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Trial registered on ANZCTR


Registration number
ACTRN12621001161819
Ethics application status
Approved
Date submitted
20/07/2021
Date registered
27/08/2021
Date last updated
27/08/2021
Date data sharing statement initially provided
27/08/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
A phase 1 clinical trial to evaluate the safety, pharmacokinetics/pharmacodynamics, and immunogenicity of single and multiple ascending subcutaneous doses of RS2102 in healthy adult subjects
Scientific title
A single center, randomized, double-blind and placebo-controlled phase 1 study to evaluate the safety and tolerability, pharmacokinetics/pharmacodynamics, and immunogenicity of single and multiple ascending subcutaneous doses of RS2102 in healthy adult subjects
Secondary ID [1] 304832 0
None
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Systemic lupus erythematosus 322919 0
Condition category
Condition code
Inflammatory and Immune System 320492 320492 0 0
Autoimmune diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Part 1 (Single Ascending Dose Study, SAD):

Part 1 (Single Ascending Dose Study, SAD) will be conducted in Australia, as a single-center, randomized, double-blind and placebo-controlled single ascending subcutaneous dose study. Seven cohorts will be included as a tentative plan, the order of cohorts may be adjusted based on the safety of the previous cohort (s), and additional cohort (s) may be added to obtain additional safety and Pharmacokinetics (PK)/ Pharmacodynamics (PD) data based on the approval from Safety Review Committee (SRC).
In Part 1 of the study, each cohort follows the principle of sentinel administration (i.e., 2 subjects are enrolled and dosed first in each cohort, 1 is randomly assigned to the active drug and 1 to the placebo). If no significant safety risk is observed within 48 hours after dose administration, the remaining 6 subjects can be dosed.
Cohorts 1 to 7 are sequential. After all subjects of the cohort reach D15 post-dose, the safety data will be thoroughly assessed, and the Safety Review Committee (SRC) will determine whether it is appropriate to escalate to the next dose level. The dose levels for subsequent cohorts may be adjusted based on the SRC review.

Cohorts Planned Dose Levels* & Dose Frequency Subjects
1) 0.16 µg/ - Once, Abdominal Subcutaneous 6 on Active and 2 on Placebo
2) 0.5 µg/kg - Once, Abdominal Subcutaneous 6 on Active and 2 on Placebo
3) 1.5 µg/kg - Once, Abdominal Subcutaneous 6 on Active and 2 on Placebo
4) 5 µg/kg - Once, Abdominal Subcutaneous 6 on Active and 2 on Placebo
5) 15 µg/kg - Once, Abdominal Subcutaneous 6 on Active and 2 on Placebo
6) 30 µg/kg - Once, Abdominal Subcutaneous 6 on Active and 2 on Placebo
7) 60 µg/kg - Once, Abdominal Subcutaneous 6 on Active and 2 on Placebo

* The dose levels are tentative. Dose cohorts/levels adjustment were allowed based on the SRC review.

The dosing will be supervised by the Principal Investigator, sub-investigator along with experienced and trained site staff (which would include but limited to study nurse, study pharmacist, study coordinators).

Part 1 includes a screening period (D-28 to D-1) and an observation period (D1 to D29). Eligible subjects should be admitted no later than Day -1, receiving abdominal subcutaneous injection of RS2102 in the morning on Day 1, and are suggested to discharge after completing all sampling and lab tests on Day 7 (the discharge time can be adjusted according to the site decision, but should be based on the safety of subjects). Subjects then complete all other on-site visits. All subjects should receive safety monitoring and sampling for pharmacokinetics, pharmacodynamics and immunogenicity at scheduled timepoints.

Part 2 (Multiple-ascending-dose study, MAD):

Part 2 (Multiple Ascending Dose Study, MAD) will be conducted in China, as a single-center, randomized, double-blind, and placebo-controlled multiple ascending subcutaneous dose study. The tentative plan for this second part includes four cohorts (the dose cohorts and frequency/treatment duration are tentative until data from Part 1 are available), with 8 subjects in each cohort. Each subject receives medication once a week for 4 weeks (i.e., QW, 4 times in total) as a tentative plan.

After all subjects of the cohort reach 2 weeks after the last administration, the safety data will be thoroughly assessed, and the Safety Review Committee (SRC) will determine whether it is appropriate to escalate to the next dose level. The dose levels/frequency for subsequent cohorts may be adjusted based on the SRC review.
Part 2 includes a screening period (D-28 to -1) and an observation period (D1 to D50). Eligible subjects should be admitted no later than Day -1, receiving the first dose on Day 1 and suggested to be discharged after completing sampling and safety tests on Day 8 (the discharge time can be adjusted according to the site decision, but should be based on the safety of subjects); be admitted again no later than Day 21, receive the last dose on Day 22 and suggested to be discharged after completing sampling and safety tests on Day 28 (the discharge time can be adjusted according to the site decision, but should be based on the safety of subjects); all subjects should complete all other on-site visits. On the morning of the dosing date, all subjects will be administered the abdominal subcutaneous injection. Before and after dosing, safety monitoring will be conducted, and sampling for pharmacokinetics, pharmacodynamics and immunogenicity will be completed.

Note: based on results from SAD, if the risk-benefit didn’t support MAD in healthy volunteers, the sponsor may decide to close this Part 2 study and open another protocol for MAD study in patients.
Intervention code [1] 321212 0
Treatment: Drugs
Comparator / control treatment
Placebo for injection with no active ingredients - 0.9% sodium chloride injection
Route of administration - Subcutaneous injection
Control group
Placebo

Outcomes
Primary outcome [1] 328321 0
Safety and tolerability outcomes based on review of AEs, vital signs, ECGs, laboratory findings, physical exams and injection site reaction
Timepoint [1] 328321 0
AEs will be collected from the start of study drug administration and until the last visit/contact. SAEs will be collected from the time a subject consent to participate in the study up to the last visit/contact. After the last visit/contact, if Investigator is informed of SAE and assesses the SAE to be related to the study drug, the SAE should be reported to the Sponsor.

Part 1 - Single Ascending Dose: Safety assessments include:

Injection site reaction - at Day 1 (dosing), Day 2, 3, 5 and 7 post dose. Injection site reaction is measured by observation and recording.

Vital signs - at Screening, Day -1 (pre dose), Day 1 (dosing), 2, 3, 5, 7, 29/End of study visit post dose. Vital signs measurements will include heart rate and systolic and diastolic blood pressure, and body temperature. Heart rate will be assessed using pulse oximeter, systolic and diastolic blood pressure is measured using a sphygmomanometer and 12-lead ECG will be measured utilizing an ECG machine.

12-lead ECG - at Screening, Day -1 (pre dose), 1 (dosing), 2, 3, 5, 29/End of study visit post dose, 12-lead ECG will be measured utilizing an ECG machine.
Hematology - at Screening, Day -1 (pre-dose) and Day 2, 3, 5, 7, 15 29/End of study visit post dose, Hematology will be assessed using blood samples.
Urinalysis - at Screening, Day -1 (pre-dose), Day 2, 3, 5, 7, 15 29/End of study visit post dose, Urinalysis will be performed using urine samples.
Biochemistry - at Screening, Day -1 (pre dose), Day 2, 3, 5, 7, 15 29/End of study visit post dose, Biochemistry testing will be performed using blood samples.
Immunoglobulin - at Screening, Day -1 (pre dose), Day 2, 3, 5, 7, 15 29/End of study visit post dose, Immunology will be performed using blood samples.
Coagulation function - at Screening, Day -1 (pre dose), Day 2, 3, 5, 7, 15 29/End of study visit post dose, Coagulation function will be performed using blood samples.
Thyroid function - at screening and Day -1 (pre-dose) and day 15 (post dose) visits, Thyroid function will be assessed using blood samples.

Part 2 - Multiple Ascending Dose: Safety assessments include:

Injection site reaction - at Day 1 (dosing), Day 2, 3, 5, 8, 15, 22, 28, 50/End of Study post dose. Injection site reaction is measured by observation and recording.
Vital signs - at Screening, Day -1 (pre dose), Day 1 (dosing), Day 2, 3, 5, 8, 15, 22, 28 and 50/End of study visit post dose. Vital signs measurements will include heart rate and systolic and diastolic blood pressure, and body temperature. Heart rate will be assessed using pulse oximeter, systolic and diastolic blood pressure is measured using a sphygmomanometer and 12-lead ECG will be measured utilizing an ECG machine.
12-lead ECG - at Screening, Day -1 (pre dose), Day 1 (dosing), Day 2, 3, 5, 8, 15, 22, 28 and 50/End of study visit post dose. 12-lead ECG will be measured utilizing an ECG machine.
Hematology - at Screening, Day -1 (pre dose), Day 8, 22, 28 and 50/End of study visit post dose, Hematology will be assessed using blood samples.
Urinalysis - at Screening, Day -1 (pre dose), Day 8, 22, 28 and 50/End of study visit post dose, Urinalysis will be performed using urine samples.
Biochemistry - at Screening, Day -1 (pre dose), Day 8, 22, 28 and 50/End of study visit post dose, Biochemistry testing will be performed using blood samples.
Immunoglobulin - at Screening, Day -1 (pre dose), Day 8, 22, 28 and 50/End of study visit post dose, Immunology will be performed using blood samples.
Coagulation function - at Screening, Day -1 (pre dose), Day 8, 22, 28 and 50/End of study visit post dose, Coagulation function will be performed using blood samples.
Secondary outcome [1] 398587 0
Serum drug concentration and PK parameters of RS2102 after subcutaneous administration, including but not limited to:
­Part 1: AUC(0-t), AUC(0-8), Cmax, Tmax, CL/F, VZ/F and T1/2.
­Part 2: AUC(0-t), AUC(0-t), Cmax,ss, Tmax,ss, T1/2, Css(avg) and accumulation coefficient.
Timepoint [1] 398587 0
Part 1:

Samples will be collected within 1 h pre-dose on Day 1, and at 2, 4, 8, 10, 24, 48, 96, 144, 336, and 672 h post-dose for PK analysis.

Part 2:

Samples will be collected within 1 h pre-dose on Day 1, and at 2, 4, 8, 10, 24, 48, 96h post-dose, within 1 h pre-dose on Day 8, 15 and 22, and at 2, 4, 8, 10, 24, 48, 96, 144, 336, 672 h after the last dose for PK analysis.
Secondary outcome [2] 398588 0
PD changes in cell counts of Treg and its subtypes, CD4+ Tconv, CD8+ Tconv and NK cells, and the expression of CD25 and Ki67 in these cells and changes in Cytokines. This is a composite secondary outcome and the method of assessment is using peripheral blood sample for flow cytometry.
Timepoint [2] 398588 0
Part 1:

Samples will be collected within 1 h pre-dose on Day 1, and at 24, 48, 96, 144, 240, 336, 504, and 672h post-dose for PD and cytokine analysis.

Part 2:

Samples will be collected within 1 h pre-dose on Day 1, and at 24, 48, 96h post-dose, and pre-dose on Day 8, 11, 15 and 22, and at 24, 48, 96, 144, 336, 672 h after the last dose for PD and cytokine analysis.
Secondary outcome [3] 398590 0
The number of subject and titer of anti-drug antibody to RS2102. Peripheral Blood sample will be used for analysis..
Timepoint [3] 398590 0
Part 1:

Samples will be collected within 1 h pre-dose, and at 144 hours (D7), 336 hours (D15) and 672 hours (D29) post-dose for Anti-Drug Antibody (ADA) analysis.

Part 2:

Samples will be collected within 1 h pre-dose on Day 1 and 22, and at 144 h (D28), 336 h (D36) and 672 h (D50) post-dose for Anti-Drug Antibody (ADA) analysis.
Secondary outcome [4] 399176 0
Appropriate the neutralization activity for anti-drug antibody to RS2102 will be assessed. Peripheral Blood sample will be used for analysis.
Timepoint [4] 399176 0
Part 1:

Samples will be collected within 1 h pre-dose, and at 144 hours (D7), 336 hours (D15) and 672 hours (D29) post-dose for Anti-Drug Antibody (ADA) analysis.

Part 2:

Samples will be collected within 1 h pre-dose on Day 1 and 22, and at 144 h (D28), 336 h (D36) and 672 h (D50) post-dose for Anti-Drug Antibody (ADA) analysis.
Secondary outcome [5] 399177 0
Cross-reaction to IL-2 will be assessed where feasible. Peripheral Blood sample will be used for analysis.
Timepoint [5] 399177 0
Part 1:

Samples will be collected within 1 h pre-dose, and at 144 hours (D7), 336 hours (D15) and 672 hours (D29) post-dose for Anti-Drug Antibody (ADA) analysis.

Part 2:

Samples will be collected within 1 h pre-dose on Day 1 and 22, and at 144 h (D28), 336 h (D36) and 672 h (D50) post-dose for Anti-Drug Antibody (ADA) analysis.

Eligibility
Key inclusion criteria
1. Subject is a healthy adult subject, male or female, 18 to 55 years of age (inclusive) at the time of informed consent.

2. Subject has a body mass index (BMI equal to weight/height squared) between 18 and 28 kg/m2 (inclusive), and weight of: male greater than or equal to 50 kg and female greater than or equal to 48 kg.

3. Good overall health judged by investigator based on the results of medical history, physical examination, vital signs, laboratory tests, 12-lead ECG, and chest radiography at screening.

4. All female or male subjects and their partners of childbearing potential must be willing to follow contraception requirements as per protocol and all female and male subjects who have egg or sperm donation plan must follow egg or sperm donation requirements.

5. Subject is willing and able to comply with the scheduled visits and treatment plan, laboratory testing and other study procedures.

6. Subject is capable of providing a signed and dated informed consent form (ICF) indicating the subject has been informed of all pertinent aspects of the study described in ICF.
Minimum age
18 Years
Maximum age
55 Years
Gender
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
1) Suspected allergy to the study drug (including IL-2 and polyethylene glycol) or any component of the study drug, or history of anaphylaxis or severe allergic reaction to any drug, food, toxin or other contact exposure per PI discretion.
2) Subject with a history of malignant tumor (except for subjects with non-melanoma skin cancer that was cured more than 2 years ago and cervical intraepithelial neoplasia that was cured more than 5 years ago).
3) Subjects who had undergone any surgery in the previous 3 months prior to screening, or subject has not recovered from prior surgery as judged by investigators, or plan to receive the operation during the study and within 1 month after completing all study visits.
4) Subject with historical or current evidence of clinically significant cardiovascular, neurological, psychiatric, renal, hepatic, immunological, gastrointestinal, urogenital, nervous system, musculoskeletal, skin, sensory, endocrine, or hematological abnormalities, which is considered by the investigator to potentially impact the study results or affect absorption, distribution, metabolism and excretion of drug or places the subjects at unnecessary risk.
5) Active tuberculosis indicated by clinical symptoms, signs, laboratory tests or chest X-ray; latent tuberculosis indicated by T-spot or Quanti-FERON TB test;
6) Subject has investigator judged clinically significant infections within 1 month prior to screening, including acute and chronic infections such as abscess, furuncle, carbuncle and other local infections, respiratory tract infections, urinary and reproductive infections, systemic infections, etc. (Minor skin or respiratory infections that have completely resolved even within 1 month are acceptable at the discretion of the investigator).
7) Subject with any autoimmune diseases or immune dysfunction at screening.
8) Subject participated in any clinical trial of drug or medical device within 2 months prior to screening (or 5 half-lives of drug, whichever is longer).
Subject who is receiving or has a history of receiving any of the following medications:
9) Use of prescription drug within 14 days prior to baseline or during the study (except for hormonal contraception, topical medications at the discretion of the investigator, brief use of medications that are not expected to interfere with safety or data quality at the discretion of the Principal Investigator and Sponsor).
10) Use of over-the-counter drugs, including natural health products (brief use of a supplement in this period that is not expected to interfere with safety or data may be allowed at the discretion of the Principal Investigator and Sponsor) within 14 days prior to baseline, with the exception of occasional use of paracetamol (up to 2 g daily), ibuprofen, or regular doses of vitamins.
11) Subject who has received any live vaccine within 1 month prior to screening or need to receive live vaccine during the study (including 30 days after the last dose of study drug).
Subject who meets any of the following laboratory endpoints in screening or baseline examination:
12) QTc greater than 450 ms or other significant ECG abnormalities with clinical significance as judged by the investigator.
13) White blood cell count, neutrophil count, lymphocyte count or hemoglobin in hematology out of the normal reference range and is judged as clinically significant by the investigator.
14) Alanine aminotransferase (ALT) greater than 1.5 times the upper limit of normal (ULN) and/or aspartate aminotransferase (AST) greater than 1.5 times ULN and/or bilirubin greater than 1.5 times ULN.
15) Subject who is positive for hepatitis B surface antigen, hepatitis B e antigen, anti-hepatitis C virus antibody, syphilis antibody or HIV antibody.
Subject under any of the following general conditions:
16) Smoker: average daily smoking of more than 5 cigarettes (or other nicotine-containing products) at the time of screening.
17) Drinker: positive breath alcohol test (positive with greater than or equal to 0 mg/dL) at screening; or long-term fixed alcohol consumption within 3 months prior to screening, the subject drinks more than 14 units of alcohol per week [1 unit equal to 150 mL of wine, rice wine or low-alcohol liquor, 360 mL of beer, or 45 mL of high-alcohol (Alcohol by volume greater than 40 percentage) liquor].
18) Drug abuser: positive in urine drug screening test.
19) Woman who is pregnant or breastfeeding.
20) At the discretion of the investigator and sponsor, subject is unable to complete the study or otherwise is unsuitable for this study.

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)
1. Randomization Allocation
2. Sealed envelopes
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Use of randomization allocation worksheet provided by statistician
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s

Intervention assignment
Parallel
Other design features
Phase
Phase 1
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
Detailed methodology for summarization and statistical analysis of data collected in this study will be included in the statistical analysis plan (SAP), which will be retained by Reistone Bio-pharma and/or the contract research organization (CRO) designated by the sponsor. Appropriate modifications may be made in the SAP for plans or changes identified in the protocol. However, any significant modifications to the definition and analysis of the primary study endpoint should also be reflected in the protocol amendment.

The study results are mainly described by descriptive statistical method. Unless otherwise specified, the continuous endpoints are generally described by the number of cases, mean, standard deviation, median, minimum and maximum. The binary/categorical endpoints are generally described by numbers and percentages.

PK endpoints (blood concentration and parameters) will be summarized by geometric mean, geometric coefficient of variation, mean, standard deviation, median, maximum and minimum. Demographic and baseline characteristics will be statistically described and listed.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 20032 0
Nucleus Network - Melbourne
Recruitment postcode(s) [1] 34740 0
3004 - Melbourne
Recruitment outside Australia
Country [1] 23996 0
China
State/province [1] 23996 0

Funding & Sponsors
Funding source category [1] 309204 0
Commercial sector/Industry
Name [1] 309204 0
Atridia Pty Ltd
Address [1] 309204 0
Suite202, 46 Market St
Sydney NSW 2000
AUSTRALIA
Country [1] 309204 0
Australia
Primary sponsor type
Commercial sector/Industry
Name
Atridia Pty Ltd
Address
Suite202, 46 Market St
Sydney NSW 2000
AUSTRALIA
Country
Australia
Secondary sponsor category [1] 310164 0
None
Name [1] 310164 0
Address [1] 310164 0
Country [1] 310164 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 309057 0
Alfred Hospital Ethics Committee
Ethics committee address [1] 309057 0
55 Commercial Road, Melbourne 3004 VIC
Ethics committee country [1] 309057 0
Australia
Date submitted for ethics approval [1] 309057 0
24/06/2021
Approval date [1] 309057 0
16/07/2021
Ethics approval number [1] 309057 0

Summary
Brief summary
Systemic lupus erythematosus (SLE) is an autoimmune disease with multiple organ involvement characterized by chronic immune activation, severe inflammation and organ damage. Although multiple genetic and environmental factors act synergistically to promote immunopathology and tissue damage in SLE patients, dysregulation of cytokines plays an important role in SLE patients. Interleukin 2 (IL-2) deficiency has been implicated in SLE progression and immunopathology in SLE patients.

RS2102 is PEG-modified, N88R-mutated IL-2. N88R mutation reduces the affinity of RS2102 for Interleukin-2 Receptor beta and gamma chains and further improves the selectivity of RS2102 binding to Interleukin-2 Receptor alpha, beta and gamma chains, allowing it specifically activate Treg cells. Meanwhile, PEG modification can prolong the half-life of RS2102 in vivo and maintain the efficacy duration. Therefore, RS2102 can be used for the treatment of autoimmune diseases such as SLE by specifically binding Interleukin-2 Receptor alpha, beta and gamma chains and activating Treg cells, which are expected to be administered once every 2 weeks in clinical settings.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 112818 0
Dr Ben Snyder
Address 112818 0
Nucleus Network
5th Floor, Burnet Tower, AMREP Precinct,
89 Commercial Road, Melbourne, Victoria 3004, Australia
Country 112818 0
Australia
Phone 112818 0
+61335939817
Fax 112818 0
+61(03)90768911
Email 112818 0
b.snyder@nucleusnetwork.com.au
Contact person for public queries
Name 112819 0
Ms Raina Patel
Address 112819 0
Reistone Biopharma
29-126 to 129 Floor
1 Lincoln Street
Massachusetts, USA MA 01001
Country 112819 0
United States of America
Phone 112819 0
+16306777246
Fax 112819 0
Email 112819 0
raina.patel@reistonebio.com
Contact person for scientific queries
Name 112820 0
Dr Ben Snyder
Address 112820 0
Nucleus Network
5th Floor, Burnet Tower, AMREP Precinct,
89 Commercial Road, Melbourne, Victoria 3004, Australia
Country 112820 0
Australia
Phone 112820 0
+61335939817
Fax 112820 0
+61 (03) 9076 8911
Email 112820 0
b.snyder@nucleusnetwork.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
What supporting documents are/will be available?
No other documents available
Summary results
No Results