MIRANDA: Efficacy and Safety of Tozorakimab in Symptomatic Chronic Obstructive Pulmonary Disease With a History of Exacerbations

Sponsor

AstraZeneca (Industry)

Overall Status

Not yet recruiting

CT.gov ID

NCT06040086

Collaborator

(none)

1,240

Enrollment

Locations

Arms

38.5

Anticipated Duration (Months)

38.8

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose of this Phase III study is to evaluate the efficacy and safety of tozorakimab administered subcutaneously (SC) in adult participants with symptomatic COPD with a history of ≥ 2 moderate or ≥ 1 severe exacerbations of COPD in the 12 months prior to enrolment. Participants should be receiving optimised treatment with inhaled maintenance therapy (ICS/LABA/LAMA triple therapy, or dual therapy if triple is not considered appropriate) throughout at least the last 3 months prior to enrolment.

Condition or Disease	Intervention/Treatment	Phase
Chronic Obstructive Pulmonary Disease (COPD)	Drug: Placebo Drug: Tozorakimab	Phase 3

Study Design

Study Type:

Interventional

Anticipated Enrollment :

1240 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose:

Treatment

Official Title:

A Phase III, Multicentre, Randomised, Double-blind, Chronic-dosing, Parallel-group, Placebo-controlled Study to Evaluate the Efficacy and Safety of Tozorakimab in Participants With Symptomatic Chronic Obstructive Pulmonary Disease (COPD) With a History of COPD Exacerbations (MIRANDA)

Anticipated Study Start Date :

Sep 22, 2023

Anticipated Primary Completion Date :

Sep 10, 2026

Anticipated Study Completion Date :

Dec 7, 2026

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Tozorakimab Dosing subcutaneously tozorakimab	Drug: Tozorakimab Administered subcutaneously tozorakimab and placebo throughout the study.
Placebo Comparator: Placebo Dosing subcutaneously with equivalent volume to tozorakimab	Drug: Placebo Placebo administered subcutaneously, equivalent volume to tozorakimab throughout the study.

Arm

Intervention/Treatment

Experimental: Tozorakimab

Dosing subcutaneously tozorakimab

Drug: Tozorakimab

Administered subcutaneously tozorakimab and placebo throughout the study.

Placebo Comparator: Placebo

Dosing subcutaneously with equivalent volume to tozorakimab

Drug: Placebo

Placebo administered subcutaneously, equivalent volume to tozorakimab throughout the study.

Outcome Measures

Primary Outcome Measures

Annualized rate of moderate to severe COPD exacerbations in participants who are former smokers. [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]).

Secondary Outcome Measures

Annualized rate of moderate to severe COPD exacerbations in former or current smokers. [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.
Change from baseline in SGRQ total score from in former smokers [Over 52 weeks]
Difference in mean change from baseline in SGRQ total score in former smokers.
Change from baseline in SGRQ total score from in the overall population of current and former smokers. [Over 52 weeks]
Difference in mean change from baseline in SGRQ total score in the overall population of current and former smokers.
Annualized rate of severe COPD exacerbations in former smokers [Variable duration period up to study completion, maximum of approximately 3 years]
The rate ratio of severe COPD exacerbations will be assessed in former smokers.
Annualized rate of severe COPD exacerbations in former or current smokers [Variable duration period up to study completion, maximum of approximately 3 years]
The rate ratio of severe COPD exacerbations will be assessed in the overall population of current and former smokers.
Change from baseline in E-RS:COPD total score in former smokers [Over 52 weeks]
Difference in mean change in E-RS:COPD total score from baseline in former smokers.
Change from baseline in E-RS:COPD total score in former or current smokers [Over 52 weeks]
Difference in mean change in E-RS:COPD total score from baseline in the overall population of current and former smokers.
Change from baseline in pre-bronchodilator, pre dose trough FEV1 (mL) in former smokers [Week 52, over 52 weeks]
Change from baseline in pre-bronchodilator, pre dose trough FEV1 (mL) in former smokers.
Change from baseline in pre-bronchodilator, pre dose trough FEV1 (mL) in former or current smokers [Week 52, over 52 weeks]
Change from baseline in pre-bronchodilator, pre dose trough FEV1 (mL) in the overall population of current and former smokers.
Time to first moderate to severe COPD exacerbation [Over 52 weeks]
Time to first moderate to severe COPD exacerbation compared with placebo.
Time to first severe COPD exacerbation [Variable duration period up to study completion, maximum of approximately 3 years]
Time to first severe COPD exacerbation compared with placebo.
Change from baseline in CAT total score [Week 52]
Change from baseline in CAT total score compared with placebo.
Proportion of participants achieving MCID in CAT score [Week 52]
Proportion of participants achieving MCID in CAT score (percentage of participants with a decrease in CAT total score of ≥ 2 points from baseline).
Proportion of participants achieving MCID in SGRQ total score [Week 52]
Proportion of participants achieving MCID in SGRQ score (percentage of participants with a decrease in SGRQ total score of ≥ 4 points from baseline).
Proportion of participants achieving MCID in E-RS:COPD total score [Week 52]
Proportion of participants achieving MCID in E-RS:COPD total score (percentage of participants with a decrease in E-RS:COPD total score of ≥ 2 points from baseline).
Annualized rate of healthcare resource utilization [Variable duration period up to study completion, maximum of approximately 3 years]
Annualized rate of healthcare resource utilization.
Change from baseline in rescue medication [Over 52 weeks]
Change from baseline (difference in mean number of puffs/day) in rescue medication use.
Trough serum concentrations of tozorakimab [Over 52 weeks]
Pharmacokinetics: concentrations of tozorakimab in trough serum.
Presence of anti-drug antibodies [Over 52 weeks]
Immunogenicity: presence of tozorakimab anti-drug antibodies in blood serum.
Time to death [Variable duration period up to study completion, maximum of approximately 3 years]
Time to death (all-cause mortality)

Eligibility Criteria

Criteria

Ages Eligible for Study:

40 Years to 130 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

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

Exclusion Criteria:

Clinically important pulmonary disease other than COPD.
Radiological findings suggestive of a respiratory disease other than COPD that is significantly contributing to the participant's respiratory symptoms. Radiological findings of pulmonary nodules suspicious for lung cancer, as per applicable guidances, without appropriate follow up prior to randomisation. Radiological findings suggestive of acute infection.
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
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.
COPD exacerbation, within 2 weeks prior to randomization, that was treated with systemic corticosteroids and/or antibiotics, and/or led to hospitalization.
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.
Suspicion of, or confirmed, ongoing SARS-CoV-2 infection.
Significant COVID-19 illness within the 6 months prior to enrolment.
Unstable cardiovascular disorder.
Diagnosis of cor pulmonale, pulmonary arterial hypertension and/or right ventricular failure.
History of active severe inflammatory bowel disease or colitis within one year prior to enrolment, or unexplained diarrhoea within the 4 weeks prior to randomisation.
History of known immunodeficiency disorder, including a positive test for HIV-1 or HIV
History of positive test or treatment for hepatitis B or hepatitis C (except for cured hepatitis C)
Evidence of active liver disease, including jaundice during screening.
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.
Participants who have evidence of active TB.
History of partial or total lung resection.
Scheduled major surgical procedure during the course of the study.
Participants that have previously received tozorakimab.
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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Research Site	Sheffield	Alabama	United States	35660
2	Research Site	Newport Beach	California	United States	92663
3	Research Site	Boynton Beach	Florida	United States	33435
4	Research Site	Ormond Beach	Florida	United States	32174
5	Research Site	Bowling Green	Kentucky	United States	42101
6	Research Site	McKinney	Texas	United States	75069
7	Research Site	Brussels		Belgium	1070
8	Research Site	Edegem		Belgium	2650
9	Research Site	Mechelen		Belgium	2800
10	Research Site	Roeselare		Belgium	8800
11	Research Site	Sao Bernardo do Campo		Brazil	09715090
12	Research Site	Burlington	Ontario	Canada	L7N 3V2
13	Research Site	Marburg		Germany	35037
14	Research Site	Athens		Greece	11521
15	Research Site	Exohi Thessaloniki		Greece	57010
16	Research Site	Heraklion		Greece	71409
17	Research Site	Ioannina		Greece	45500
18	Research Site	Thessaloniki		Greece	57010
19	Research Site	Cork		Ireland	T12 DV56
20	Research Site	Dublin		Ireland	D09 V2N0
21	Research Site	Dublin		Ireland	D24 NR0A
22	Research Site	Galway		Ireland	H91 YR71
23	Research Site	Arnhem		Netherlands	6815 AD
24	Research Site	Breda		Netherlands	4818 CK
25	Research Site	Den Bosch		Netherlands	5223 GZ
26	Research Site	Groningen		Netherlands	9728 NT
27	Research Site	Harderwijk		Netherlands	3844 DG
28	Research Site	Heerlen		Netherlands	6419 PC
29	Research Site	Roermond		Netherlands	6043 CV
30	Research Site	Rotterdam		Netherlands	3045 PM
31	Research Site	Rotterdam		Netherlands	3083 AN
32	Research Site	Zutphen		Netherlands	7207 AE