A single, ascending-dose design with five dose-cohorts of 8 subjects. Forty healthy adults aged 18 to 45, inclusive, will be recruited and admitted at multiple sites. Each subject will be randomized to receive either SAR440894 or matching placebo via 60-minute intravenous infusion. In each cohort of 8 subjects, the randomization ratio will be 6 active to 2 placebo, and 2 sentinel subjects (one from each active and placebo group) will be dosed first. Dosing of the next dose-cohort will be dependent on acceptable meeting predefined safety criteria in the preceding cohort. Each subject's participation will take place over approximately 150 days, not including the screening visit. There are no hypotheses for this phase I study. The primary objective will be to determine the safety of single ascending intravenous (IV) infusions of SAR440894 when administered in healthy adults.
A single, ascending-dose design with five dose-cohorts of 8 subjects. Forty healthy adults aged 18 to 45, inclusive, will be recruited and admitted at multiple sites. Each subject will be randomized to receive either SAR440894 or matching placebo via 60-minute intravenous infusion. In each cohort of 8 subjects, the randomization ratio will be 6 active to 2 placebo, and 2 sentinel subjects (one from each active and placebo group) will be dosed first. Dosing of the next dose-cohort will be dependent on acceptable meeting predefined safety criteria in the preceding cohort. Each subject's participation will take place over approximately 150 days, not including the screening visit. There are no hypotheses for this phase I study. The primary objective will be to determine the safety of single ascending intravenous (IV) infusions of SAR440894 when administered in healthy adults. The secondary objectives are: 1) to determine the pharmacokinetics (PK) of single ascending doses of 60-minute IV infusions SAR440894 in healthy adults and 2) to asses the immunogenicity of single ascending doses of 60-minute IV infusions SAR440894 in healthy adults.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
DOUBLE
Enrollment
42
Pharmaceutical Product Development - Orlando Clinical Research Unit
Orlando, Florida, United States
Duke University School of Medicine - Duke Clinical Research Institute - Duke Clinical Research Unit
Durham, North Carolina, United States
PPD - Austin Clinical Research Unit
Austin, Texas, United States
Frequency of Adverse Events (AEs)
The number of participants who experienced at least one unsolicited AE. An AE is defined as any untoward medical occurrence associated with the use of an intervention in humans, whether or not considered intervention-related. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of medicinal (investigational) product. Any medical condition that was present at screening was considered a baseline finding and not reported as an AE. However, if the severity (i.e., grade) of any pre-existing medical condition increases, it was recorded as an AE. For participants who enrolled prior to protocol v11.0, AEs were assessed with protocol defined criteria. For participants who enrolled under protocol v11.0, AEs were assessed with NCI CTCAE, Version 5.0.
Time frame: Day 1 through Day 150
Frequency of Serious Adverse Events (SAEs)
The number of participants who experienced at least one SAE throughout the course of the study. An AE is considered "serious" if, in the view of either the investigator or sponsor, it results in any of the following outcomes: * Death * A life-threatening adverse event * Inpatient hospitalization or prolongation of existing hospitalization * A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions, or * A congenital anomaly/birth defect.
Time frame: Day 1 through Day 150
Frequency of Clinically Significant Vital Signs Results
The number of participants who experienced at least one clinically significant vital signs abnormality post-dosing is summarized by parameter. Clinical significance was determined by the site investigator for all results that met toxicity grading criteria. For participants who enrolled prior to protocol v11.0, vital signs results were graded according to protocol-defined toxicity criteria. For participant who enrolled under protocol v11.0, vital signs results were graded according to the NCI CTCAE, Version 5.0.
Time frame: Day 1 through Day 150
Frequency of Clinically Significant Chemistry Laboratory Results
The number of participants who experienced at least one clinically significant chemistry laboratory abnormality post-dosing is summarized by parameter. Clinical significance was determined by the site investigator for all results that were outside the normal range. For participants who enrolled prior to protocol v11.0, laboratory results were graded according to protocol-defined toxicity criteria. For participants who enrolled under protocol v11.0, laboratory results were graded according to the NCI CTCAE, Version 5.0.
Time frame: Day 1 through Day 150
Frequency of Clinically Significant Hematology Laboratory Results
The number of participants who experienced at least one clinically significant hematology laboratory abnormality post-dosing is summarized by parameter. Clinical significance was determined by the site investigator for all results that were outside the normal range. For participants who enrolled prior to protocol v11.0, laboratory results were graded according to protocol-defined toxicity criteria. For participants who enrolled under protocol v11.0, laboratory results were graded according to the NCI CTCAE, Version 5.0.
Time frame: Day 1 through Day 150
Frequency of Clinically Significant Coagulation Laboratory Results
The number of participants who experienced at least one clinically significant coagulation laboratory abnormality post-dosing is summarized by parameter. Clinical significance was determined by the site investigator for all results that were outside the normal range. For participants who enrolled prior to protocol v11.0, laboratory results were graded according to protocol-defined toxicity criteria. For participants who enrolled under protocol v11.0, laboratory results were graded according to the NCI CTCAE, Version 5.0.
Time frame: Day 1 through Day 150
Frequency of Clinically Significant Urinalysis Laboratory Results
The number of participants who experienced at least one clinically significant urinalysis laboratory abnormality post-dosing is summarized by parameter. Clinical significance was determined by the site investigator for all results that were outside the normal range. For participants who enrolled prior to protocol v11.0, laboratory results were graded according to protocol-defined toxicity criteria. For participants who enrolled under protocol v11.0, laboratory results were graded according to the NCI CTCAE, Version 5.0.
Time frame: Day 1 through Day 150
Frequency of Clinically Significant Electrocardiogram (ECG) Results
The number of participants who experienced at least one clinically significant ECG result post-dosing. Clinical significance was determined by the site investigator.
Time frame: Day 1 through Day 150
Maximum Concentration (Cmax) of SAR440894 in Plasma
PK parameters were estimated from the SAR440894 plasma concentration-time data after a complete dose using Phoenix WinNonlin Non-compartmental analysis.
Time frame: Day 1 through Day 150
Minimum Concentration (Cmin) of SAR440894 in Plasma
PK parameters were estimated from the SAR440894 plasma concentration-time data after a complete dose using Phoenix WinNonlin Non-compartmental analysis.
Time frame: Day 1 through Day 150
Time of Maximum Concentration (Tmax) of SAR440894 in Plasma
PK parameters were estimated from the SAR440894 plasma concentration-time data after a complete dose using Phoenix WinNonlin Non-compartmental analysis.
Time frame: Day 1 through Day 150
Time of Minimum Concentration (Tmin) of SAR440894 in Plasma
PK parameters were estimated from the SAR440894 plasma concentration-time data after a complete dose using Phoenix WinNonlin Non-compartmental analysis.
Time frame: Day 1 through Day 150
Area Under the Concentration-Time Curve From 0 h (Pre-Dose) to the Lase Concentration Above the Lower Limit of Quantitation (AUC0-last) of SAR440894 in Plasma
PK parameters were estimated from the SAR440894 plasma concentration-time data after a complete dose using Phoenix WinNonlin Non-compartmental analysis.
Time frame: Day 1 through Day 150
Area Under the Concentration-Time Curve From 0 h (Pre-Dose) to Infinity (AUC0-inf) of SAR440894 in Plasma
PK parameters were estimated from the SAR440894 plasma concentration-time data after a complete dose using Phoenix WinNonlin Non-compartmental analysis. AUC0-inf was estimated for parameters meeting the following lambda-z acceptance criteria: rsq\_adjusted (adjusted r squared) \>= 0.90 and includes at least 3 time points after Tmax.
Time frame: Day 1 through Day 150
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Terminal Phase Elimination Rate Constant (Lambda-z) of SAR440894 in Plasma
PK parameters were estimated from the SAR440894 plasma concentration-time data after a complete dose using Phoenix WinNonlin Non-compartmental analysis. AUC0-inf was estimated for parameters meeting the following lambda-z acceptance criteria: rsq\_adjusted (adjusted r squared) \>= 0.90 and includes at least 3 time points after Tmax.
Time frame: Day 1 through Day 150
Terminal Half-Life (t1/2) of SAR440894 in Plasma
PK parameters were estimated from the SAR440894 plasma concentration-time data after a complete dose using Phoenix WinNonlin Non-compartmental analysis. AUC0-inf was estimated for parameters meeting the following lambda-z acceptance criteria: rsq\_adjusted (adjusted r squared) \>= 0.90 and includes at least 3 time points after Tmax.
Time frame: Day 1 through Day 150
Clearance (CL) of SAR440894 in Plasma
PK parameters were estimated from the SAR440894 plasma concentration-time data after a complete dose using Phoenix WinNonlin Non-compartmental analysis. AUC0-inf was estimated for parameters meeting the following lambda-z acceptance criteria: rsq\_adjusted (adjusted r squared) \>= 0.90 and includes at least 3 time points after Tmax.
Time frame: Day 1 through Day 150
Volume of Distribution (Vd) of SAR440894 in Plasma
PK parameters were estimated from the SAR440894 plasma concentration-time data after a complete dose using Phoenix WinNonlin Non-compartmental analysis. AUC0-inf was estimated for parameters meeting the following lambda-z acceptance criteria: rsq\_adjusted (adjusted r squared) \>= 0.90 and includes at least 3 time points after Tmax.
Time frame: Day 1 through Day 150
Incidence of Anti-drug Antibody (ADA) Assay Results
Incidence of ADA is defined as either treatment-induced or treatment-boosted ADA at any time point post dosing. For immunogenicity assays, a positive result is defined as a positive screening assay followed by a positive confirmation assay. Treatment-induced ADA is defined as a negative result at baseline and a positive result post-dose. Treatment-boosted ADA is defined as a positive result at both baseline and post-dose, with a 4-fold increase in titer.
Time frame: Day 1 through Day 150