This study has been transitioned to CTIS with ID 2023-503571-19-00 check the CTIS register for the current data. The objective of this phase III study is to evaluate the efficacy and safety of Tozorakimab according to 300 mg every 8 weeks (Q8W) and…
ID
Source
Brief title
Condition
- Lower respiratory tract disorders (excl obstruction and infection)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
To evaluate the effect of 2 dose regimens of Tozorakimab as add on to SoC
compared with SoC plus placebo on the rate of moderate to severe COPD
exacerbations in former smokers.
Secondary outcome
Key Secondary Endpoints:
- To evaluate the effect of 2 dose regimens of Tozorakimab as add on to SoC
compared with SoC plus placebo on the rate of moderate to severe COPD
exacerbation in former and current smokers.
- To evaluate the effect of 2 dose regimens of Tozorakimab as add on to SoC
compared with SoC plus placebo on change in pre-BrochoDilator lung function.
- To evaluate the effect of 2 dose regimens of Tozorakimab as add on to SoC
compared with SoC plus placebo on respiratory symptoms.
- To evaluate the effect of 2 dose regimens of Tozorakimab as add on to SoC
compared with SoC plus placebo on respiratory health status/health-related
quality of life.
Background summary
Chronic obstructive pulmonary disease (COPD) is the fourth leading cause of
death in the world. The disease is characterized by
persistent respiratory symptoms and respiratory limitation due to airway and/or
alveolar abnormalities.
COPD is only partially reversible, usually progressive and associated with an
enhanced chronic inflammatory response in the lungs. The expression of
interleukin-33 (IL-33) is increased in the lungs of COPD patients, inversely
related to lung function and plays a role in inflammatory and epithelial
processes within COPD.
Tozorakimab is a monoclonal antibody that binds to IL-33 and thereby robustly
and specifically blocks IL-33 and the associated signal cascades. The mechanism
of action of Tozorakimab is hypothesized to have a positive impact on airway
inflammation, phlegm and cough symptoms and lung function during disease
progression in COPD and that it affects the frequency and severity reduce
exacerbations.
Study objective
This study has been transitioned to CTIS with ID 2023-503571-19-00 check the CTIS register for the current data.
The objective of this phase III study is to evaluate the efficacy and safety of
Tozorakimab according to 300 mg every 8 weeks (Q8W) and 300 mg every 4 weeks
(Q4W) dosing regimens administered in adult participants with symptomatic COPD
and a history of >= 2 moderate or >= 1 severe exacerbation of COPD in the past 12
months.
The rationale for this change follows recent data from Phase II studies in
moderate to severe atopic dermatitis and asthma, in which lower trough PK
concentrations (30%-35%) were observed compared with the Phase I healthy
volunteer study. With this updated exposure data,
predicted IL-33 lung inhibition reduces from 94% to 92%, but remains above 90%
for the 300 mg Q4W regimen; the 2% drop suggests this dose is on the flat
portion of the dose response curve. However, the predicted IL-33 inhibition for
the 300 mg Q8W regimen reduces
by approximately 5% to below 80%.
On this basis, together with the acceptable safety profile of tozorakimab
across all dosing regimens, randomisation to the 300 mg Q8W arms will be
stopped after approval of this amendment.
There will be no impact on participants already randomised to the 300 mg Q8W
arm, who will continue to complete the study. Data collected from this arm will
only be used for characterisation of the dose-response curve, and not for
confirmatory hypothesis testing. The overall sample size and multiple testing
procedures are amended accordingly.
Study design
This is a Phase III, multicenter, randomized, double-blind, chronic dose,
parallel group, placebo-controlled study to evaluate the efficacy and safety of
Tozorakimab 300 mg Q4W administered subcutaneously, in adult participants with
symptomatic COPD and history of COPD exacerbations.
The randomization will be stratified by region, maintenance inhalation therapy
(dual vs triple), and smoking status (current vs former). The study includes:
former and current smokers, but randomization to the cohort of current smokers
will be maximized to ensure that at least 75% of participants are former
smokers. Approximately 80% of the participants in the study will be on triple
(ICS/LABA/LAMA) therapy.
Intervention
Subjects are randomized in a 1:1 ratio to the 300 mg Q4W Tozorakimab group or
to a matched placebo recipient group. Subjects get administered s.c. every 4
weeks during the treatment period at a total of 13 administrations between Day
0 and Week 52.
Study burden and risks
The subject is asked to visit the site at least 15 times. During the
intervention period, the subject receives 13 administrations of the study
intervention. The test subject will undergo a physical examination during
hospital visit. The subject will undergo a spirometry test at least 11 times
during the study. The subject will undergo twice a CT scan during the study.
The subject must complete assignments in an eDiary every day during the
intervention and follow-up periods. Women of childbearing potential should
provide a urine sample for pregnancy testing during screening, follow-up, and
each pre-study drug visit. The study drug may cause gastrointestinal side
effects and severe hypersensitivity. The study physician will supervise the
administration of the study medication and observe the subject for a minimum of
1 to 2 hours.
Prinses Beatrixlaan 582
Den Haag 2595BM
NL
Prinses Beatrixlaan 582
Den Haag 2595BM
NL
Listed location countries
Age
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 dual or triple treatment with COPD and 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 >= 2.
Exclusion criteria
1. Clinically important pulmonary disease other than COPD.
2. Radiological findings suggestive of a respiratory disease other than COPD
that is significantly 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. Medical history 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 or using smoked marijuana within the 6 months
prior to randomization and during the study.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EU-CTR | CTIS2023-503571-19-00 |
| EudraCT | EUCTR2021-003797-30-NL |
| CCMO | NL79306.100.22 |