Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12622001387718
Ethics application status
Approved
Date submitted
4/10/2022
Date registered
28/10/2022
Date last updated
28/01/2024
Date data sharing statement initially provided
28/10/2022
Date results information initially provided
6/11/2023
Type of registration
Prospectively registered

Titles & IDs
Public title
A first-in-human study to investigate subcutaneous doses of SAR444559 compared with placebo in healthy adult participants.
Scientific title
A randomized, double-blind, placebo-controlled, phase 1, single centre, First-in-human, two-part study to investigate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity of single (SAD17442) and multiple (MAD17443) ascending, subcutaneous doses of SAR444559 in healthy adult participants.
Secondary ID [1] 308101 0
SAD17442-MAD17443
Universal Trial Number (UTN)
U1111-1278-4028
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Autoimmune disorder 327800 0
Condition category
Condition code
Inflammatory and Immune System 324871 324871 0 0
Autoimmune diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Part 1:
SAR444559: Single dose administration of SAR444559 on Day 1, of approximatively 9 single ascending dose levels. The starting dose will be 0.03 mg.

Treatment duration will be 7 weeks, including a 4-day in-house institutionalisation period after single dose administration and a follow-up period up to the end of study (EOS) visit.

Mode of administration: Subcutaneous (SC) injection administered by the clinical study site staff in the clinical study center. The dose increment factors for dose escalation will be based on the observed cell depletion and may be adjusted following emerging safety and tolerability.

Part 2:
SAR444559: Multiple dose administrations of SAR444559 every 2 weeks (Q2W) on days 1, 15, and 29, of up to 3 ascending repeated dose levels.
The starting dose of part 2 will be determined upon review of adverse event, PK and PD data from Part 1 by a safety review committee. The dose increment factors for dose escalation will be based on the observed cell depletion and may be adjusted following emerging safety, tolerability.

Treatment duration will be approximately 11 weeks including 4-day in-house institutionalisation periods after each dose administration (3 total doses) and follow-up periods between and after each of the three institutionalizations up to the end of study (EOS) visit. Mode of administration: SC injections administered by the clinical study site staff in the clinical study centre.

Participants in part 1 and part 2 are recruited independently, and part 2 will be undertaken in unique participant cohorts.

The strategies used to monitor adherence to and/or fidelity of the intervention will include supervised administration at site, appropriate record of each administration information, and double confirmation of the dosing by another member of the study site staff other than the one administrating the study intervention.
Intervention code [1] 324553 0
Treatment: Drugs
Comparator / control treatment
Part 1:
Placebo: Single dose administration of matching placebo dosages, SC injection.
The composition of the placebo treatment: Histidine 20 mM, sucrose 8 % w/v, PS80 0.08 % w/v, pH 6.0
Part 2:
Placebo: Multiple dose administration of matching placebo dosages, SC injections.
The composition of the placebo treatment: Histidine 20 mM, sucrose 8 % w/v, PS80 0.08 % w/v, pH 6.0
Control group
Placebo

Outcomes
Primary outcome [1] 332685 0
Number of participants with adverse events (AEs) /treatment-emergent adverse events (TEAEs): by assessment of vital signs (heart rate [pulse oximeter], systolic and diastolic blood pressure [in a seated and standing position using an automated BP monitor], body temperature [using an ear thermometer], respiratory rate [pulse oximeter]), clinical laboratory evaluations (haematology, liver function, renal function, serology for hepatitis, vaccine titres) assessed using blood samples, and 12-lead ECG.
Timepoint [1] 332685 0
Part 1: Baseline up to end of study (Day 50)
- Vital signs assessed at Baseline, 24, 48, 72, 96, 168, 240, 336, 504, 672, 840, 1008, 1176 hours post-single dose
- Blood samples collected at Baseline, 24, 72, 96, 168, 336, 672, 1008, 1176 hours post-dose
- 12-lead ECG performed at Baseline, 24, 48, 72, 96, 168, 336, 672, 1176 hours post-dose

Part 2: Baseline up to end of study (Day 78)
- Vital signs assessed at Baseline, and 24, 48, 72, 168 and 312 hours post first dose. 0 hours (prior to second dose), and 24, 48, 72, 168, 312 hours after second dose. 0 hours (prior to third dose), and 24, 48, 72, 168, 336, 504, 672, 840 and 1176 hours after third dose.
- Blood samples collected the day before Baseline, at Baseline, and 24, 72, 168 and 312 hours post first dose. 1 day prior to second dose, and 24, 72 and 312 hours after second dose. 1 day before third dose, 24, 72, 336, 672 and 1176 after third dose
- 12-lead ECG performed at Baseline, 48 and 72 hours post first dose. 0 hours prior to second dose, and 48 and 72 hours after second dose. 0 hours prior to third dose, and 48, 72, 336, 672 and 1176 hours after third dose.
Primary outcome [2] 336417 0
Comprehensive ophthalmic examination outcomes: Assessment of eye lid, cornea, iris, lens, anterior chamber, vitreous body, retina, macula, optic nerve, fraction, visual acuity, intraocular pressure. Methods used for the assessment/measurement include Uncorrected or CVA with patient glasses, Standard Luminance EDTRS BCVA, Goldmann Applanation Tonometry, Gonioscopy, Anterior Segment OCT and IOL Master, SD-OCT and OPTOS, Slit lamp biomicrospcopy, dilated ophthalmoscopy, Posterior Segment US (B Scan).
Timepoint [2] 336417 0
Primary outcome [3] 336418 0
Comprehensive ophthalmic examination outcomes: Assessment of eye lid, cornea, iris, lens, anterior chamber, vitreous body, retina, macula, optic nerve, fraction, visual acuity, intraocular pressure. Methods used for the assessment/measurement include Uncorrected or CVA with patient glasses, Standard Luminance EDTRS BCVA, Goldmann Applanation Tonometry, Gonioscopy, Anterior Segment OCT and IOL Master, SD-OCT and OPTOS, Slit lamp biomicrospcopy, dilated ophthalmoscopy, Posterior Segment US (B Scan).
Timepoint [3] 336418 0
Part 1: Baseline up to end of study (Day 50)
Ophthalmologic examination at: Baseline, 48, 168 and 1176 hours post single dose, as well as at any time (in case of) the participant experiences ocular signs or symptoms, including, eg, blurred vision, narrowed vision (tunnel vision) or blind spots, discomfort, eye pain or pressure with or without headache/nausea/vomiting, loss of vision, red eyes, dry eyes.
Part 2: Baseline up to end of study (Day 78)
Ophthalmologic examination at: Baseline, 48 hours post first dose, 48 hours after second dose, 48 and 1176 hours after third dose, as well as at any time (in case of) the participant experiences ocular signs or symptoms, including, eg, blurred vision, narrowed vision (tunnel vision) or blind spots, discomfort, eye pain or pressure with or without headache/nausea/vomiting, loss of vision, red eyes, dry eyes.
Secondary outcome [1] 414369 0
Assessment of pharmacokinetic (PK) parameters using blood samples: at least Cmax, Tmax, AUClast, AUC (part 1) and AUC0-tau (part 2)
Timepoint [1] 414369 0
Part 1: Baseline up to end of study (Day 50)
Blood samples collected at: Baseline, 24, 48, 72, 96, 168, 240, 336, 504, 672, 840, 1008 and 1176 hours post single dose.

Part 2: Baseline up to end of study (Day 78)
Blood samples collected at: Baseline, and 24, 48, 72 and 168 hours post first dose. 0 hours prior to second dose, and 72 hours after second dose. 0 hours prior to third dose, and 24, 48, 72, 168, 336, 504, 672, 840, 1176 hours after third dose.
Secondary outcome [2] 414370 0
Anti-SAR444559 antibodies using blood samples
Timepoint [2] 414370 0
Part 1: Baseline up to end of study (Day 50)
Blood samples will be collected: at Baseline, and 168, 672, 1176 hours post single dose.

Part 2: Baseline up to end of study (Day 78)
Blood samples will be collected: at Baseline and 168 hours post first dose, 0 hours prior to third dose, and 336 and 1176 hours after third dose.
Secondary outcome [3] 415196 0
Exploratory:
Assessment of PD parameters using blood samples: CD38 expressing white blood cells measured by Fluorescence activated cell shortening (FACS)
Timepoint [3] 415196 0
Part 1: Baseline up to end of study (Day 50)
Blood samples will be collected: at Baseline, and 24, 48, 96, 168, 336, 672 and 1176 hours after single dose.
Part 2: Baseline up to end of study (Day 78)
Blood samples will be collected: at Baseline, and 24 hours after first dose, 0 hours prior to second dose, and 0 hours prior to third dose and 24, 336, 672 and 1176 hours after third dose.

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 within 50 to 100 kg and body mass index (BMI) within the range 18 to 32 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
Male participants who agree to refrain from donating and cryopreservating sperm
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:
-History or presence of cardiovascular, respiratory (excluding fully resolved childhood asthma with no history of hospitalization), hepatic, renal, gastrointestinal, endocrinological, hematological, or neurological disorders capable of significantly altering the absorption, metabolism, or elimination of drugs; constituting a risk when taking the study intervention; or interfering with the interpretation of data.
- Significant ocular disease including but not limited to any history of glaucoma, any retinal pathology or history of retinal issues including retinal tears/holes/detachment, history of ocular inflammation/uveitis, moderate/severe refractive errors, pathologic gonioscopy result, and shallow anterior chamber.
-Live vaccines: Last administration of a vaccine within 3 months before randomization.

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)
Randomization lists for each study part are generated by Sanofi and will be provided to the unblinded pharmacist. The open randomization list will be filed in a sealed envelope with tamper-proof adhesive tape and stored at the pharmacy. The study interventions will be allocated in accordance with those lists by the unblinded pharmacist. Investigators will remain blinded to each participant’s assigned study intervention throughout the course of the study.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)

Permuted block randomisation
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
Parallel
Other design features
Single-center, randomized, double-blind, parallel group, single and repeated dose escalation study.
Phase
Phase 1
Type of endpoint/s
Safety
Statistical methods / analysis

Recruitment
Recruitment status
Stopped early
Data analysis
Data collected is being analysed
Reason for early stopping/withdrawal
Safety concerns
Date of first participant enrolment
Anticipated
5/12/2022
Actual
6/12/2022
Date of last participant enrolment
Anticipated
15/04/2024
Actual
9/10/2023
Date of last data collection
Anticipated
27/11/2023
Actual
7/12/2023
Sample size
Target
102
Accrual to date
Final
40
Recruitment in Australia
Recruitment state(s)
QLD,VIC
Recruitment hospital [1] 23302 0
Q-Pharm Pty - Clive Berghofer Research Centre (CBCRC) - Herston
Recruitment postcode(s) [1] 38675 0
4007 - Herston

Funding & Sponsors
Funding source category [1] 312358 0
Commercial sector/Industry
Name [1] 312358 0
Sanofi-Aventis R&D
Country [1] 312358 0
France
Primary sponsor type
Commercial sector/Industry
Name
Sanofi-Aventis Australia Pty Ltd
Address
12-24 Talavera Rd, Macquarie Park, NSW 2113
Country
Australia
Secondary sponsor category [1] 313921 0
Commercial sector/Industry
Name [1] 313921 0
Sanofi-Aventis R&D
Address [1] 313921 0
1 avenue Pierre Brossolette
91380 Chilly-Mazarin Cedex
Country [1] 313921 0
France

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 311718 0
Alfred Hospital Ethics Committee
Ethics committee address [1] 311718 0
55 Commercial Rd, Melbourne, VIC 3004
Ethics committee country [1] 311718 0
Australia
Date submitted for ethics approval [1] 311718 0
05/10/2022
Approval date [1] 311718 0
02/11/2022
Ethics approval number [1] 311718 0

Summary
Brief summary
This is a parallel, randomized, placebo-controlled, two-part, Phase 1, Investigator- and participant blinded, first-in-human (FIH) study to assess the safety, tolerability, pharmacokinetic (PK), pharmacodynamic (PD) profiles, and immunogenicity of single (SAD17442) and multiple (MAD17443) ascending, subcutaneous doses of SAR444559 in male and female healthy participants aged 18 to 55 years.
Part 1 – SAD17442:
- The study duration per participant will be up to 12 weeks, including screening period.
- The treatment duration will be 7 weeks including a 4-day in-house institutionalization period after single dose administration and a follow-up period up to the end of study (EOS) visit.
PD is as assessed as exploratory part of the protocol.
The number of visits will be 10 ambulatory on-site visits and one 4-day in-house period, and 4 to 5 ambulatory visits to the ophthalmologist.
Part 2 – MAD17443:
- The study duration per participant will be approximately 16 weeks, including screening period and treatment period of 11 weeks.
- The treatment duration will be approximately 11 weeks including 4-day in-house institutionalization periods after each dose administration (3 total doses) and follow-up periods between and after each of the three institutionalizations up to the end of study (EOS) visit.
PD is as assessed as exploratory part of the protocol. The number of visits will be 10 ambulatory on-site visits and three 4-day in-house periods, and 4 to 5 ambulatory visits to the ophthalmologist.
Trial website
Trial related presentations / publications
Public notes
Participants not fully vaccinated against COVID-19 according to local guidelines and those having received non-live vaccines including COVID-19 with last administration of a vaccine within 1 month before randomization are excluded from participation in this study

Contacts
Principal investigator
Name 122118 0
Dr Richard Friend
Address 122118 0
Level 5 Clive Berghofer Cancer Centre Research Centre,
300 Herston Road, Herston, QLD 4006
Country 122118 0
Australia
Phone 122118 0
+610439726233
Fax 122118 0
Email 122118 0
r.friend@nucleusnetwork.com.au
Contact person for public queries
Name 122119 0
Dr Nucleus Network Brisbane
Address 122119 0
Level 5 Clive Berghofer Cancer Centre Research Centre,
300 Herston Road, Herston, QLD 4006
Country 122119 0
Australia
Phone 122119 0
+61 1800 243 733
Fax 122119 0
Email 122119 0
brisbane@nucleusnetwork.com
Contact person for scientific queries
Name 122120 0
Dr Richard Friend
Address 122120 0
Level 5 Clive Berghofer Cancer Centre Research Centre,
300 Herston Road, Herston, QLD 4006
Country 122120 0
Australia
Phone 122120 0
+61 7 3707 2720
Fax 122120 0
Email 122120 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?
Researchers may enquire about the availability of data from Sanofi sponsored clinical trials using the Vivli Enquiry Form (https://vivli.org/members/enquiries-about-studies-not-listed-on-the-vivli-platform/).


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
17251Clinical study report    Researchers may enquire about the availability of ... [More Details]



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