RSV Infection
Conditions
Keywords
LRTI by RSV infection
Brief summary
Study D5290C00008 is a Phase 2, open-label, uncontrolled, single-dose study to evaluate the safety and tolerability, pharmacokinetic(s) (PK), occurrence of antidrug antibody (ADA), and efficacy of nirsevimab in immunocompromised children who are ≤ 24 months of age at the time of dose administration. Approximately 100 subjects will be enrolled. Subjects will be followed for approximately 1 year after dose administration.
Detailed description
Respiratory syncytial virus (RSV) is the most common cause of lower respiratory tract infection (LRTI) among infants and young children, resulting in annual epidemics in Japan. Children with congenital or acquired immunodeficiencies, transplant recipients, and those receiving immunosuppressive therapy are at increased risk for severe RSV-associated LRTI with prolonged viral shedding and higher viral loads, resulting in prolonged hospitalizations, admissions to the intensive care unit (ICU), and the need for mechanical ventilation. Palivizumab (Synagis®) is the only approved agent for RSV prophylaxis, and its half-life (t1/2) is approximately 1 month, infants and young children need to receive monthly intramuscular doses of palivizumab throughout the RSV season to maintain protection. This constitutes a significant burden on healthcare providers as well as the infants/children and their families. Nirsevimab may provide a cost-effective opportunity to protect all infants from RSV disease based on an improvement in potency and the extended t1/2 that is expected to support once-per-RSV-season dosing.
Interventions
DRUGNirsevimab
Single fixed IM dose of nirsevimab 50 mg if body weight \< 5 kg or 100 mg if body weight ≥ 5 kg, and subjects entering their second RSV season will receive a single fixed IM dose of nirsevimab 200 mg
Sponsors
Iqvia Pty Ltd
AstraZeneca
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
PREVENTION
Masking
NONE
Masking description
Open: no masking is used. All involved know the identity of the intervention assignment.
Eligibility
Sex/Gender
ALL
Age
0 Years to 2 Years
Healthy volunteers
No
Inclusion criteria
* Neonate, infant, or young child ≤ 24 months of age at the time of dose administration who, per investigator judgement, are: 1. In their first year of life AND entering their first RSV season at the time of dose administration OR 2. In their second year of life AND entering their second RSV season at the time of dose administration * The subject must meet at least 1 of the following conditions at the time of informed consent. 1. Diagnosed with combined immunodeficiency (severe combined immunodeficiency, X-linked hyper-immunoglobulin M \[IgM\] syndrome, etc); antibody deficiency (X linked agammaglobulinemia, common variable immunodeficiency, non-X-linked hyper-IgM syndromes, etc); or other immunodeficiency (Wiskott-Aldrich syndrome, DiGeorge syndrome, etc), or 2. Diagnosed with human immunodeficiency virus infection, or 3. History of organ or bone marrow transplantation, or 4. Subject is receiving immunosuppressive chemotherapy, or 5. Subject is receiving systemic high-dose corticosteroid therapy (prednisone equivalents ≥ 0.5 mg/kg every other day, other than inhaler or topical use), or 6. Subject is receiving other immunosuppressive therapy (eg, azathioprine, methotrexate, mizoribine, mycophenolate mofetil, cyclophosphamide, cyclosporine, tacrolimus, cytokine inhibitors, etc) * Written informed consent and any locally required authorization obtained from the subject's parent(s)/legal representative(s) prior to performing any protocol-related procedures, including screening evaluations. * Subject's parent(s)/legal representative(s) able to understand and comply with the requirements of the protocol including follow-up visits as judged by the investigator. * Subject is available to complete the follow-up period, which will be approximately 1 year after receipt of nirsevimab
Exclusion criteria
* Subject who meets any of the palivizumab indications approved in Japan other than immunocompromised condition. 1. Subject born at ≤ 28 weeks gestation and is ≤ 12 months of age 2. Subject born at 29 to 35 weeks gestation and is ≤ 6 months of age 3. Age ≤ 24 months with a history of bronchopulmonary dysplasia requiring medical management within the past 6 months 4. Age ≤ 24 months with current hemodynamically significant congenital heart disease (CHD) 5. Age ≤ 24 months with Down syndrome * Requirement for oxygen supplementation, mechanical ventilation, extracorporeal membrane oxygenation, continuous positive airway pressure, or other mechanical respiratory or cardiac support at screening * A current, active infection, including RSV infection, at the time of screening or at the time of investigational product administration. * Any fever (≥ 100.4°F \[≥ 38.0°C\], regardless of route) or acute illness within 7 days prior to investigational product administration. * Any serious concurrent medical condition (renal failure, hepatic dysfunction, suspected active or chronic hepatitis infection, seizure disorder, unstable neurologic disorder, etc), except those resulting in an immune deficiency condition. * Clinically significant congenital anomaly of the respiratory tract. * Receipt of palivizumab. * Any known allergy or history of allergic reaction to any component of nirsevimab. * Any known allergy or history of allergic reaction to immunoglobulin products, blood products, or other foreign proteins. * Concurrent enrollment in another interventional study, or prior receipt of any investigational agent. * Anticipated survival of less than 1 year at the time of informed consent. * Any condition that, in the opinion of the investigator, would interfere with evaluation of the investigational product or interpretation of study results. * Children of employees of the sponsor, clinical study site, or any other individuals involved with the conduct of the study, or immediate family members of such individuals.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Treatment-Emergent Serious AEs (TESAEs), AEs of Special Interest (AESIs), and New Onset Chronic Disease (NOCDs) | TEAEs were collected from the first dose administration (Day 1) up to 360 days post dose | An AE was any untoward medical occurrence in a clinical study participant, temporally associated with the use of study treatment, whether or not considered related to the treatment. TEAEs were AEs whose onset occurred after receiving nirsevimab and within 360 days post dose. A TESAE was any AE that resulted in death, was life-threatening, required inpatient hospitalization, resulted in persistent or significant disability/incapacity, was a congenital abnormality, or was medically significant. AESIs were defined as AEs of immediate (type I) hypersensitivity (including anaphylaxis), thrombocytopenia, and immune complex disease following the administration of nirsevimab based on investigator assessment and Medical Dictionary for Regulatory Activities (MedDRA) preferred term (PT) codes. An NOCD was a newly diagnosed medical condition of a chronic, ongoing nature post administration of treatment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Serum Concentrations of Nirsevimab | Baseline (Day 1) and on Days 8 (for Japanese participants), 31, 151 and 361 | Serum concentrations of nirsevimab at selected time points were evaluated to confirm that adequate exposures for protection from respiratory syncytial virus (RSV) lower respiratory tract infection (LRTI) are maintained for at least 5 months after dosing. |
| Number of Participants With Anti-Drug Antibody (ADA) Response to Nirsevimab | Baseline (Day 1) and on Days 31, 151 and 361 | Blood samples were analyzed for the presence of ADAs for nirsevimab using validated assays. |
| Number of Participants With Medically Attended (MA) RSV LRTI (Inpatient and Outpatient) and Hospitalizations | Through 150 days post dose | Number of participants with LRTI and hospitalizations due to reverse transcriptase-polymerase chain reaction (RT-PCR)-confirmed RSV was assessed. MA RSV LRTI consisted of participants with protocol-defined LRTI, positive central RT-PCR RSV test result, Investigator assessed LRTI at an inpatient or outpatient setting. MA RSV LRTI with hospitalization consisted of participants with protocol-defined LRTI, positive central RT-PCR RSV test result, Investigator assessed LRTI at an inpatient setting. |
Countries
Belgium, Japan, Poland, South Africa, Spain, Ukraine, United Kingdom, United States
Participant flow
Recruitment details
This Phase 2, open-label, uncontrolled, single-dose study was conducted at 28 investigational sites in 8 countries (Belgium, Japan, Poland, South Africa, Spain, Ukraine, United Kingdom and United States) in immunocompromised children who were \<=24 months of age at the time of enrollment between 19 Aug 2020 and 17 Feb 2023.
Pre-assignment details
This study consisted of a screening period (Visit 1, Day -30 to Day -1); a dosing visit (Visit 2, Day 1) where participants received treatment with nirsevimab and a follow-up period up to Day 361 (Visit 3 to 7). A total of 100 children were enrolled in this study.
Participants by arm
| Arm | Count |
|---|---|
| Nirsevimab 50 mg/100 mg Participants in their first year of life with a body weight \<5 kg received a single fixed IM dose of 50 mg nirsevimab and those with body weight \>=5 kg received a single fixed IM dose of 100 mg nirsevimab. | 48 |
| Nirsevimab 200 mg Participants in their second year of life received a single fixed IM dose of 200 mg (2 × 100 mg) of nirsevimab. | 52 |
| Total | 100 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 2 | 1 |
| Overall Study | Lost to Follow-up | 1 | 0 |
| Overall Study | Other | 0 | 1 |
| Overall Study | Withdrawal by parent/guardian | 0 | 1 |
Baseline characteristics
| Characteristic | Total | Nirsevimab 200 mg | Nirsevimab 50 mg/100 mg |
|---|---|---|---|
| Age, Continuous | 12.97 months STANDARD_DEVIATION 6.232 | 17.90 months STANDARD_DEVIATION 3.748 | 7.64 months STANDARD_DEVIATION 3.27 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 7 Participants | 3 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 93 Participants | 49 Participants | 44 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized American Indian or Alaskan Native | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Asian | 28 Participants | 12 Participants | 16 Participants |
| Race/Ethnicity, Customized Black or African American | 20 Participants | 11 Participants | 9 Participants |
| Race/Ethnicity, Customized Multiple categories checked | 2 Participants | 2 Participants | 0 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Other | 4 Participants | 2 Participants | 2 Participants |
| Race/Ethnicity, Customized White | 45 Participants | 25 Participants | 20 Participants |
| Sex: Female, Male Female | 35 Participants | 17 Participants | 18 Participants |
| Sex: Female, Male Male | 65 Participants | 35 Participants | 30 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 2 / 48 | 1 / 52 |
| other Total, other adverse events | 35 / 48 | 41 / 52 |
| serious Total, serious adverse events | 12 / 48 | 20 / 52 |
Outcome results
Primary
Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Treatment-Emergent Serious AEs (TESAEs), AEs of Special Interest (AESIs), and New Onset Chronic Disease (NOCDs)
An AE was any untoward medical occurrence in a clinical study participant, temporally associated with the use of study treatment, whether or not considered related to the treatment. TEAEs were AEs whose onset occurred after receiving nirsevimab and within 360 days post dose. A TESAE was any AE that resulted in death, was life-threatening, required inpatient hospitalization, resulted in persistent or significant disability/incapacity, was a congenital abnormality, or was medically significant. AESIs were defined as AEs of immediate (type I) hypersensitivity (including anaphylaxis), thrombocytopenia, and immune complex disease following the administration of nirsevimab based on investigator assessment and Medical Dictionary for Regulatory Activities (MedDRA) preferred term (PT) codes. An NOCD was a newly diagnosed medical condition of a chronic, ongoing nature post administration of treatment.
Time frame: TEAEs were collected from the first dose administration (Day 1) up to 360 days post dose
Population: The As-treated population consisted of all participants who were enrolled and received any dose of nirsevimab.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Nirsevimab 50 mg/100 mg | Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Treatment-Emergent Serious AEs (TESAEs), AEs of Special Interest (AESIs), and New Onset Chronic Disease (NOCDs) | TESAE | 12 Participants |
| Nirsevimab 50 mg/100 mg | Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Treatment-Emergent Serious AEs (TESAEs), AEs of Special Interest (AESIs), and New Onset Chronic Disease (NOCDs) | AESI based on selected MedDRA PT codes | 16 Participants |
| Nirsevimab 50 mg/100 mg | Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Treatment-Emergent Serious AEs (TESAEs), AEs of Special Interest (AESIs), and New Onset Chronic Disease (NOCDs) | AESI based on investigator assessment | 3 Participants |
| Nirsevimab 50 mg/100 mg | Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Treatment-Emergent Serious AEs (TESAEs), AEs of Special Interest (AESIs), and New Onset Chronic Disease (NOCDs) | NOCD | 0 Participants |
| Nirsevimab 50 mg/100 mg | Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Treatment-Emergent Serious AEs (TESAEs), AEs of Special Interest (AESIs), and New Onset Chronic Disease (NOCDs) | Any TEAE | 36 Participants |
| Nirsevimab 200 mg | Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Treatment-Emergent Serious AEs (TESAEs), AEs of Special Interest (AESIs), and New Onset Chronic Disease (NOCDs) | NOCD | 0 Participants |
| Nirsevimab 200 mg | Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Treatment-Emergent Serious AEs (TESAEs), AEs of Special Interest (AESIs), and New Onset Chronic Disease (NOCDs) | Any TEAE | 45 Participants |
| Nirsevimab 200 mg | Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Treatment-Emergent Serious AEs (TESAEs), AEs of Special Interest (AESIs), and New Onset Chronic Disease (NOCDs) | TESAE | 20 Participants |
| Nirsevimab 200 mg | Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Treatment-Emergent Serious AEs (TESAEs), AEs of Special Interest (AESIs), and New Onset Chronic Disease (NOCDs) | AESI based on investigator assessment | 2 Participants |
| Nirsevimab 200 mg | Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Treatment-Emergent Serious AEs (TESAEs), AEs of Special Interest (AESIs), and New Onset Chronic Disease (NOCDs) | AESI based on selected MedDRA PT codes | 13 Participants |
Secondary
Number of Participants With Anti-Drug Antibody (ADA) Response to Nirsevimab
Blood samples were analyzed for the presence of ADAs for nirsevimab using validated assays.
Time frame: Baseline (Day 1) and on Days 31, 151 and 361
Population: The As-treated population consisted of all participants who were enrolled and received any dose of nirsevimab. Only those participants with data available were analyzed.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Nirsevimab 50 mg/100 mg | Number of Participants With Anti-Drug Antibody (ADA) Response to Nirsevimab | Day 1 | 0 Participants |
| Nirsevimab 50 mg/100 mg | Number of Participants With Anti-Drug Antibody (ADA) Response to Nirsevimab | Day 31 | 0 Participants |
| Nirsevimab 50 mg/100 mg | Number of Participants With Anti-Drug Antibody (ADA) Response to Nirsevimab | Day 151 | 1 Participants |
| Nirsevimab 50 mg/100 mg | Number of Participants With Anti-Drug Antibody (ADA) Response to Nirsevimab | Day 361 | 2 Participants |
| Nirsevimab 200 mg | Number of Participants With Anti-Drug Antibody (ADA) Response to Nirsevimab | Day 361 | 7 Participants |
| Nirsevimab 200 mg | Number of Participants With Anti-Drug Antibody (ADA) Response to Nirsevimab | Day 1 | 0 Participants |
| Nirsevimab 200 mg | Number of Participants With Anti-Drug Antibody (ADA) Response to Nirsevimab | Day 151 | 0 Participants |
| Nirsevimab 200 mg | Number of Participants With Anti-Drug Antibody (ADA) Response to Nirsevimab | Day 31 | 1 Participants |
Secondary
Number of Participants With Medically Attended (MA) RSV LRTI (Inpatient and Outpatient) and Hospitalizations
Number of participants with LRTI and hospitalizations due to reverse transcriptase-polymerase chain reaction (RT-PCR)-confirmed RSV was assessed. MA RSV LRTI consisted of participants with protocol-defined LRTI, positive central RT-PCR RSV test result, Investigator assessed LRTI at an inpatient or outpatient setting. MA RSV LRTI with hospitalization consisted of participants with protocol-defined LRTI, positive central RT-PCR RSV test result, Investigator assessed LRTI at an inpatient setting.
Time frame: Through 150 days post dose
Population: The As-treated population consisted of all participants who were enrolled and received any dose of nirsevimab.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Nirsevimab 50 mg/100 mg | Number of Participants With Medically Attended (MA) RSV LRTI (Inpatient and Outpatient) and Hospitalizations | MA RSV LRTI | 0 Participants |
| Nirsevimab 50 mg/100 mg | Number of Participants With Medically Attended (MA) RSV LRTI (Inpatient and Outpatient) and Hospitalizations | MA RSV LRTI with hospitalization | 0 Participants |
| Nirsevimab 200 mg | Number of Participants With Medically Attended (MA) RSV LRTI (Inpatient and Outpatient) and Hospitalizations | MA RSV LRTI | 0 Participants |
| Nirsevimab 200 mg | Number of Participants With Medically Attended (MA) RSV LRTI (Inpatient and Outpatient) and Hospitalizations | MA RSV LRTI with hospitalization | 0 Participants |
Secondary
Serum Concentrations of Nirsevimab
Serum concentrations of nirsevimab at selected time points were evaluated to confirm that adequate exposures for protection from respiratory syncytial virus (RSV) lower respiratory tract infection (LRTI) are maintained for at least 5 months after dosing.
Time frame: Baseline (Day 1) and on Days 8 (for Japanese participants), 31, 151 and 361
Population: The As-treated population consisted of all participants who were enrolled and received any dose of nirsevimab. Only those participants with data available are included in the analysis.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Nirsevimab 50 mg/100 mg | Serum Concentrations of Nirsevimab | Day 8 | 139.24 mcg/mL | Geometric Coefficient of Variation 22.26 |
| Nirsevimab 50 mg/100 mg | Serum Concentrations of Nirsevimab | Day 151 | 19.80 mcg/mL | Geometric Coefficient of Variation 101.19 |
| Nirsevimab 50 mg/100 mg | Serum Concentrations of Nirsevimab | Day 31 | 66.00 mcg/mL | Geometric Coefficient of Variation 141.06 |
| Nirsevimab 50 mg/100 mg | Serum Concentrations of Nirsevimab | Day 361 | 1.86 mcg/mL | Geometric Coefficient of Variation 119.96 |
| Nirsevimab 50 mg/100 mg | Serum Concentrations of Nirsevimab | Baseline (Day 1) | NA mcg/mL | — |
| Nirsevimab 200 mg | Serum Concentrations of Nirsevimab | Day 361 | 1.93 mcg/mL | Geometric Coefficient of Variation 158.95 |
| Nirsevimab 200 mg | Serum Concentrations of Nirsevimab | Baseline (Day 1) | NA mcg/mL | — |
| Nirsevimab 200 mg | Serum Concentrations of Nirsevimab | Day 8 | 206.79 mcg/mL | Geometric Coefficient of Variation 16.58 |
| Nirsevimab 200 mg | Serum Concentrations of Nirsevimab | Day 31 | 109.77 mcg/mL | Geometric Coefficient of Variation 91.74 |
| Nirsevimab 200 mg | Serum Concentrations of Nirsevimab | Day 151 | 24.14 mcg/mL | Geometric Coefficient of Variation 121.54 |