| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| COVID-19 at high risk of disease progression |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Virus Diseases [C02] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | SOC |
| E.1.2 | Classification code | 10021881 |
| E.1.2 | Term | Infections and infestations |
| E.1.2 | System Organ Class | 10021881 - Infections and infestations |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 23.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10084268 |
| E.1.2 | Term | COVID-19 |
| E.1.2 | System Organ Class | 10021881 - Infections and infestations |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 23.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10084401 |
| E.1.2 | Term | COVID-19 respiratory infection |
| E.1.2 | System Organ Class | 10021881 - Infections and infestations |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
To evaluate the pharmacokinetics by IV or IM administration of sotrovimab in children from birth to <18 years
To evaluate the safety and tolerability of sotrovimab by IV or IM administration |
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| E.2.2 | Secondary objectives of the trial |
To evaluate disease progression following IV or IM administration of sotrovimab.
To characterize the effect of IV or IM administration of sotrovimab on SARS-CoV-2 viral load in respiratory tract samples among participants infected with SARS-CoV-2 |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Age
1.Participant must be 32 weeks estimated gestational age (EGA), day of life (DOL) 0 to <18 years of age inclusive, at either the time of participant’s signed assent (if age-appropriate) or parent(s)/legally authorized representative signing the informed consent.
Type of Participant and Disease Characteristics
2. Participants with mild-moderate COVID-19, as defined by:
• A positive SARS-CoV-2 test result by any validated qRT-PCR or other nucleic acid amplification test (NAAT) AND
• SpO2 ≥94% on room air AND
• Have one or more of the following symptoms: fever, chills, cough, sore throat, malaise, headache, joint or muscle pain, change in smell or taste, vomiting, diarrhea, shortness of breath, poor appetite or poor feeding, nasal congestion/runny nose, lethargy AND
• Less than or equal to 7 days from onset of symptoms to dosing day (Day 1).
3. Participants at risk of disease progression with at least one of the following criteria:
• Age <1 year
• Diabetes mellitus
• Genetic or metabolic diseases
• Obesity (as defined as body mass index (kg/m2) ≥95th percentile for age and sex based on local growth charts for children ≥2 years of age)
• Cardiovascular disease
• Sickle cell disease
• Pulmonary disease
• Neurologic disease
• Immunosuppressed (due to certain medical conditions or being on medications that weaken the immune system
o Use of systemic corticosteroids is included as defined by dose ≥0.5 mg/kg/day or 20 mg/day prednisone equivalents (whichever dose is the lower of the two) taken for ≥2 weeks
• Baseline medical complexity (gastrostomy- or jejunostomy-dependence, parenteral nutrition dependence, tracheostomy-dependence, baseline oxygen requirement, use of CPAP/BiPAP/ventilator support).
Weight
4. Body weight with the range stated below:
• Preterm newborn infants and term newborn infants: ≥2 kg
• Children 2 years to <18 years:
o Body mass index (BMI) ≥5th percentile for age based on local growth charts.
Sex and Contraceptive/Barrier Requirements
5. Male and/or female
• Contraception and barriers as well as pregnancy testing is required for females only, as appropriate for the age and sexual activity of pediatric participants and as required by local regulations regarding the methods of contraception for those participating in clinical studies.
• A female participant is eligible to participate if she is not breastfeeding and is either:
• Premenarcheal or
• Not pregnant as confirmed by a negative pregnancy test (serum or highly sensitive urine as required by local regulations) at Screening, before the first dose of study intervention, if of reproductive potential.
o If a urine test cannot be confirmed as negative, a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive.
o See protocol for additional requirements for pregnancy testing during the study participation.
Women of childbearing potential (WOCBP) must commit to using a contraceptive method that is highly effective, with a failure rate of <1%, during the study intervention period and for at least 36 weeks after the last dose of study intervention. The investigator should evaluate potential for contraceptive method failure in relationship to the first dose of study intervention.
The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a female with an early undetected pregnancy.
6. The investigator, or a person designated by the investigator, will obtain written informed consent from each study participant’s legal guardian and the participant’s assent, when applicable, before any study specific activity is performed (unless a waiver of informed consent has been granted by an Institutional Review Board/Ethics Committee. All legal guardians should be fully informed, and participants should be informed to the fullest extent possible, about the study in language and terms they are able to understand.
7. The participant capable of providing signed and dated written assent signs and dates a written assent form (age appropriate) and the parent/guardian signs and dates a written informed consent form (ICF) for study participation prior to the initiation of any study-related activities.
Other
8. A legal guardian or primary caregiver must be available to help the study-site personnel ensure follow-up; support the participant to attended assessment days according to the SoA (e.g., able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures); consistently and consecutively be available to provide information on the participant using the rating scales during the scheduled study visits; accurately and reliably dispense study intervention as directed.
9. A legal guardian or primary caregiver must be able to accurately maintain the child’s take-home record, including items of general health.
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|
| E.4 | Principal exclusion criteria |
Medical Conditions
1. Pregnant or breastfeeding.
2. Currently hospitalized, or judged by the investigator as likely to require hospitalization in the next 24 hours, due to severe or critical COVID-19.
Note: If the infant has been hospitalized due to other reasons (e.g., prematurity) or will be hospitalized for reason of administering the study treatment then they can be included in the study.
3. Respiratory rate:
• 0-6 months: >60 breaths/minute (min)
• 6 months to 5 years: >30 breaths/min
• 6 years to <18 years: >20 breaths/min
4. Shortness of breath at rest or respiratory distress.
5. Shock (septic, neurogenic, anaphylactic, cardiogenic, or hypovolemic shock; systemic inflammatory response syndrome).
6. Multiorgan dysfunction.
7. Participants who, in the judgement of the investigator are likely to die in the next 7 days.
8. Multisystem inflammatory syndrome in children (MIS-C) [CDC HAN, 2020], defined as a participant:
a. Participants presenting with fever ≥38°C, laboratory evidence of inflammation (such as elevated C-reactive protein [CRP], erythrocyte sedimentation rate [ESR], fibrinogen, procalcitonin, d-dimer, ferritin, lactic acid, lactate dehydrogenase [LDH], interleukin 6 [IL-6], neutrophilia, lymphopenia or hypoalbuminemia) and evidence of clinically severe illness requiring hospitalization, with multisystem (≥2) organ involvement (cardiac, renal, respiratory, hematologic, gastrointestinal, dermatologic or neurological);
AND
b. No alternative plausible diagnoses;
AND
c. Positive for current or recent SARS-CoV-2 infection by RT-PCR, serology, or antigen test; or exposure to a suspected or confirmed COVID-19 case within the 4 weeks prior to the onset of symptoms.
9. Post-conceptional age less than 32 completed weeks at time of Screening.
10. History of sudden infant death or unexplained death in a sibling.
11. For Cohort B only: Participant has any condition that would prohibit receipt of IM injections in the investigator’s opinion such as coagulation disorder, bleeding diathesis, or thrombocytopenia (platelet count <50,000/mm3).
Prior/Concomitant Therapy
12. Prior, current, or planned future use of any of the following treatments during the study period: COVID-19 convalescent plasma, mAbs against SARS-CoV-2 (e.g., casirivimab/imdevimab), intravenous immunoglobulin (IVIG) for any indication, or dexamethasone specifically for treatment of COVID-19.
13. Current use of COVID-19 treatment (authorized, approved, or investigational).
14. The following exclusions related to use of an authorized or approved vaccine for SARS-CoV-2 are applicable:
a) Receipt of any authorized or approved vaccine for SARS-CoV-2 within 48 hours prior to dosing.
b) Planned use of any authorized or approved vaccine for SARS-CoV-2 within 90 days of study drug administration per current CDC recommendations.
15. Receipt of any non-SARS-CoV-2 vaccines within 14 days (for non-live vaccines) or 28 days (for live vaccine) of Screening.
Prior/Concurrent Clinical Study Experience
16. Has participated, or is participating, in a clinical research study evaluating COVID-19 convalescent plasma, mAbs against SARS-CoV-2 (e.g. casirivimab/imdevimab) or IVIG within 3 months or within 5 half-lives of the investigational product (whichever is longer) prior to the Screening visit.
17. Has participated, is participating, or plans to participate during the study period in a clinical research study evaluation of any authorized, approved or investigational vaccine for SARS-CoV-2.
18. Currently enrolled in another clinical study.
Other Exclusions
19. Infants <24 weeks of age: maternal receipt of IVIG, SARS-CoV-2-directed convalescent plasma or SARS-CoV-2-directed mAb(s) within 3 months prior to birth or within 5 half-lives of the investigational product (whichever is longer).
20. Participants who, in the judgment of the investigator, will be unlikely or unable to comply with the requirements of the protocol through the end of the study.
21. Known hypersensitivity to any constituent present in the investigational product. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Body weight-adjusted serum clearance of sotrovimab
Serum PK of sotrovimab administered by IM injection or IV infusion (PK parameters may include Cmax, Tmax, AUCinf, t1/2, Vz, CL, F)
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Incidence of adverse events (AEs), serious adverse events (SAEs), and adverse events of special interest (AESI) through Day 29 and Week 36 |
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| E.5.2 | Secondary end point(s) |
Progression of COVID-19 through Day 29 as defined by need for attended medical visit* or escalation to higher level of medical care or death (*An attended medical visit includes visit to a hospital emergency room for management of illness or hospitalization for acute management of illness)
Development of severe and/or critical respiratory COVID-19 as manifested by requirement for supplemental oxygen through Day 29* (For participants who require oxygen or respiratory support for premorbid conditions, disease progression is defined as any sustained (>24 hours) increase in the level or method of oxygen support required)
Change from baseline in viral load in nasal secretions measured by qRT-PCR at Day 5, Day 8, and Day 11 |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Please refer to E.5.2 above. |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | No |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 5 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Colombia |
| Philippines |
| South Africa |
| Argentina |
| Brazil |
| Greece |
| Russian Federation |
| United States |
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| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
The end of the study is defined as the date of last scheduled procedure for the last participant in the study globally.
A participant is considered to have completed the study if he/she completes the Week 36 visit.
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 1 |
| E.8.9.1 | In the Member State concerned days | 18 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 4 |
| E.8.9.2 | In all countries concerned by the trial days | 3 |
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