a History of Exacerbations.
Official Title  ICMJE A Phase III, Multicentre, Randomised, Double-blind, Chronic-dosing, Parallel-group, Placebo-controlled Study to Evaluate the Efficacy and Safety of Two Dose Regimens of Tozorakimab in Participants With Symptomatic Chronic Obstructive Pulmonary Disease (COPD) With a History of COPD Exacerbations (TITANIA)
Brief Summary The purpose of this Phase III study is to evaluate the efficacy and safety of tozorakimab Dose 1 and Dose 2 administered subcutaneously (SC) in adult participants with symptomatic COPD and history of ≥ 2 moderate or ≥ 1 severe exacerbation of COPD in the previous 12 months. Participants should be receiving optimised treatment with maintenance inhaled therapy (ICS/LABA/LAMA triple therapy, or dual therapy if triple is not considered appropriate) in stable doses throughout at least 3 months prior to enrolment.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Masking Description:
unblinded administrator/pharmacist
Primary Purpose: Treatment
Condition  ICMJE Chronic Obstructive Pulmonary Disease (COPD)
Intervention  ICMJE
  • Drug: Tozorakimab
    Administered subcutaneously tozorakimab Dose 1 and placebo through Week 52.
  • Drug: Tozorakimab
    Administered subcutaneously tozorakimab Dose 2 through Week 52.
  • Drug: Placebo
    Placebo administered subcutaneously, equivalent volume to tozorakimab through week 52.
Study Arms  ICMJE
  • Experimental: Tozorakimab Dose 1
    Dosing subcutaneously tozorakimab Dose 1 and placebo
    Intervention: Drug: Tozorakimab
  • Experimental: Tozorakimab Dose 2
    Dosing subcutaneously tozorakimab Dose 2
    Intervention: Drug: Tozorakimab
  • Placebo Comparator: Placebo
    Dosing subcutaneously with equivalent volume to tozorakimab
    Intervention: Drug: Placebo
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: December 2, 2021)
1272
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE August 28, 2025
Estimated Primary Completion Date June 5, 2025   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Participant must be ≥ 40 years of age and capable of giving signed informed consent.
  2. Documented diagnosis of COPD for at least one year prior to enrolment.
  3. Post BD FEV1/FVC < 0.70 and post-BD FEV1 >20% of predicted normal value.
  4. Documented history of ≥ 2 moderate or ≥ 1 severe COPD exacerbations within 12 months prior to enrolment.
  5. Documented optimized inhaled dual or triple therapy at a stable dose for at least 3 months prior to enrolment.
  6. Smoking history of ≥ 10 pack-years.
  7. CAT total score ≥10, with each of the phlegm (sputum) and cough items with a score ≥ 2

Exclusion Criteria:

  1. Clinically important pulmonary disease other than COPD.
  2. Radiological findings suggestive of a respiratory disease other than COPD that is contributing to the participant's respiratory symptoms.
  3. Current diagnosis of asthma, prior history of asthma, or asthma-COPD overlap. Childhood history of asthma is allowed and defined as asthma diagnosed and resolved before the age of 18.
  4. Any unstable disorder, including, but not limited to, cardiovascular, gastrointestinal, hepatic, renal, neurological, musculoskeletal, infectious, endocrine, metabolic, haematological, psychiatric disorder, major physical and/or cognitive impairment that could affect safety, study findings or participants ability to complete the study.
  5. COPD exacerbation, within 2 weeks prior to randomization, that was treated with systemic corticosteroids and/or antibiotics, and/or led to hospitalization.
  6. Active significant infection within the 4 weeks prior to randomization, pneumonia within 6 weeks prior to randomization, or medical condition that predisposes the participant to infection.
  7. Suspicion of, or confirmed, ongoing SARS-CoV-2 infection.
  8. Significant COVID-19 illness within the 6 months prior to enrolment.
  9. Unstable cardiovascular disorder.
  10. Diagnosis of cor pulmonale, pulmonary arterial hypertension and/or right ventricular failure.
  11. History of known immunodeficiency disorder, including a positive test for HIV-1 or HIV 2.
  12. History of positive test or treatment for hepatitis B or hepatitis C (except for cured hepatitis C).
  13. Evidence of active liver disease, including jaundice during screening.
  14. Malignancy, current or within the past 5 years, except for adequately treated non-invasive basal cell and squamous cell carcinoma of the skin and cervical carcinoma-in-situ treated with apparent success more than one year prior to enrolment. Suspected malignancy or undefined neoplasms.
  15. Participants who have evidence of active TB.
  16. Participants that have previously received tozorakimab.
  17. Any clinically significant abnormal findings in physical examination, vital signs, ECG, or laboratory testing during the screening period, which in the opinion of the investigator may put the participant at risk because of their participation in the study, or may influence the results of the study, or the participant's ability to complete the entire duration of the study.
  18. Active vaping of any products within the 6 months prior to randomization and during the study.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 40 Years to 130 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: AstraZeneca Clinical Study Information Center 1-877-240-9479 information.center@astrazeneca.com
Listed Location Countries  ICMJE Australia,   Brazil,   Chile,   China,   Colombia,   France,   Germany,   Greece,   Israel,   Italy,   Peru,   Philippines,   Poland,   Puerto Rico,   Romania,   Russian Federation,   Taiwan,   Thailand,   United Kingdom,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT05158387
Other Study ID Numbers  ICMJE D9180C00004
2021-003771-34 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Current Responsible Party AstraZeneca
Original Responsible Party Same as current
Current Study Sponsor  ICMJE AstraZeneca
Original Study Sponsor  ICMJE Same as current
Collaborators  ICMJE Not Provided
Investigators  ICMJE Not Provided
PRS Account AstraZeneca
Verification Date January 2023

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP