Asthma
Conditions
Keywords
Asthma, Uncontrolled Asthma, Severe Uncontrolled Asthma
Brief summary
Subjects who completed either D5180C00007 or D5180C00009 will be offered the opportunity to consent for the Multicentre, Double-blind, Randomized, Placebo Controlled, Parallel Group, Phase 3, Safety Extension Study to Evaluate the Safety and Tolerability of Tezepelumab in Adults and Adolescents with Severe Uncontrolled Asthma. The study consists of a treatment phase, followed by a follow-up phase where subjects will not receive IP. The length of the follow up phase is determined by which study the subject had previously completed.
Detailed description
Subjects who have not met investigational product discontinuation criteria and have attended the EOT visit in either study D5180C00007 or D5180C00009 will be offered the opportunity to consent for the Multicentre, Double-blind, Randomized, Parallel Group, Placebo Controlled, Phase 3, Safety Extension Study to Evaluate the Safety and Tolerability of Tezepelumab versus placebo in Adults and Adolescents (12 years of age and older) with a history of asthma exacerbations and inadequately controlled severe asthma receiving medium or high dose inhaled corticosteroid (ICS) plus at least one additional asthma controller medication with or without oral corticosteroids Following treatment, subjects will enter a follow-up phase, determined by the predecessor study they had previously completed. Subjects will not receive IP during the follow-up phase. For subjects who entered the study from study D5180C00007 and did not meet IP Discontinuation criteria, the follow-up phase will extend from week 104 to Week 140. Subjects who entered the study from study D5180C00009 will have their follow-up phase extend to week 116.
Interventions
BIOLOGICALTezepelumab
Tezepelumab subcutaneous injection
OTHERPlacebo
Placebo subcutaneous injection
Sponsors
Amgen
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Masking description
Double-Blind
Intervention model description
Subjects previously randomized in one of the predecessor studies to tezepelumab will be assigned and remain on tezepelumab dosing in the Destination Study. Subjects randomized to placebo arm in the predecessor studies will be re-randomized in a 1:1 ratio to either tezepelumab or placebo. Given the randomization scheme of subjects in the predecessor studies, this will give an overall subject distribution of 3:1 (tezepelumab:placebo), assuming a similar number of subjects rollover from each arm in the predecessor studies.
Eligibility
Sex/Gender
ALL
Age
13 Years to 81 Years
Healthy volunteers
No
Inclusion criteria
* Provision of signed and dated written informed consent * Negative urine test for female subjects of childbearing potential prior to administration of IP at visit 1 * Females of childbearing potential who are sexually active with a nonsterilized male partner must use a highly effective method of contraception from screening, and must agree to continue using such precautions for 16 weeks after the final dose of IP. * Female or male subjects who have not met investigational product discontinuation criteria and have attended the EOT visit in either study D5180C00007 (NAVIGATOR) or D5180C00009 (SOURCE) To enter the extended follow-up phase of the study, the following inclusion criteria also apply: * Provision of signed and dated Addendum for Extended Follow-up to informed consent, as well as assent by adolescent subjects where applicable, prior to any mandatory study specific procedures, sampling and analyses before Extended Follow Up. * Must have entered DESTINATION from D5180C00007 study and have completed IP dosing to Week 100, have not met IP Discontinuation criteria and have attended the EOT Visit.
Exclusion criteria
* Any clinically important pulmonary disease other than asthma * Any disorder, including, but not limited to cardiovascular, gastrointestinal, hepatic, renal, neurological, musculoskeletal, infectious, endocrine, metabolic, hematological, psychiatric, or major physical impairment that is not stable * History of chronic alcohol or drug abuse within 12 months prior to visit 1 * Current malignancy or malignancy that developed during a predecessor study * Major surgery or planned surgical procedures requiring general anesthesia or inpatient status for \> 1 day during the conduct of the study * Treatment with systemic immunosuppressive/immunomodulating drugs except for OCS used in the treatment of asthma/asthma exacerbations within the last 12 weeks prior to randomization * Concurrent enrolment in another clinical study involving an IP * Any clinically meaningful abnormal finding in physical examination, vital signs, ECG,haematology, clinical chemistry, or urinalysis during the predecessor study * Pregnant, breastfeeding, or lactating To enter the extended follow-up phase of the study (which extends from week 104 to week 140), the following
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Exposure Adjusted Incidence Rates of AEs/SAEs | Baseline (Week 0 in predecessor study) to Week 104. For subjects switching treatments from placebo in the predecessor to tezepelumab in DESTINATION, all data collected after first dose of tezepelumab are excluded. | Includes adverse events with an onset date between the date of first dose of IP in the predecessor and minimum (date of last dose of IP + 33 days, date of death, date of study withdrawal, day prior to start of another biologic). The analysis is based on the Safety Analysis Set. Exposure adjusted rates are defined as number of subjects with AEs divided by total time at risk across all subjects, multiplied by 100 |
| Total Time at Risk | Baseline (Week 0 in predecessor study) to Week 104. For subjects switching treatments from placebo in the predecessor to tezepelumab in DESTINATION, all data collected after first dose of tezepelumab are excluded. | Includes time between the date of first dose of IP in the predecessor and minimum (date of last dose of IP + 33 days, date of death, date of study withdrawal, day prior to start of another biologic). The analysis is based on the Safety Analysis Set. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Annualized Asthma Exacerbation Rate (AAER) | Baseline (Week 0 in predecessor study) to Week 104. For subjects switching treatments from placebo in the predecessor to tezepelumab in DESTINATION, all data collected after first dose of tezepelumab are excluded. | The annualized exacerbation rate is based on exacerbations reported by the investigator in the eCRF. The analysis is based on the primary population (Full Analysis Set) |
Countries
Argentina, Australia, Austria, Brazil, Canada, France, Germany, Israel, Poland, Russia, Saudi Arabia, South Africa, South Korea, Taiwan, Turkey (Türkiye), Ukraine, United States, Vietnam
Participant flow
Recruitment details
Participants who completed treatment and attended end of treatment visit in predecessor studies NAVIGATOR (NCT03347279) or SOURCE (NCT03406078) were eligible for this long-term extension study. In the predecessor studies, a total of 1059 and 150 subjects were randomised and dosed in NAVIGATOR and SOURCE respectively. In DESTINATION, a total of 951 subjects (827 from NAVIGATOR and 124 from SOURCE) were randomised at 182 centres in 18 countries to receive treatment with tezepelumab or placebo.
Pre-assignment details
Of the 1209 patients randomized and dosed in predecessor studies, 951 were randomised in DESTINATION and 950 received treatment. The patients receiving tezepelumab in the predecessors continued to receive tezepelumab, while patients receiving placebo in the predecessors were re-randomized 1:1 to either receive tezepelumab in DESTINATION or to continue placebo, resulting in a 3:1 randomization ratio in DESTINATION.
Participants by arm
| Arm | Count |
|---|---|
| NAVIGATOR Rand Teze All subjects randomised to tezepelumab in the NAVIGATOR predecessor and treated with at least one dose in the predecessor, regardless of whether they participated in the DESTINATION study. | 528 |
| NAVIGATOR Rand Pbo All subjects randomised to placebo in the NAVIGATOR predecessor and treated with at least one dose in the predecessor, regardless of whether they participated in the DESTINATION study and regardless of their treatment assignment in DESTINATION. | 531 |
| SOURCE Rand Teze All subjects randomised to tezepelumab in the SOURCE predecessor and treated with at least one dose in the predecessor, regardless of whether they participated in the DESTINATION study. | 74 |
| SOURCE Rand Pbo All subjects randomised to placebo in the SOURCE predecessor and treated with at least one dose in the predecessor, regardless of whether they participated in the DESTINATION study and regardless of their treatment assignment in DESTINATION. | 76 |
| Total | 1,209 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Long Term Extension (DESTINATION) | Death | 8 | 2 | 2 | 1 | 0 | 0 |
| Long Term Extension (DESTINATION) | Did not complete safety follow-up visits | 1 | 0 | 2 | 0 | 0 | 0 |
| Long Term Extension (DESTINATION) | Due to COVID-19 pandemic | 0 | 0 | 0 | 0 | 0 | 1 |
| Long Term Extension (DESTINATION) | Lost to Follow-up | 2 | 1 | 1 | 0 | 1 | 0 |
| Long Term Extension (DESTINATION) | Pregnancy | 1 | 0 | 0 | 0 | 0 | 0 |
| Long Term Extension (DESTINATION) | Withdrawal by Subject | 3 | 3 | 3 | 1 | 3 | 0 |
| Predecessor Study | Death | 0 | 2 | 0 | 1 | 0 | 0 |
| Predecessor Study | Did not receive treatment / Non-compliance with protocol / did not complete safety follow-up visits | 3 | 4 | 0 | 0 | 0 | 0 |
| Predecessor Study | Lost to Follow-up | 5 | 2 | 0 | 0 | 1 | 0 |
| Predecessor Study | Withdrawal by Subject | 8 | 15 | 0 | 5 | 2 | 0 |
Baseline characteristics
| Characteristic | NAVIGATOR Rand Teze | Total | SOURCE Rand Pbo | SOURCE Rand Teze | NAVIGATOR Rand Pbo |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 41 Participants | 82 Participants | 0 Participants | 0 Participants | 41 Participants |
| Age, Categorical >=65 years | 96 Participants | 200 Participants | 14 Participants | 16 Participants | 74 Participants |
| Age, Categorical Between 18 and 65 years | 391 Participants | 927 Participants | 62 Participants | 58 Participants | 416 Participants |
| Age, Continuous | 49.9 Years STANDARD_DEVIATION 16.3 | 49.9 Years STANDARD_DEVIATION 15.7 | 53.4 Years STANDARD_DEVIATION 11.9 | 53.5 Years STANDARD_DEVIATION 12.1 | 49.0 Years STANDARD_DEVIATION 15.9 |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Asian | 146 Participants | 317 Participants | 11 Participants | 11 Participants | 149 Participants |
| Race/Ethnicity, Customized Black of African American | 30 Participants | 62 Participants | 0 Participants | 1 Participants | 31 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 83 Participants | 188 Participants | 14 Participants | 10 Participants | 81 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 445 Participants | 1021 Participants | 62 Participants | 64 Participants | 450 Participants |
| Race/Ethnicity, Customized Other | 19 Participants | 43 Participants | 1 Participants | 0 Participants | 23 Participants |
| Race/Ethnicity, Customized White | 332 Participants | 785 Participants | 64 Participants | 62 Participants | 327 Participants |
| Sex: Female, Male Female | 335 Participants | 766 Participants | 45 Participants | 49 Participants | 337 Participants |
| Sex: Female, Male Male | 193 Participants | 443 Participants | 31 Participants | 25 Participants | 194 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 8 / 528 | 5 / 531 | 1 / 206 | 2 / 74 | 0 / 76 | 0 / 32 |
| other Total, other adverse events | 390 / 528 | 384 / 531 | 98 / 206 | 53 / 74 | 58 / 76 | 23 / 32 |
| serious Total, serious adverse events | 82 / 528 | 94 / 531 | 17 / 206 | 18 / 74 | 19 / 76 | 4 / 32 |
Outcome results
Primary
Exposure Adjusted Incidence Rates of AEs/SAEs
Includes adverse events with an onset date between the date of first dose of IP in the predecessor and minimum (date of last dose of IP + 33 days, date of death, date of study withdrawal, day prior to start of another biologic). The analysis is based on the Safety Analysis Set. Exposure adjusted rates are defined as number of subjects with AEs divided by total time at risk across all subjects, multiplied by 100
Time frame: Baseline (Week 0 in predecessor study) to Week 104. For subjects switching treatments from placebo in the predecessor to tezepelumab in DESTINATION, all data collected after first dose of tezepelumab are excluded.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| NAVIGATOR Rand Teze | Exposure Adjusted Incidence Rates of AEs/SAEs | Any AE with outcome=death incidence rate | 0.76 Patients with AEs per 100 person-years |
| NAVIGATOR Rand Teze | Exposure Adjusted Incidence Rates of AEs/SAEs | Any AE leading to discontinuation of IP incidence rate | 1.64 Patients with AEs per 100 person-years |
| NAVIGATOR Rand Teze | Exposure Adjusted Incidence Rates of AEs/SAEs | Any SAE incidence rate | 7.85 Patients with AEs per 100 person-years |
| NAVIGATOR Rand Teze | Exposure Adjusted Incidence Rates of AEs/SAEs | Any AE incidence rate | 49.62 Patients with AEs per 100 person-years |
| NAVIGATOR Rand Pbo | Exposure Adjusted Incidence Rates of AEs/SAEs | Any SAE incidence rate | 12.45 Patients with AEs per 100 person-years |
| NAVIGATOR Rand Pbo | Exposure Adjusted Incidence Rates of AEs/SAEs | Any AE with outcome=death incidence rate | 0.14 Patients with AEs per 100 person-years |
| NAVIGATOR Rand Pbo | Exposure Adjusted Incidence Rates of AEs/SAEs | Any AE incidence rate | 62.66 Patients with AEs per 100 person-years |
| NAVIGATOR Rand Pbo | Exposure Adjusted Incidence Rates of AEs/SAEs | Any AE leading to discontinuation of IP incidence rate | 3.00 Patients with AEs per 100 person-years |
| SOURCE Rand Teze | Exposure Adjusted Incidence Rates of AEs/SAEs | Any SAE incidence rate | 13.14 Patients with AEs per 100 person-years |
| SOURCE Rand Teze | Exposure Adjusted Incidence Rates of AEs/SAEs | Any AE with outcome=death incidence rate | 1.55 Patients with AEs per 100 person-years |
| SOURCE Rand Teze | Exposure Adjusted Incidence Rates of AEs/SAEs | Any AE leading to discontinuation of IP incidence rate | 1.55 Patients with AEs per 100 person-years |
| SOURCE Rand Teze | Exposure Adjusted Incidence Rates of AEs/SAEs | Any AE incidence rate | 47.15 Patients with AEs per 100 person-years |
| SOURCE Rand Pbo | Exposure Adjusted Incidence Rates of AEs/SAEs | Any AE incidence rate | 69.97 Patients with AEs per 100 person-years |
| SOURCE Rand Pbo | Exposure Adjusted Incidence Rates of AEs/SAEs | Any AE leading to discontinuation of IP incidence rate | 2.00 Patients with AEs per 100 person-years |
| SOURCE Rand Pbo | Exposure Adjusted Incidence Rates of AEs/SAEs | Any SAE incidence rate | 17.99 Patients with AEs per 100 person-years |
| SOURCE Rand Pbo | Exposure Adjusted Incidence Rates of AEs/SAEs | Any AE with outcome=death incidence rate | 0.00 Patients with AEs per 100 person-years |
Primary
Total Time at Risk
Includes time between the date of first dose of IP in the predecessor and minimum (date of last dose of IP + 33 days, date of death, date of study withdrawal, day prior to start of another biologic). The analysis is based on the Safety Analysis Set.
Time frame: Baseline (Week 0 in predecessor study) to Week 104. For subjects switching treatments from placebo in the predecessor to tezepelumab in DESTINATION, all data collected after first dose of tezepelumab are excluded.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| NAVIGATOR Rand Teze | Total Time at Risk | 917.0 Year |
| NAVIGATOR Rand Pbo | Total Time at Risk | 699.0 Year |
| SOURCE Rand Teze | Total Time at Risk | 129.4 Year |
| SOURCE Rand Pbo | Total Time at Risk | 100.0 Year |
Secondary
Annualized Asthma Exacerbation Rate (AAER)
The annualized exacerbation rate is based on exacerbations reported by the investigator in the eCRF. The analysis is based on the primary population (Full Analysis Set)
Time frame: Baseline (Week 0 in predecessor study) to Week 104. For subjects switching treatments from placebo in the predecessor to tezepelumab in DESTINATION, all data collected after first dose of tezepelumab are excluded.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| NAVIGATOR Rand Teze | Annualized Asthma Exacerbation Rate (AAER) | 0.82 events per year |
| NAVIGATOR Rand Pbo | Annualized Asthma Exacerbation Rate (AAER) | 1.93 events per year |
| SOURCE Rand Teze | Annualized Asthma Exacerbation Rate (AAER) | 1.07 events per year |
| SOURCE Rand Pbo | Annualized Asthma Exacerbation Rate (AAER) | 1.76 events per year |
95% CI: [0.35, 0.51]
95% CI: [0.38, 0.96]