ANZCTR - Registration

Registration number

ACTRN12621001161819

Ethics application status

Approved

Date submitted

20/07/2021

Date registered

27/08/2021

Date last updated

10/02/2023

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]

None

Universal Trial Number (UTN)

Trial acronym

Linked study record

Health condition

Health condition(s) or problem(s) studied:

Systemic lupus erythematosus

Condition category

Condition code

Inflammatory and Immune System

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]

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]

Safety and tolerability outcomes based on review of AEs, vital signs, ECGs, laboratory findings, physical exams and injection site reaction

Timepoint [1]

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]

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]

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]

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]

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]

The number of subject and titer of anti-drug antibody to RS2102. Peripheral Blood sample will be used for analysis..

Timepoint [3]

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]

Appropriate the neutralization activity for anti-drug antibody to RS2102 will be assessed. Peripheral Blood sample will be used for analysis.

Timepoint [4]

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]

Cross-reaction to IL-2 will be assessed where feasible. Peripheral Blood sample will be used for analysis.

Timepoint [5]

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

Sex

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

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

Completed

Date of first participant enrolment

Anticipated

30/08/2021

Actual

30/08/2021

Date of last participant enrolment

Anticipated

16/03/2022

Actual

18/08/2022

Date of last data collection

Anticipated

5/05/2022

Actual

22/09/2022

Sample size

Target

56

Accrual to date

Final

56

Recruitment in Australia

Recruitment state(s)

VIC

Recruitment hospital [1]

Nucleus Network - Melbourne

Recruitment postcode(s) [1]

3004 - Melbourne

Recruitment outside Australia

Country [1]

China

State/province [1]

Funding & Sponsors

Funding source category [1]

Commercial sector/Industry

Name [1]

Atridia Pty Ltd

Country [1]

Australia

Primary sponsor type

Commercial sector/Industry

Name

Atridia Pty Ltd

Country

Australia

Secondary sponsor category [1]

None

Name [1]

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Alfred Hospital Ethics Committee

Ethics committee address [1]

55 Commercial Road, Melbourne 3004 VIC

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

24/06/2021

Approval date [1]

16/07/2021

Ethics approval number [1]

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

Public notes

Contacts

Principal investigator

Name

Dr Dr Ofer Gonen

Address

Nucleus Network
5th Floor, Burnet Tower, AMREP Precinct,
89 Commercial Road, Melbourne, Victoria 3004, Australia

Country

Australia

Phone

+61335939817

Email

[email protected]

Contact person for public queries

Name

Fiona Zhang

Address

Reistone Biopharma Co. Ltd., 298 Xiangke Road, 2/F, 203, Zhangjiang, Hi-Tech Park, Pudong, Shanghai, China

Country

China

Phone

+18817582504

Email

[email protected]

Contact person for scientific queries

Name

Dr Ofer Gonen

Address

Nucleus Network
5th Floor, Burnet Tower, AMREP Precinct,
89 Commercial Road, Melbourne, Victoria 3004, Australia

Country

Australia

Phone

+61335939817

Email

[email protected]

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