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Trial registered on ANZCTR


Registration number
ACTRN12619001399189
Ethics application status
Approved
Date submitted
11/09/2019
Date registered
14/10/2019
Date last updated
29/09/2020
Date data sharing statement initially provided
14/10/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
A phase I biosimilar study to compare the pharmacokinetics, safety and tolerability of Abcertin, and EU-sourced Cerezyme® in healthy volunteers following a single infusion via the veins.
Scientific title
A randomized, double-blind, 2-treatment, 2-period, crossover phase I study to compare the pharmacokinetics, safety and tolerability of 60 IU/kg of Abcertin, and EU-sourced Cerezyme® in healthy volunteers following a single intravenous administration.
Secondary ID [1] 299179 0
None
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Gaucher's disease 314273 0
Condition category
Condition code
Human Genetics and Inherited Disorders 312627 312627 0 0
Other human genetics and inherited disorders
Metabolic and Endocrine 312847 312847 0 0
Other metabolic disorders
Neurological 313006 313006 0 0
Other neurological disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Test Product
Treatment A: Abcertin (400 IU/vial)
(Imiglucerase manufactured by ISU Abxis, Republic of Korea)
60 IU/kg body weight
Reference Product
Treatment B: EU-sourced Cerezyme® (400 IU/vial)
(Imiglucerase manufactured by Genzyme Europe B.V., the Netherlands)
60 IU/kg body weight
Administered as a single dose via intravenous infusion over 2 hours, at infusion rate of 0.5 unit/kg body weight/minute.
Two treatments (A or B) to be administered on Day 1 of Periods 1 and 2, according to the treatment sequence assigned with a washout of at least 28 days between doses, not exceeding 35 days.
Intervention code [1] 315470 0
Treatment: Drugs
Comparator / control treatment
Reference Product
Treatment B: EU-sourced Cerezyme® (400 IU/vial)
(Imiglucerase manufactured by Genzyme Europe B.V., the Netherlands)
Control group
Active

Outcomes
Primary outcome [1] 321279 0
To compare the pharmacokinetics of Abcertin to reference product EU-sourced Cerezyme®, after single intravenous administration of 60 IU/kg.
Assessed by pre dose, during dose and post dose blood sample collection and analysis.
pharmacokinetic parameters being assessed in this outcome:
Area under the concentration-time curve (AUC) from time zero to infinity (AUC(0-inf))
Timepoint [1] 321279 0
Day 1:
Predose blood sample, Blood sample During dose (10, 20, 40, 60, 90, 120 min), Blood sample post dose (5, 10, 20,30,40,50,60,70,80,90,120 mins)
Secondary outcome [1] 374522 0
Composite outcome-To compare the safety, tolerability and immunogenicity of Abcertin to reference formulation EU-sourced Cerezyme®, after single intravenous administration of 60 IU/kg
Outcome measured by
- Adverse events assessments including subjective/objective symptoms: checked at any time
- Physical examination
- 12-lead ECG
- Vital signs
- Local injection site tolerability
- Anti-drug antibodies (ADA), neutralizing antibodies (NAb), titer
- Safety laboratory test: Hematology, Coagulation, Blood Chemistry, Urinalysis
Timepoint [1] 374522 0
- Adverse events assessments including subjective/objective symptoms: checked at any time through the study
- Physical examination at Visit 1(-28 to -1 day pre infusion), 2 (Infusion day- treatment 1), 3 (5 days post infusion), 4 (Infusion day - treatment 2), 5 (5 days post infusion), and 6 (28 to 35 days post infusion -treatment 2)
- 12-lead ECG at Visit 1(-28 to -1 day pre infusion), 2 (Infusion day- treatment 1), 3 (5 days post infusion), 4 (Infusion day - treatment 2), 5 (5 days post infusion), and 6 (28 to 35 days post infusion -treatment 2)
- Vital signs at Visit 1(-28 to -1 day pre infusion), 2 (Infusion day- treatment 1), 3 (5 days post infusion), 4 (Infusion day - treatment 2), 5 (5 days post infusion), and 6 (28 to 35 days post infusion -treatment 2)
- Local injection site tolerability visit 2 (Infusion day- treatment 1), 3 (5 days post infusion), 4 (Infusion day - treatment 2), 5 (5 days post infusion),
- Anti-drug antibodies (ADA), neutralizing antibodies (NAb), titer visit 2 (Infusion day- treatment 1) and 6 (28 to 35 days post infusion -treatment 2)
- Safety laboratory test: Hematology, Coagulation, Blood Chemistry, Urinalysis at Visit 1(-28 to -1 day pre infusion), 2 (Infusion day- treatment 1), 3 (5 days post infusion), 4 (Infusion day - treatment 2), 5 (5 days post infusion), and 6 (28 to 35 days post infusion -treatment 2)
Secondary outcome [2] 375141 0
Pharmacokinetics:
Maximum serum concentration (Cmax)
Time to Cmax (tmax)
Area under the concentration-time curve (AUC) from time zero to time of last measurable concentration (AUC(0-last))
Terminal half-life (t½)
Total body clearance (CL)
Volume of distribution based on the terminal phase (Vz)
Timepoint [2] 375141 0
Day 1:
Predose blood sample, Blood sample During dose (10, 20, 40, 60, 90, 120 min), Blood sample post dose (5, 10, 20,30,40,50,60,70,80,90,120 mins)

Eligibility
Key inclusion criteria
(1) Subject must be able to give voluntary written informed consent prior to any study-related procedures.
(2) Subject must have availability for the entire study period.
(3) Male or female subjects aged 18 years to 45 years inclusive.
(4) Body mass index (BMI) greater than or equal to 18.5 and less than or equal to 30.0 kg/m2 (Weight 55-105 kg, inclusive).
(5) Female subjects of childbearing potential must be non-pregnant and non-lactating, and have a negative pregnancy test at Screening, and at (each) admission to the clinical research center.
(6) Females of childbearing potential, with a fertile male sexual partner, must use adequate contraception from Screening until 90 days after the follow-up visit. Adequate contraception is defined as using hormonal contraceptives or an intrauterine device combined with at least one of the following forms of contraception: a diaphragm or cervical cap, or a condom.
(7) Males must use adequate contraception and must not donate sperm from first admission to the clinical research center until 90 days after the follow-up visit. Adequate contraception for the male subject and his female partner, is defined as using hormonal contraceptives or an intrauterine device combined with at least one of the following forms of contraception: a diaphragm or cervical cap, or a condom.
(8) Subject must be healthy as determined by clinical Investigator, based on medical history, physical examination, 12-lead ECG, and laboratory evaluations (hematology, clinical chemistries, coagulation, and urinalysis tests).
(9) All values for clinical laboratory tests of blood and urine should not be clinically significant as judged by the Principal Investigator.
Minimum age
18 Years
Maximum age
45 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
(1) Intake of any investigational drug in another study within 30 days (or 5 half-lives, whichever is greater) prior to intake of IMP in this study or have received the last dose of a study drug more than 30 days ago (or 5 half-lives, whichever is greater) but who are on extended follow-up, or planned intake of an investigational drug (other than for this study) during the course of this study.
(2) With ongoing symptoms indicating acute diseases within 28 days prior to dosing of IMP; Acute disease refers to any new onset of symptoms/signs or diagnosis of disease whether infectious, inflammatory, traumatic, etc. in origin (regardless whether the subject was hospitalized or not).
(3) With any medical history that may affect drug distribution, metabolism and excretion (e.g., hepatic or renal disease).
(4) Positive screen on hepatitis B surface antigen (HbsAg), hepatitis C virus (HCV) antibodies or anti-HIV 1 and 2 antibodies. If a potential subject is considered by Investigator to have false positive result (ex. HIV antibodies) at screening, then a repeat test should be done as soon as possible and if retest is negative, the subject can be considered eligible for the study.
(5) Clinically significant hypersensitivity, or severe allergic reactions (either spontaneous or following IMP administration), also including known or suspected clinically relevant drug hypersensitivity to any components of the IMP or comparable drugs, including Latex.
(6) Vaccination with a live vaccine within 3 months prior to the first dosing of IMP or planning a vaccination with a live vaccine before the follow-up visit.
(7) With the results of safety laboratory test
a. AST (sGOT) or ALT (sGPT) > 1.5 times of upper normal limit, or
b. Total bilirubin > 1.5 times of upper normal limit
Note: Safety laboratory tests can be repeated if the subject is clinically asymptomatic in relation to abnormal result and Investigator strongly believes this is not clinically significant. One re-test is allowed. If the result still meets the exclusion criteria, subject will be excluded.
(8) Subject who has immune deficiency or medication with immunosuppressive agents.
(9) Treatment with any medication prescribed or over-the-counter (OTC) products including herbal remedies within 14 days prior to Day 1 or longer if the medication has a long half-life, unless agreed as not clinically significant by the Investigator and Sponsor. Exceptions: hormonal contraceptives, acetaminophen less than or equal to 3 g/day, vitamins at daily recommended doses.
(10) Donated whole blood products (e.g., plasma, platelets) within 60 days, or transfused within 20 days before Screening.
(11) History of alcohol or drug abuse or drug addiction (including cannabis products) within the last 12 months before Screening.
(12) Subject is unwilling to comply with the alcohol restrictions. The subject should refrain from drinking any alcohol within 72 hours prior to Day -1, and should not consume more than 3-4 units of alcohol per day to a maximum of 14 units of alcohol per week (1 unit of 10 mL of pure alcohol, 12 ounces [360 mL] of beer, 5 ounces [150 mL] of wine, or 1.5 ounces [45 mL] of 80 proof distilled spirits) throughout the study.
(13) Heavy smoker (> 5 cigarettes/day) or the subject could not stop smoking during study period while inpatient at the clinical research center.
(14) Positive tests for drugs of abuse or alcohol at Screening or admission to the study site (Day -1).
(15) Family member or employee of the Investigator or study site staff or study team.
(16) Those who are not suitable for participation in the study based on the Investigators’ judgment for any other reason including laboratory test results.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Sealed opaque randomization envelopes.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
computer-generated randomization code
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
Intervention assignment
Crossover
Other design features
Phase
Phase 1
Type of endpoint/s
Pharmacokinetics
Statistical methods / analysis
Pharmacokinetics
The drug concentration-actual sampling time data of subjects in the Pharmacokinetic (PK) analysis set will be used to compute PK parameters using the standard non-compartmental methods.
Pharmacokinetic biosimilarity between Abcertin and EU-sourced Cerezyme® will be assessed using an ANOVA on the log-transformed parameter. The ANOVA model will contain fixed effects for treatment, period, and sequence, and subjects nested within sequence. The point estimates and 90% confidence intervals (CIs) for the difference among treatments will be calculated. The point estimates and 90% CIs will then be exponentially back transformed to provide point and CI estimates for the ratio of geometric least squares (LS) means for imiglucerase for the following comparisons: Abcertin versus EU-sourced Cerezyme®. PK biosimilarity of Abcertin will be concluded if the 90% CI falls entirely within 80.00% to 125.00% for AUC(0-inf).
As a sensitivity analysis, a similar analysis will be performed using subject within sequence as a random effect instead of as a fixed effect.
Individual secondary PK endpoints stratified by treatments and periods will be listed and summarized in tabular format using descriptive statistics as appropriate. Descriptive statistics for all secondary PK endpoints will include the number of subjects with sufficient data to reliably calculate the selected PK endpoint (N), mean, standard deviation (SD), percent coefficient of variation (%CV), median, minimum and maximum values, geometric mean, and geometric %CV, as appropriate.
In addition, the ANOVA model will also be performed on Cmax and AUC(0-last). As a sensitivity analysis, an additional analysis will be performed using subject within sequence as a random effect instead of as a fixed effect.
Pharmacodynamics:
The number and proportion of positive ADA and NAbs responses will be provided by treatment, visit and sequence. The titer levels (if available) from positive ADA samples assays, will be listed.
Safety:
Descriptive statistics for all safety endpoints will be provided for all treatments including mean, SD, median, minimum and maximum values or by number and proportion, as appropriate. All safety data (scheduled and unscheduled) will be presented in data listings. The number and proportion of subjects experiencing serious and non-serious AEs will be tabulated. Adverse events will be coded according to the Medical Dictionary for Regulatory Activities (MedDRA).
Vital signs, 12-lead ECGs, and clinical laboratory parameters being monitored for safety will be summarized using descriptive statistics by scheduled visit and treatment, and data listings of clinically significant abnormalities/outliers.
Physical examination results will be listed; local injection site tolerance results (pain, redness, itch, bruising, and etc.) will be listed and summarized, as appropriate

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
3/02/2020
Actual
7/02/2020
Date of last participant enrolment
Anticipated
13/03/2020
Actual
7/05/2020
Date of last data collection
Anticipated
30/06/2020
Actual
9/07/2020
Sample size
Target
40
Accrual to date
Final
42
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 14718 0
Scientia Clinical Research - Randwick
Recruitment postcode(s) [1] 27758 0
2031 - Randwick

Funding & Sponsors
Funding source category [1] 303721 0
Commercial sector/Industry
Name [1] 303721 0
ISU Abxis Co., LTD
Country [1] 303721 0
Korea, Republic Of
Primary sponsor type
Commercial sector/Industry
Name
ISU Abxis Co., LTD
Address
5th fl. Global R&D Center Building C, 22 Daewangpangyoro 712-beongil, Bundang-gu, Seongnam-si, Gyeonggi-do, South Korea,13488
Country
Korea, Republic Of
Secondary sponsor category [1] 303836 0
Commercial sector/Industry
Name [1] 303836 0
Parexel International Pvt Ltd
Address [1] 303836 0
Suite B, Level 6,
15 Talavera Road
North Ryde- 2113
NSW, Australia
Country [1] 303836 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 304246 0
Bellberry Limited
Ethics committee address [1] 304246 0
Ethics committee country [1] 304246 0
Australia
Date submitted for ethics approval [1] 304246 0
25/09/2019
Approval date [1] 304246 0
21/11/2019
Ethics approval number [1] 304246 0

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

Contacts
Principal investigator
Name 96270 0
Dr Charlotte Lemech, MD
Address 96270 0
Charlotte Lemech
Scientia Clinical Research Limited
Level 5, Bright Building. Corner High and Avoca Street. Randwick NSW 2031. Australia
Country 96270 0
Australia
Phone 96270 0
+61 29382 5807
Fax 96270 0
Email 96270 0
charlotte.lemech@scientiaclinicalresearch.com.au
Contact person for public queries
Name 96271 0
Scientia Clinical Research Recruitment
Address 96271 0
Scientia Clinical Research Limited
Level 5, Bright Building. Corner High and Avoca Street. Randwick NSW 2031. Australia
Country 96271 0
Australia
Phone 96271 0
+61 1800 727 874
Fax 96271 0
Email 96271 0
contactus@scientiaclinicalresearch.com.au
Contact person for scientific queries
Name 96272 0
Scientia Clinical Research Recruitment
Address 96272 0
Scientia Clinical Research Limited
Level 5, Bright Building. Corner High and Avoca Street. Randwick NSW 2031. Australia
Country 96272 0
Australia
Phone 96272 0
+61 1800 727 874
Fax 96272 0
Email 96272 0
contactus@scientiaclinicalresearch.com.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Not approved by sponsor yet.


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
9324Informed consent form    378303-(Uploaded-05-05-2020-10-40-43)-Study-related document.pdf



Results publications and other study-related documents

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No documents have been uploaded by study researchers.

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