Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12620001249943
Ethics application status
Approved
Date submitted
16/11/2020
Date registered
20/11/2020
Date last updated
21/04/2022
Date data sharing statement initially provided
20/11/2020
Type of registration
Prospectively registered

Titles & IDs
Public title
Intravenous immunoglobulin rich in neutralising antibodies to SARS-CoV-2 (COVID-19) as a passive immunity modality in healthy individuals: an open-label, active control Phase 1/2 Study
Scientific title
Intravenous immunoglobulin rich in neutralising antibodies to SARS-CoV-2 as a passive
immunity modality in healthy individuals : an open label, active control Phase 1/2 Study to investigate the safety profile and to characterise the pharmacokinetics of COVID-19 convalescent plasma and hyperimmune intravenous immunoglobulin G specific to SARS-CoV-2.
Secondary ID [1] 302801 0
Sponsor ID: AEG-CTP-01
Universal Trial Number (UTN)
U1111-1261-2497
Trial acronym
Covimmune Hyperimmune Aegros Trial (CHAT)
Linked study record
N/A

Health condition
Health condition(s) or problem(s) studied:
COVID-19 319763 0
Condition category
Condition code
Inflammatory and Immune System 317697 317697 0 0
Other inflammatory or immune system disorders
Infection 317698 317698 0 0
Other infectious diseases
Respiratory 317732 317732 0 0
Other respiratory disorders / diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Hyperimmune intravenous immunoglobulin G specific to SARS-CoV-2. Single intravenous infusion of 5% purified IgG formulated to 32mL per vial.
Single dose will be 32mL of 5% purified IgG per participant.
As there will be only one infusion of investigational product per participant which will be administered and directly monitored within an early phase clinical trial unit strategies for compliance to therapy is not specifically addressed in this trial protocol.
Allocation to investigational product for this non-randomised trial will be that the first 15 participants will receive convalescent plasma then participants 16-30 will receive study drug. Stratification will be by age and sex.
Sentinel group for interventional arm will comprise 3 participants. Sentinel group participants will receive the same dose of investigational product as other participants however will be observed overnight in early phase clinical trial unit.
Intervention code [1] 319082 0
Prevention
Comparator / control treatment
COVID-19 convalescent plasma. Single intravenous infusion of a standard unit of 250mL +/- 50mL plasma containing SARS-CoV-2 with a neutralising antibody titre of at least 1:160.
Sentinel group for control arm will comprise 3 participants. Sentinel group participants will receive the same dose of investigational product as other participants however will be observed overnight in the early phase clinical trial unit.
Control group
Active

Outcomes
Primary outcome [1] 325739 0
Safety
• Treatment emergent adverse events
• Adverse events of special interest (infusion related reactions, TRALI, TACO)
• Solicited adverse reactions for 7 days after dose of study drug
• Unsolicited adverse events for study period after dose of study drug
• SAEs throughout the entire study period
• AEs leading to withdrawal throughout the entire study period
• Safety clinical laboratory assessments
• Vital signs
• Physical examination

Blood samples for clinical laboratory assessment
Haematology, clinical chemistry, liver function tests, inflammatory markers, HIV, HBV, HCV

Vital signs
Day 1 assessment will comprise 4 hours continuous cardio-respiratory monitoring in early phase clinical trial unit (ECG telemetry, blood pressure, temperature, oximetry). Thereafter vital signs will be collected at scheduled study visits where a symptom-directed physical examination will occur.

Adverse events
AEs will be collected by electronic patient reported outcomes at scheduled study visits. Participants will record safety data into the ePRO under supervision of the study site staff. The ePRO will prompt for safety information since last visit/last contact with study staff.
Timepoint [1] 325739 0
Safety data will be collected from enrolment until Day 182 post-dose.
Secondary outcome [1] 388942 0
Pharmacokinetics: plasma samples will be collected to determine levels of adminstered anti-SARS-CoV-2 IgG (total and subclasses)
• Area under the concentration-time curve from time 0 to infinity (AUC0-inf)
• Area under the concentration-time curve from time 0 to last quantifiable concentration (AUC0-last)
• Maximum concentration (Cmax)
• Time to maximum concentration (tmax)
• Time to last measurable concentration (tlast)
• Apparent terminal elimination rate constant (lambda z)
• Percentage of extrapolated area under the concentration-time curve (%AUCextrap)
• Terminal half-life (t½)
• Systemic clearance (CL)
• Volume of distribution (Vz)
Timepoint [1] 388942 0
Plasma samples will be collected on Day 1 (at pre-dose, 10 minutes, 4 hours, 6 hours post infusion), then at Day 2, Day 3, Day 7, Day 14, Day 28 and Day 42

Eligibility
Key inclusion criteria
1. Adult participants 18 years and over at the time of consent
2. Healthy adults or adults with pre-existing medical conditions who are in a stable condition. A stable medical condition is defined as disease not requiring significant change in therapy or hospitalisation for worsening disease during the 3 months before enrolment
3. Cognitive ability to understand informed consent process and to give informed consent to the experimental treatment
4. Willing and able to adhere to follow-up schedule
5. Female participants of childbearing potential may be enrolled in the study if the participant fulfills all the following criteria:
• Has a negative pregnancy test at Screening and on Day 1.
• Has practiced adequate contraception or has abstained from all activities that could result in pregnancy for at least 28 days prior to Day 1.
• Has agreed to continue adequate contraception throughout the study period Day 1 to Day 42.
• Is not currently breastfeeding.
Adequate female contraception is defined as consistent and correct use of a Therapeutic Goods Administration (TGA) approved contraceptive method in
accordance with the product label. For example:
• Abstinence, where abstinence is the preferred and usual lifestyle of the participant
• Double barrier method (a condom and one other method of adequate contraception)
• Hormonal methods associated with inhibition of ovulation.
Acceptable hormonal methods include: oral contraceptives, contraceptive medication patch, contraceptive medication injection, estrogen / progestin vaginal ring, or contraceptive medication implant.
• Intrauterine device
• Sterilisation of a female participant’s monogamous male partner (with medical assessment of surgical success) prior to entry into the study
Note: periodic abstinence (e.g. calendar, ovulation, symptom-thermal, postovulation methods) and withdrawal are not acceptable methods of contraception.
6. Male participants with female partners planning pregnancy should follow adequate contraception for the entire study period Day 1 to Day 42.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
1. Is acutely ill or febrile 72 hours prior to or at Screening. Fever is defined as a body temperature greater than or equal to 37.5°C. Participants meeting this criterion may be rescheduled within the relevant window periods. Afebrile participants with minor illnesses can be enrolled at the discretion of the investigator.
2. Concurrent, diagnosed, viral or bacterial infections that in the investigator’s opinion should exclude their participation.
3. Current infection with SARS-CoV-2 (positive result with either rapid antigen or PCR test)
4. Known infection with SARS-CoV-2 and resolution of symptoms within the last 60 days.
5. Vaccination against COVID-19 within the last 60 days.
6. Anti-SARS-CoV-2 anti-spike antibody level greater than or equal to 5000 AU per the Abbott AdviseDx SARS CoV-2 IgG II assay (or equivalent)
7. Anti-SARS-CoV-2 anti-nucleocapsid level above positive cut off level of 50 AU per the Abbott ARCHITECT SARS CoV-2 IgG assay (or equivalent).
8. Planned simultaneous participation in another interventional study to prevent or treat COVID-19.
9. Planned administration of any vaccine, including any type of COVID-19 vaccine, is not permitted until completion of the Week 6 (day 42+/-3) visit.
10. Proven hypersensitivity or allergic reaction to blood products or immunoglobulins or sodium citrate
11. Selective IgA deficiency (less than 70 mg/dL)
12. Has received systemic immunosuppressants or immune-modifying drugs for >14 days in total within 6 months prior to Screening (for corticosteroids greater than or equal to 20 mg/day of prednisone equivalent).
13. Immunosuppressive or immunodeficient state, asplenia, recurrent severe infections
14. Has received systemic immunoglobulins or blood products within 3 months prior to the day of screening.
15. Has participated in an interventional clinical study within 28 days prior to the day of enrolment.
16. Pregnant or breastfeeding.
17. Inability to adhere to follow up schedule
18. Not a suitable volunteer in the opinion of the investigator

Study design
Purpose of the study
Prevention
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Allocation is not concealed.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 1 / Phase 2
Type of endpoint/s
Safety
Statistical methods / analysis
Total sample size will be 30, with 15 participants allocated to each group.
There will be a sentinel group for safety purposes consisting of smaller cohort of 3 from each arm of the study.
No formal sample size calculation has been performed, and the sample size is empirical. However, the sample size selected is considered sufficient to adequately characterise the general safety and PK profile of this type of study in healthy participants.

The general analytical approach for all endpoints will be descriptive in nature. All summaries will present the data by treatment group.
For continuous variables, descriptive statistics will include the number of non-missing values, mean, standard deviation (SD), median, minimum, and maximum.
For categorical variables, descriptive statistics will include frequency counts and percentages per category.
In general, missing values will not be imputed.
This is a pilot study; multiplicity adjustment will not be considered.

Safety Population
The safety population will include all enrolled participants who receive any amount of investigational product. The safety population will be used for the summaries of all safety data, and participants will be analysed according to the actual treatment received.

Intent to Treat (ITT) Population
The ITT population will include all enrolled participants regardless of investigational product received or not. The ITT population will be used for all summaries of baseline, demographics and exploratory endpoints, and participants will be analysed according to the treatment allocated.

Pharmacokinetic (PK) Population
The PK population will include all enrolled participants who receive any amount of investigational product and have at least one evaluable PK parameter. The PK population will be used for the summaries of all PK data, and participants will be analysed according to the actual treatment received.

Participant Disposition
The number of participants enrolled, allocated, treated, and discontinued from investigational product and/or study will be summarised according to the treatment group. The primary reason for investigational product and/or study discontinuation will be summarised according to the reported categories. The number and percentage (%) of participants in each analysis population will also be presented. Major protocol deviations will be summarised and listed by category of deviations.

Demographic and baseline characteristics will be summarised by treatment group using descriptive statistics. Medical history will be listed by participant and coded using Version 23.1 of Medical Dictionary for Regulatory Activities (MedDRA) dictionary.

Adverse Events
Adverse events (AEs) will be coded using the latest version of Medical Dictionary for Regulatory Activities (MedDRA), and AE data will be summarised by System Organ Class (SOC) and Preferred Term (PT). The frequency and percentage of participants by reported SOC/PT will be summarised, with the number of AEs counted as well. Adverse events will also be summarised by AE severity/grade and AE relationship to study treatment. A participant with two or more AEs within the same level of summarisation (in terms of SOC or PT) will be counted only once in that level.
All AE summaries will be restricted to treatment-emergent AEs (TEAEs) only. Treatment emergent AEs are defined as AEs which commence, or worsen in severity, on or after the time of start of investigational product administration.
AEs of special interest (infusion-related reactions, TRALI, TACO) will be listed and summarised separately using frequency counts and percentage, by treatment group.
A by-patient AE data listing, including verbatim term, MedDRA SOC and PT, severity, outcome and relationship to study treatment, will be provided. Separate listings will be generated for serious AEs and AEs leading to discontinuation of study treatment.

Laboratory Data
Laboratory data (haematology, clinical chemistry, inflammatory markers) will be summarised and listed at each protocol scheduled time point, by treatment group. Observed and changes from baseline values will be presented. Number of participants with abnormal laboratory test values including their clinical significance (if available) will be summarised as well. Shift tables from baseline to post-dose assessments will also be generated for each safety laboratory parameter with values of within normal range and out of normal range (high and low) used for the shift categories.

PK concentration
Pharmacokinetic concentration data will be summarised and listed for all participants according to the protocol specified PK sampling time points by using PK population. All concentrations below the limit of quantification (BLQ) or missing data will be presented in the concentration data listings. In addition to the general statistics, the summary of PK concentration data will include geometric statistics and coefficient of variation. Concentrations that are BLQ will be treated as zero for the computation of descriptive statistics, except geometric mean. For the calculation of the geometric mean, concentrations that are BLQ will be treated as equal to the limit of quantification. Missing values will be omitted from the calculation of descriptive statistics. Individual and mean PK concentration-time profiles for each treatment group will also be presented graphically on both linear and logarithmic concentration scales.

PK parameters
Pharmacokinetic parameters will be computed from the individual PK concentration data using a non-compartmental approach. The actual PK sampling time points will be used for the estimation of PK parameters. Concentrations that are recorded as BLQ prior to the first quantifiable value will be set to zero. Concentrations that are recorded as BLQ at the end of the sampling period will be set to missing and will not be used for the estimation of PK parameters. If a BLQ value falls between two quantifiable concentrations, the value will be set equal to the limit of quantification unless its exclusion can be justified.
PK parameters will be summarised by treatment group for all participants using descriptive statistics (including geometric statistics and coefficient of variation). Geometric mean and geometric coefficient of variation will be calculated for all parameters except tmax, tlast and t½. The three PK parameters, AUC0-inf, AUC0-last, and Cmax, will be compared between the two treatment groups by using an Analysis of Variance (ANOVA) model for the assessment of bioequivalence. The logarithm transformed PK parameters will be used for the modelling. The geometric mean ratio and its 90% confidence interval will be estimated from the model with subsequent antilog transformations applied. The 90% confidence interval of geometric mean ratio will be compared against the equivalence margins of (0.80, 1.25). If the 90% confidence interval of the geometric mean ratio fails within (0.80, 1.25) for all the above three PK parameters, a bioequivalence between hyperimmune IG to SARS-CoV-2 and SARS-CoV-2 convalescent plasma could be concluded. However, this study is not powered to conduct the formal bioequivalence comparison, the conclusion of bioequivalence should be based on the overall assessment of the totality of the data. The above equivalence margins of (0.80, 1.25) are used as a guidance only.

Interim analysis
An interim analysis is planned to analyse IgG PK profiles of all participants, after the last (30th) participant has completed Day 42 (Visit 11). Safety data could be assessed at interim analyses (IA) by a data safety review committee, which will however not impact on the overall type I error control of the study.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
29/03/2021
Actual
28/04/2021
Date of last participant enrolment
Anticipated
31/07/2022
Actual
Date of last data collection
Anticipated
28/02/2023
Actual
Sample size
Target
30
Accrual to date
11
Final
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 18033 0
Scientia Clinical Research - Randwick
Recruitment hospital [2] 18034 0
Royal North Shore Hospital - St Leonards
Recruitment postcode(s) [1] 32009 0
2031 - Randwick
Recruitment postcode(s) [2] 32010 0
2065 - St Leonards

Funding & Sponsors
Funding source category [1] 307228 0
Commercial sector/Industry
Name [1] 307228 0
Aegros Ltd.
Country [1] 307228 0
Australia
Primary sponsor type
Commercial sector/Industry
Name
Aegros Ltd.
Address
5 Eden Park Drive
Macquarie Park NSW 2113
Country
Australia
Secondary sponsor category [1] 307833 0
None
Name [1] 307833 0
Address [1] 307833 0
Country [1] 307833 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 307324 0
Bellberry Limited
Ethics committee address [1] 307324 0
Ethics committee country [1] 307324 0
Australia
Date submitted for ethics approval [1] 307324 0
02/11/2020
Approval date [1] 307324 0
08/12/2020
Ethics approval number [1] 307324 0
REGIS Application ID 2020/ETH02775
Ethics committee name [2] 308144 0
Lifeblood Ethics Committee
Ethics committee address [2] 308144 0
Ethics committee country [2] 308144 0
Australia
Date submitted for ethics approval [2] 308144 0
28/12/2020
Approval date [2] 308144 0
23/02/2021
Ethics approval number [2] 308144 0
20-12NSW-08

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 106834 0
A/Prof Roderick Clifton-Bligh
Address 106834 0
Head, Department of Endocrinology
Royal North Shore Hospital
Reserve Rd, St Leonards NSW 2065
Country 106834 0
Australia
Phone 106834 0
+61 2 9463 1680
Fax 106834 0
Email 106834 0
[email protected]
Contact person for public queries
Name 106835 0
Guy Gavagna
Address 106835 0
Aegros Ltd.
5 Eden Park Drive
Macquarie Park NSW 2113
Country 106835 0
Australia
Phone 106835 0
+61298563500
Fax 106835 0
Email 106835 0
[email protected]
Contact person for scientific queries
Name 106836 0
Guy Gavagna
Address 106836 0
Aegros Ltd.
5 Eden Park Drive
Macquarie Park NSW 2113
Country 106836 0
Australia
Phone 106836 0
+61298563500
Fax 106836 0
Email 106836 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Pharmacokinetic data will be commercial in confidence.


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
9761Study protocol http://www.aegros.com.au[email protected] Protocol manuscript will be submitted for publicat... [More Details]



Results publications and other study-related documents

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