Phase 1 Study of SAR440894 vs Placebo

Study Overview
=================
Brief Summary
-----------------
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.

Detailed Description
-----------------
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.

Official Title
-----------------
A Phase 1, Randomized, Double-Blind, Multi-Site, Single Dose Escalation Study to Evaluate the Safety, Pharmacokinetics, and Immunogenicity of SAR440894 vs Placebo in Healthy Adults

Conditions
-----------------
Chikungunya Virus Infection

Intervention / Treatment
-----------------
* Other: Placebo
* Biological: SAR440894


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Must be a healthy adult 18 to 45 years of age, inclusive, with a body mass index (BMI) greater than 18 or less than 35 kg/m^2, inclusive. Participants of childbearing potential* having vaginal intercourse must use an effective method of contraception** from 45 days before study product administration through the final study visit. *Not sterilized via hysterectomy or bilateral oophorectomy and/or salpingectomy or be less than 1 year from the last menses if menopausal. **Includes any of the following (a) exclusive non-male sexual relationships; (b) monogamous relationship with vasectomized partner (greater than or equal to 180 days between procedure and subject receipt of investigational product); (c) bilateral tubal ligation or tubal occlusion (eg., Essure(R)); (d) effective intrauterine device (IUD); (e) hormonal implants (eg., Implanon(R)); (f) other hormonal contraceptives (such as birth control pills, vaginal rings, patches or injections); (g) barrier methods (condom, diaphragm, cervical cap) PLUS spermicide (gel or foam) Women of childbearing potential must agree not to donate ova or oocytes (ie, human eggs) during the study. Male subjects (including those with vasectomies) whose partners are of childbearing potential should use condoms with spermicide and not donate sperm for the duration of the study. Must have adequate venous access for IV infusions and blood draws. Agrees to be available for all study visits and willing to cooperate fully with the requirements* of the study protocol. *Requirements include remaining in confinement for at least 72 hours after receiving study product and other activities outlined in the protocol's Schedule of Events. Is able to understand the informed consent process and procedures and signs the consent form. Will agree not to donate any blood or blood products* for the duration of the study. Includes whole blood, red blood cells, platelets, plasma, or plasma derivatives. Will agree to avoid travel to endemic areas (as defined by the Center for Disease Control (CDC)) for Chikungunya Virus (CHIKV) at any point during the Follow-up period (https://www.cdc.gov/chikungunya/geo/index.html). Exclusion Criteria: Has any medical condition (renal dysfunction) that, in the opinion of the site PI or appropriate sub-investigator listed on Form Food and Drug Administration (FDA) 1572, is a contraindication to study participation. Has any clinically significant (CS) electrocardiogram (ECG) abnormalities in the opinion of the site Principal Investigator (PI) or appropriate sub-investigator been listed on Form FDA 1572. Use of any prohibited prescription medication (excluding contraceptives in females) within 14 days before study product administration, through Day 56** *Prohibited medications include immunosuppressives; immune modulators; oral corticosteroids (topical/intranasal steroids are acceptable); prescription Non-Steroidal Anti-inflammatory Drugs (NSAIDs); anti-neoplastic agents; any vaccine (licensed or investigational). If study activities overlap with the influenza season, subjects will be instructed to obtain influenza vaccine at least 45 days prior to proposed dosing or delay vaccination until after Day 56. Subjects will be instructed to obtain the last dose of any vaccine for SARS-CoV-2 (COVID-19) at least 45 days prior to proposed dosing or delay vaccination until after Day 56. Use of nonprescription systemic drugs within 7 days before study product administration (includes vitamins, antacids*, over-the-counter drugs**, herbal/dietary supplements, etc.) through Day 28*** *Nonprescription drugs and supplements may be allowed before Day 28 at the discretion of the site PI. **Includes proton pump inhibitors and H2-blockers (Histamine-2 blockers) ***Nonprescription drugs and supplements may be allowed before Day 28 at the discretion of the site PI. In the event an OTC oral contraceptive becomes available during the course of the study, it must be reviewed and approved by the site PI. Hypertension, with confirmed systolic blood pressure (BP) greater than 140 mm Hg or confirmed diastolic BP greater than 90 mm Hg, measured after 5 minutes of rest at Screening. Hypotension, with confirmed systolic BP less than 90 mm Hg. Resting heart rate (HR) less than 45 bpm or greater than 100 bpm at Screening. Body weight less than 50 kg. History of a significant illness, per the investigators' clinical judgment, within 2 weeks before dosing (subjects can screen after illness is resolved for 2 weeks). Known diagnosis of prolonged QT interval, congenital long QT syndrome, bradyarrhythmias, or uncompensated heart failure. Males with a mean QTcF greater than 450 msec or females with a mean QTcF greater than 470 msec (Fridericia's correction) at Screening.* *ECG tracings should be recorded at least 1 minute apart, after at least 5 minutes of rest in the supine position. If the mean QTcF value from the 3 tracings exceeds the limits stated, the subject is disqualified. Any history of malignancy ever, except low-grade skin cancer (ie, basal cell carcinoma thought to be cured). History of drug abuse, alcohol abuse, or significant psychiatric history according to the investigators' judgment within 12 months before Screening. Positive for hepatitis B virus surface antigen, hepatitis C virus antibody, or human immunodeficiency virus (HIV) antibody at Screening. Excessive consumption of beverages containing xanthine bases, or more than 400 mg of caffeine per day within 1 week of study product administration through the final study visit. Consumption of alcohol within 24 hours before study product administration. Use of nicotine-containing products within 45 days before study product administration through the final study visit. Positive drug screen*, positive cotinine screen, or positive breathalyzer test for alcohol at Screening or admission (Day -1). *Cannabinoids, amphetamines, barbiturates, cocaine, opiates, benzodiazepines and phencyclidine. Subjects should be notified by phone not to consume any poppy seeds within 24 hours before the Screening urine test to avoid a false positive opioid test result. If female, serum positive pregnancy test at Screening or serum positive pregnancy test on Day -1. Breastfeeding throughout the duration of the study Total WBC and platelet counts, hemoglobin*, total bilirubin*, alanine/aspartate aminotransferase* and sodium* are Grade 1 or higher** at Screening visit***. *For sodium; potential subjects excluded prior to Protocol Version 6.0 with Grade 1 sodium values may be rescreened. For hemoglobin; a lower limit within 0.5 g/dL of the lower limit of normal (LLN) is allowable at Screening. For total bilirubin; ULN values will be allowed at Screening and Day -1/baseline provided the AST and ALT are within normal limits. Potential subjects excluded prior to Protocol Version 6.0 with bilirubin values below the Version 6.0 upper limit may be rescreened. For ALT/AST; subjects who screened prior to Protocol Version 11.0 were excluded if AST/ALT results were Grade 1 or higher at Screening. Subjects who screen with Protocol Version 11.0, AST/ALT is exclusionary if Screening results are 1.5 × ULN or if assessed as CS by the site PI. Grade 1 or higher toxicity, see Appendix C and Appendix D for subjects who screened and enrolled prior to Protocol Version 11.0. Subjects who screen and enroll with Protocol Version 11.0, toxicity will be assessed with the NCI CTCAE, Version 5.0 - November 2017. Safety laboratory tests drawn on Day -1 or Screening if within 48 hours of planned dosing will serve as baseline values. Day -1 laboratory tests with a Grade 1 severity, other than those noted above, will not exclude subjects from participation. All other abnormal laboratory values collected at Screening and on Day -1 will be exclusionary at the discretion of the PI. Potassium, bicarbonate or creatinine/eGFR* results are Grade 1 or higher at either Screening or Day -1/Baseline visits. *For creatinine; subjects who screened prior to Protocol Version 11.0 were excluded if creatinine results were Grade 1 or higher. Subjects who screen with Protocol Version 11.0, creatinine is not an exclusionary criterion, instead subjects should have a calculated eGFR using Chronic Kidney Disease Epidemiology Collaboration Creatinine Equation (CKD-EPI) of >/= 90 mL/min/1.73m2 to be enrolled in the study. Received an experimental agent (vaccine, drug, biologic, device, or medication) within 45 days or 5 half-lives (whichever is longer) before study product administration.* *Prior participation at any time in noninvasive methodology trials in which no drugs were given is acceptable. Is participating in or plans to participate in another clinical trial with an interventional agent that will be received during this trial. Has donated more than 500 mL of blood or blood products* within the month before Screening. *Includes whole blood, red blood cells, platelets, plasma, or plasma derivatives. Has a history of serologically-proven Chikungunya virus (CHIKV) exposure at any point, or positive anti CHIKV antibodies (ie., positive IgM or IgG) at Screening. Has received blood products within 120 days prior to Screening. Has received mAb in the past 3-months or 5 half-lives (whichever is longer) prior to Screening, whether licensed or investigational, or plans to receive a mAb outside of this study.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1<br>0.3 mg/kg of SAR440894 (n=6) or placebo (n=2) administered once during a 60-minute intravenous (IV) infusion. 2 sentinel subjects will receive dosing for review of safety data (SAR440894 n=1, placebo n=1) before remainder of cohort. | Other: Placebo<br>* One time 60-minute IV infusion of lyophilized placebo for SAR440894<br>Biological: SAR440894<br>* One time 60-minute IV infusion of SAR440894 monoclonal antibody (IgG1) directed against the E2 envelope protein of chikungunya virus<br>|
| Experimental: Cohort 2<br>1 mg/kg of SAR440894 (n=6) or placebo (n=2) administered once during a 60-minute intravenous (IV) infusion. 2 sentinel subjects will receive dosing for review of safety data (SAR440894 n=1, placebo n=1) before remainder of cohort. | Other: Placebo<br>* One time 60-minute IV infusion of lyophilized placebo for SAR440894<br>Biological: SAR440894<br>* One time 60-minute IV infusion of SAR440894 monoclonal antibody (IgG1) directed against the E2 envelope protein of chikungunya virus<br>|
| Experimental: Cohort 3<br>3 mg/kg of SAR440894 (n=6) or placebo (n=2) administered once during a 60-minute intravenous (IV) infusion. 2 sentinel subjects will receive dosing for review of safety data (SAR440894 n=1, placebo n=1) before remainder of cohort. | Other: Placebo<br>* One time 60-minute IV infusion of lyophilized placebo for SAR440894<br>Biological: SAR440894<br>* One time 60-minute IV infusion of SAR440894 monoclonal antibody (IgG1) directed against the E2 envelope protein of chikungunya virus<br>|
| Experimental: Cohort 4<br>10 mg/kg of SAR440894 (n=6) or placebo (n=2) administered once during a 60-minute intravenous (IV) infusion. 2 sentinel subjects will receive dosing for review of safety data (SAR440894 n=1, placebo n=1) before remainder of cohort. | Other: Placebo<br>* One time 60-minute IV infusion of lyophilized placebo for SAR440894<br>Biological: SAR440894<br>* One time 60-minute IV infusion of SAR440894 monoclonal antibody (IgG1) directed against the E2 envelope protein of chikungunya virus<br>|
| Experimental: Cohort 5<br>20 mg/kg of SAR440894 (n=6) or placebo (n=2) administered once during a 60-minute intravenous (IV) infusion. 2 sentinel subjects will receive dosing for review of safety data (SAR440894 n=1, placebo n=1) before remainder of cohort. | Other: Placebo<br>* One time 60-minute IV infusion of lyophilized placebo for SAR440894<br>Biological: SAR440894<br>* One time 60-minute IV infusion of SAR440894 monoclonal antibody (IgG1) directed against the E2 envelope protein of chikungunya virus<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Occurrence of adverse events (AEs) |  | Day 1 through Day 150 | 
| Occurrence of changes from baseline in vital signs | Vitals signs include temperature, heart rate, blood pressure, and respiratory rate. | Day 1 through Day 150 | 
| Occurrence of clinically significant (CS) changes from baseline in clinical safety laboratory values | Clinical safety laboratory evaluations include hematology, chemistry, urinalysis, and coagulation. | Day 1 through Day 150 | 
| Occurrence of clinically significant (CS) changes in ECG parameters from baseline | Significant changes are defined as the following: Any significant change in rate or rhythm as determined by the site PI, QTcF interval of greater than 450 ms (male) or greater than 460 ms (female), Increase from the QTcF baseline (defined as median of pre-dose measurements) greater than 50 ms until the change resolves. | Day 1 through Day 150 | 
| Occurrence of serious adverse events (SAEs) |  | Day 1 through Day 150 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in concentration of SAR440894 plasma human anti-drug antibody (ADA) | Will be used to determine immunogenicity of SAR440894. | Day 1 through Day 150 | 
| SAR440894 plasma concentration | Plasma concentration will be determined by using a validated enzyme-linked immunosorbent assay. Plasma concentrations will be used to determine plasma PK of SAR440894. | Day 1 through Day 150 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Chikungunya Virus, dose escalation, healthy adults, Immunogenicity, Pharmacokinetics, phase 1, placebo, SAR440894