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Trial registered on ANZCTR


Registration number
ACTRN12623001176651
Ethics application status
Approved
Date submitted
19/09/2023
Date registered
14/11/2023
Date last updated
14/01/2024
Date data sharing statement initially provided
14/11/2023
Type of registration
Prospectively registered

Titles & IDs
Public title
A randomized, double-blind, placebo-controlled study of the safety, tolerability, pharmacokinetics and pharmacodynamics of ascending single and multiple doses of SAR446422 in healthy, adult participants
Scientific title
A randomized, placebo-controlled, sequential, participant- and Investigator-masked
Phase 1 study to assess the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics ( PD) of ascending single and multiple doses of SAR446422 in female and male healthy participants 18 to 55 years of age
Secondary ID [1] 310099 0
Nil known
Universal Trial Number (UTN)
U1111-1295-2764
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Severe Autoimmune Disease 330669 0
Condition category
Condition code
Inflammatory and Immune System 327484 327484 0 0
Autoimmune diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
SAR446422
• Formulation: Powder for solution for injection and infusion supplied in a single-use glass vial. Each vial contains 100 mg SAR446422. A precoating solution supplied with SAR446422 is used to coat infusion bags in order to prevent adsorption of SAR446422 to the bag.
• Routes of administration: Intravenous (IV) infusion or Subcutaneous ( SC) injection.
• Dose regimen:
Part 1:
- The single ascending dose (SAD) study will include up to 9 cohorts treated with ascending doses, each cohort with single dose, including 5 cohorts of IV infusion with an expected dose range of 0.3 to 30 mg IV infusion followed by up to 4 cohorts with an expected dose range of 75 to 500 mg or less SC injection.
Part 2:
- The multiple ascending dose (MAD) study will include up to 4 cohorts treated with ascending SC doses with expected doses of up to 30, 60, or 120 mg. Dosing will be SC injection Q2W(Every 2 Weeks) with a total of 3 doses. In the optional MAD cohort (MAD4), any dose lower or higher than in MAD1 through MAD3 may be selected as long as the resulting predicted exposure is lower than the highest exposure in SAD study.
- SC administration for cohort 6 and higher in part1, and part2, since it will be mode of administration in later clinical development, For the safety feature, Cohort1-5 in part1 is planned to be administrated by IV infusion. The infusion duration is planned approx. 60mins, there will be an opportunity to stop infusion if acute AEs are observed.
- The doses in SAD study and MAD study may be changed based on emerging safety data and PK(Pharmacokinetics), PD(Pharmacodynamics) and ADA (Anti-Drug Antibodies) results
. the same group of participants will undertake only one part
A nurse will administer the dosage.

KLH (keyhole limpet hemocyanin)
KLH (Immucothel (Biosyn Corporation) will be used for immunization and DTH challenge in
SAD17875 and MAD17876.
• Formulation: 54.63 mg powder containing 1 mg KLH and one ampoule with 1 mL solvent,
for injection after reconstitution
• Routes of administration: IM (intramuscular injection) for immunization and ID (intradermal) for the DTH (delayed-type hypersensitivity) challenge.

• Dose regimen:
- for immunization, 100 µg of subunit KLH adsorbed to 900 µg aluminum hydroxide
(acting as adjuvant for KLH immunization) will be injected IM on Days -12 and 3 (SAD17875 Cohort 3 and higher) and Days 8 and 22 (MAD17876) in the left deltoid muscle. While the planned interval between the first KLH/aluminum IM injection and IMP administration is 12 days, this interval can be as short as 10 days and as long as
14 days.
- for the DTH challenge in SAD17875 (Cohort 3 and higher), on Day 17, 1 µg KLH (no adjuvant) will be injected ID in the left forearm (for imaging) and another 1 µg KLH (no adjuvant) will be injected ID at 1 site on the back (between the shoulder blades) (for biopsy 48 hours post injection on Day 19). For the DTH challenge in MAD17876, on Day 36, 1 µg KLH (no adjuvant) will be injected ID in the left forearm (for imaging) and another 1 µg KLH (no adjuvant) will be injected ID at 1 site on the back (between the shoulder blades) (for biopsy 48 hours post injection on Day 38). The ID injection can be administered in a sitting, semi-supine or supine position
KLH control
• Formulation: 0.9% NaCl solution.
• Route of administration: ID.
• Dose regimen: there will be no control or placebo for the immunization with KLH/aluminum hydroxide, all participants in Cohort 3 and higher will receive the active
immunization. KLH control will be injected on D17 in part 1 and D36 in part 2.
As control for the DTH challenge, the same volume as the ID KLH dose described above, injected on Day 17 (SAD17875 Cohort 3 and higher) and Day 36 (MAD17876) in the right forearm and at a site on the back approximately 10 cm from the site of KLH injection (for biopsy 48 hours post injection on Day 38).
Precoating solution
• Formulation: Coating solution for infusion supplied in a single-use glass vial. Each vial contains 16 mL precoating solution (48 mg polysorbate 80).
• Routes of administration: IV infusion.
• Dose regimen: IV dosages for which the infusion bag is required.
Aluminum hydroxide
Aluminum hydroxide (Alhydrogel, Croda International) will be used as adjuvant for KLH
immunization in SAD17875 and MAD17876.
• Formulation: 900 µg aluminum hydroxide adsorbed to KLH.
• Route of administration: IM.
• Dose regimen: as described above for KLH adsorbed to aluminum hydroxide.
Intervention code [1] 326501 0
Treatment: Drugs
Comparator / control treatment
Placebo IV
• Formulation: isotonic saline solution.
• Routes of administration: Intravenous (IV) injection
• Dose regimen: same frequency and same volume for the final formulation of the IMP as for SAR446422 in the corresponding cohort and same posture requirements.
Placebo SC
• Formulation: isotonic saline solution for injection supplied in a single-use glass vial. Each vial contains 8 mL placebo.
• Routes of administration: Subcutaneous ( SC) injection.
• Dose regimen: same frequency and same volume for the final formulation of the IMP (investigational medicinal product) as for SAR446422 in the corresponding cohort and same posture requirements and options for injection location as for SAR446422.
Control group
Placebo

Outcomes
Primary outcome [1] 335350 0
Number of participants with adverse events (AEs) /treatment-emergent adverse events (TEAEs), including injection site reactions: by assessment of vital signs (heart rate, systolic and diastolic blood pressure [in a seated and standing position using an automated BP monitor], body temperature [using an ear thermometer], clinical laboratory evaluations (hematology, biochemistry, coagulation, urinalysis) assessed using blood samples, and 12-lead ECG.
Timepoint [1] 335350 0
Part 1 Cohort1-2: Baseline up to end of study (Day 85)
- Vital signs assessed at Baseline, D1 (pre-dose, 0.5, 1, 4, 8 hours post-dose), D2, D3, D4, D5, D6, D8, D15, D22, D29, D36, D43, D57, and D85
- Blood samples collected at Baseline, D2, D6, D8, D15, D22, D29, D36, D43, D57, and D85
- 12-lead ECG performed at Baseline, D1 (0.5, 1, 4, 8 hours post-dose), D2, D3, D4, D5, D6, D8, D15, D22, D29, D36, D43, D57, and D85

Part 1 Cohort3-9:
- Vital signs assessed at Baseline, D-12, D1 (pre-dose, 0.5, 1, 4, 8 hours post-dose), D2, D3, D4, D5, D6, D8, D15, D22, D29, D36, D43, D57, and D85
- Blood samples collected at Baseline, D2, D6, D8, D15, D22, D29, D36, D43, D57, and D85
- 12-lead ECG performed at Baseline, D1 (0.5, 1, 4, 8 hours post-dose), D2, D3, D4, D5, D6, D8, D15, D22, D29, D36, D43, D57, and D85

Part 2: Baseline up to end of study (Day 113)
- Vital signs assessed at Baseline, D1 (prior to first dose, 8hours post-first dose), D2, D3, D4, D8, D9, D15 (prior to second dose, 8hours post-second dose), and D16, D17, D18, D22, D23, D29 (prior to third dose, 8hours post-second dose), D30, D31, D32, D36, D43, D50, D57, D71, D85, and D113
- Blood samples collected at Baseline and D2, D3, D4, D8, D14, D16, D17, D18, D22, D28, D30, D31, D32, D36, D43, D50, D57, D71, D85, and D113
- 12-lead ECG performed at D1 (prior to first dose, 8 hours post-dose), D2, D3, D4, D8, D15 (prior to second dose, 8 hours post-dose), D18, D29 (prior to third dose, 8 hours post-dose), D30, D31, D32, D36, D43, D50, D57, D71, D85, and D113
Secondary outcome [1] 424030 0
Part1:Assessment of pharmacokinetic (PK) parameters using blood samples:
IV: Cmax, Tmax, AUClast, AUC, t1/2z, CL, Vss;
SC: Cmax, tmax, AUClast, AUC, F, t1/2z, CL/F, Vz/F
Part2:Assessment of pharmacokinetic (PK) parameters using blood samples:
• D1 (AUCtau, tmax, Cmax)
• D15 (Ctrough)
• D29 (Cmax, tmax, AUCtau, Ctrough, t1/2z)
Timepoint [1] 424030 0
Part 1: Baseline up to end of study (Day 85)
Cohort 1 to 5 (IV dosing):
Blood samples collected at: Baseline, D1(0.5, 1, 4, 8 hours post-dose), D2, D3, D4, D5 , D6, D8, D15, D22, D29, D36, D43, and D85
Cohort 6 to 9 (SC dosing):
Blood samples collected at: Baseline, D1 (8hours post-dose), D2, D3, D4, D5 , D6, D8, D15, D22, D29, D36, D43, and D85

Part 2: Baseline up to end of study (Day 113)
Blood samples collected at: D1(prior to first dose, 8 hours post-dose), D2, D3, D4, D8, D15 before second dose, D29 (prior to third dose, 8 hours post-dose) and D30, D31, D32, D36, D43, D50, D57, D71, D85, D112
Secondary outcome [2] 424039 0
Anti-drug antibodies against SAR446422 using blood samples
Timepoint [2] 424039 0
Part 1: Baseline up to end of study (Day 85)
Blood samples collected at: D1, D15, D29, and D85
Part 2: Baseline up to end of study (Day 113)
Blood samples collected at: D1, D15 (prior to second dose), D29 (prior to third dose)and D113
Secondary outcome [3] 424040 0
Circulating immunoglobulin G antibodies against
KLH (Keyhole limpet hemocyanin) using blood samples
Timepoint [3] 424040 0
Part 1:
Blood samples collected at: D-12 pre-KLH administration, D-5, D1 pre-dose, D3 before KLH injection, D10, D17 (before KLH ID injection), D22, D29, and D36
Part 2:
Blood samples collected at: D1 pre-dose, D8 (before KLH injection), D15 (prior to second dose), D22 (before KLH injection), D29 (prior to third dose), D36 (before KLH injection), D43, D50, and D57
Secondary outcome [4] 424109 0
Skin erythema measured by photography
Timepoint [4] 424109 0
Cohort3-9 in Part 1
Conducted at: D17 (before KLH ID injection), D18, and D19.
Part 2:
Conducted at: D36 (before KLH injection), D37, and D38,.
Secondary outcome [5] 427476 0
skin blood perfusion measured by laser speckle contrast imaging (LSCI)
Timepoint [5] 427476 0
Cohort3-9 in Part 1
Conducted at: D17 (before KLH ID injection), D18, and D19.
Part 2:
Conducted at: D36 (before KLH injection), D37, and D38,.

Eligibility
Key inclusion criteria
Participants who are overtly healthy as determined by medical evaluation including medical/surgical history, physical examination, laboratory tests, and cardiac monitoring. Body weight between 50.0 and 110.0 kg, inclusive, if male, and between 40.0 and 90.0 kg, inclusive, if female, BMI between 18.0 and 32.0 kg/m2, inclusive.
A female participant not pregnant or breastfeeding, and one of the following conditions applies:
-- Is a woman of non-child-bearing potential (WONCBP) or
-- Is a woman of child-bearing potential (WOCBP) and agrees to use a contraceptive method that is highly effective
--A WOCBP must have a negative highly sensitive pregnancy test ([urine or serum] as required by local regulation) within 36 hours before the first administration of study intervention.
Male participants who agree to:
-- refrain from donating sperm;
-- Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis) and agree to remain abstinent;
OR
--Must agree to use contraception/barrier.
Minimum age
18 Years
Maximum age
55 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
Participants are excluded from the study if any of the following criteria apply:
-Any history or presence of clinically relevant cardiovascular, pulmonary, gastrointestinal, hepatic, renal, metabolic, hematological, neurological, osteomuscular, articular, psychiatric, systemic, ocular, gynecologic (if female), immunological or infectious disease, or signs of acute illness.
- Presence or history of drug hypersensitivity, or allergic disease diagnosed and treated by a physician. Anaphylaxis from any cause. Known hypersensitivity to any component of the IMP formulation. Previous exposure to KLH or hypersensitivity to shellfish. History of mild, controlled allergy may be included at Investigator’s discretion.
- Any immunization with a non-live vaccine, including against COVID-19, within 4 weeks of enrollment (SAD study Cohort 1 and 2, MAD study) or within 2 weeks of enrollment (SAD study Cohort 3 and higher).
- Any immunization with a live vaccine within 3 months of enrollment.
- Symptomatic herpes zoster within 3 months prior to Screening.
- History of recurrent oral or genital herpes.
- Evidence of active or latent TB as documented by medical history and examination, chest X-rays or a positive QuantiFERON-TB Gold Plus test.
- History of invasive opportunistic infections such as histoplasmosis, listeriosis, coccidioidomycosis, candidiasis, pneumocystis jirovecii, aspergillosis, irrespective of resolution.

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)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Who is / are masked / blinded?



Intervention assignment
Other design features
Phase
Phase 1
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
5/12/2023
Actual
5/12/2023
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
120
Accrual to date
8
Final
Recruitment in Australia
Recruitment state(s)
QLD

Funding & Sponsors
Funding source category [1] 314262 0
Commercial sector/Industry
Name [1] 314262 0
Sanofi-Aventis R&D
Country [1] 314262 0
France
Primary sponsor type
Commercial sector/Industry
Name
Sanofi-Aventis Australia Pty Ltd
Address
Talavera Corporate Centre, Building D, 12-24 Talavera Rd, Macquarie Park, NSW 2113
Country
Australia
Secondary sponsor category [1] 316201 0
None
Name [1] 316201 0
Address [1] 316201 0
Country [1] 316201 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 313381 0
Alfred Hospital Ethics Committee
Ethics committee address [1] 313381 0
55 Commercial Rd, Melbourne, VIC 3004
Ethics committee country [1] 313381 0
Australia
Date submitted for ethics approval [1] 313381 0
04/10/2023
Approval date [1] 313381 0
31/10/2023
Ethics approval number [1] 313381 0

Summary
Brief summary
This is a randomized, placebo-controlled, sequential, participant- and Investigator-masked
Phase 1 study to assess the safety, tolerability, PK, and PD of ascending single and multiple doses
of SAR446422 in female and male healthy participants 18 to 55 years of age.

Number of participants:
Up to 120 participants will be randomized to study intervention at a single study site.

Part1-SAD17875: approximately 9 dose level cohorts with 8 participants per cohort (6 active and 2 placebo). The last cohort will be optional.

Part2-MAD17876: approximately 4 dose level cohorts with 12 participants per cohort (9 active and 3 placebo). The last cohort will be optional.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 127950 0
Dr Richard Friend
Address 127950 0
Q-Pharm Pty, Level 5 Clive Berghofer Research Centre (CBRC), Herston, QLD 4007
Country 127950 0
Australia
Phone 127950 0
+61 403 415 925
Fax 127950 0
Email 127950 0
r.friend@nucleusnetwork.com.au
Contact person for public queries
Name 127951 0
Mr Nucleus Network Brisbane
Address 127951 0
Level 5 Clive Berghofer Cancer Centre Research Centre, 300C Herston Road, Herston, QLD 4006
Country 127951 0
Australia
Phone 127951 0
+61 1800 243 733
Fax 127951 0
Email 127951 0
brisbane@nucleusnetwork.com
Contact person for scientific queries
Name 127952 0
Dr Richard Friend
Address 127952 0
Q-Pharm Pty, Level 5 Clive Berghofer Research Centre (CBRC), Herston, QLD 4007
Country 127952 0
Australia
Phone 127952 0
+61 737072720
Fax 127952 0
Email 127952 0
r.friend@nucleusnetwork.com.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
Individual participant data of published results only.
When will data be available (start and end dates)?
Immediately following publication, no end date defined.
Available to whom?
Case-by-case basis at the discretion of Primary Sponsor.
Available for what types of analyses?
Data to achieve the aims in the approved proposal.
How or where can data be obtained?
Access subject to approval by Primary Sponsor (email address: contact-us@sanofi.com)


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
19674Clinical study report    Access subject to approval by Primary Sponsor (ema... [More Details]



Results publications and other study-related documents

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