Zika Virus Disease, Zika Virus Infection
Conditions
Keywords
Zika virus, Human immune globulin, Hyperimmune, Polyclonal antibodies
Brief summary
Currently, there are no licensed therapeutics against Zika virus infection. Due to this unmet medical need, Zika Virus Immune Globulin (ZIKV-IG) is being developed as a therapeutic intervention against Zika virus infection. In this first-in-human study, evaluation of ZIKV-IG safety and pharmacokinetics (absorption, metabolism and excretion) will be conducted in healthy adult volunteers.
Detailed description
This study will be evaluating safety and pharmacokinetics (PK) of one dose level of ZIKV-IG (50 mL) in healthy adult volunteers. The study is a single-center, double-blind, randomized and placebo-controlled design. The primary objective is to assess safety of intravenously (IV) administered ZIKV-IG, while the secondary objective is to determine the PK profile of ZIKV-IG in healthy adult volunteers. There will be a total of 30 subjects enrolled into the study; dosing of the first six subjects will be staggered over three separate days, wherein two subjects per day will be randomized 1:1 to either receive 50 mL of placebo IV or 50 mL of ZIKV-IG IV (the total amount of gamma immune globulin \[IgG\] protein from a single 50mL dose is 4.65g). After the first six subjects are dosed, the remaining 24 subjects will be randomized 2:1 to receive either ZIKV-IG or placebo. A safety monitoring committee will review safety data (collected up to 3 days post-dosing) of the first 12 dosed subjects prior to dosing of the remaining 18 subjects. Overall, there will be 19 subjects randomized to receive ZIKV-IG and 11 subjects randomized to receive placebo on Day 1. On Day 1 (post-dose at 1 hour, 3 hours, 8 hours) and Day 2, safety and PK assessments will be conducted while the subjects are in the Phase 1 clinic. After the discharge on Day 2, the subjects will come back to the clinic for safety and PK assessments on Days 3, 4, 6, 8, 10, 12, 15, 22, 29, 43, 57 and 85. Total study duration for each subject will be up to 4 months (from screening to Day 85).
Interventions
BIOLOGICALZika Virus Immune Globulin (ZIKV-IG)
Zika Virus Immune Globulin (ZIKV-IG) is a human immune globulin preparation containing neutralizing antibodies to Zika virus.
OTHERPlacebo
Placebo is a normal saline solution (0.9% sodium chloride).
Sponsors
Emergent BioSolutions
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
1. Informed consent voluntarily signed by subject. 2. Age: 18-55 years of age. 3. Blood type O+ or O-. 4. Body mass index (BMI) of 18-30. * Note: minimum body weight of 50 kg. 5. For female subjects (with male partners) that are not surgically sterilized (e.g., did not undergo hysterectomy, bilateral oophorectomy or tubal ligation), use of an effective method of contraception throughout the trial including: * Using hormonal contraception (oral, injectable or implant) continuously for 3 months prior to screening and willing to continue to use hormonal contraception throughout the entire trial. * Intrauterine device (IUD) inserted at least 1 month prior to screening. * Double barrier type of birth control measure (e.g., condoms, diaphragms, cervical sponge with spermicide). * True abstinence. * For female subjects who are post-menopausal, documented follicle- stimulating hormone (FSH) ≥40 milli-international units per milliliter (mIU/mL) must be obtained. If the FSH is \<40 mIU/mL, the subject must agree to use an acceptable form of contraception (see above). * Females of childbearing potential without male sexual partners must be willing to maintain their sexual status as it is throughout the study. 6. For male subjects that have not had a vasectomy, use of a condom with spermicide or true abstinence for the duration of the study. Note: female partners (that are of childbearing potential) of male study subjects (that have not had a vasectomy) should use one of the effective contraception methods (eg, hormonal contraception, IUD or barrier type). Also, male subjects must not donate sperm for the duration of the study. * Males without female sexual partners must be willing to maintain their sexual status as it is throughout the study. 7. Healthy as determined by principal investigator or a qualified designate based on medical history, physical exam, vital signs, urinalysis, blood chemistry and hematology test results at screening.
Exclusion criteria
1. Use of any investigational product within the past 30 days. 2. Use of any investigational product during the study. 3. Individuals with blood type A, B or AB. 4. Recipient of any blood product within the past 12 months. 5. Plasma donation within 7 days or significant blood loss or blood donation within 56 days of baseline. 6. Blood donation at any time during the study. 7. Females with a hemoglobin level ≤120 g/L. 8. Males with a hemoglobin level \<130 g/L. 9. History of hypersensitivity to blood or plasma products. 10. History of allergy to latex or rubber. 11. History of immunoglobulin A (IgA) deficiency. 12. History of hypercoagulable conditions (e.g., deep vein thrombosis or pulmonary embolism). 13. History of myocardial infarction. 14. History of stroke. 15. History of renal impairment/failure. 16. Currently pregnant or lactating or planning to become pregnant during the study. 17. History of flavivirus infection \[ZIKV, dengue virus (DENV), West Nile virus (WNV), Japanese encephalitis virus (JEV), yellow fever virus (YFV)\] or vaccination with licensed or investigational flavivirus vaccine. 18. Plans to travel to an area with active flavivirus (e.g., ZIKV and/or DENV) transmission during the study (and up to 10 months after the study drug administration) or has returned from an endemic area with these diseases within 30 days of screening. 19. Positive nucleic acid test (NAT) or serology for ZIKV or positive serology for WNV or DENV. 20. Positive serology test (at screening) for human immunodeficiency virus 1 and 2 (HIV), hepatitis C virus (HCV); positive test for hepatitis B virus (HBV) as determined by HBsAg. 21. History of chronic or acute severe neurologic condition (e.g., diagnosis of Guillain-Barre syndrome, epilepsy, Bell's palsy, meningitis or disease with any focal neurologic deficits). 22. Heavy smokers (≥15cigarettes a day) or electronic cigarette use. 23. History of, or suspected substance abuse problem (including alcohol). 24. Failure of drug (urine) test at screening or baseline. 25. Failure of alcohol (breath) test at screening or baseline. 26. Receipt of a live vaccine within 28 days prior to screening or anticipated receipt of a live vaccine during the study period. 27. Individuals with planned surgical procedures that will occur during the study. 28. An opinion of the investigator that it would be unwise to allow participation of the subject in the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Subjects With Adverse Events. | Up to Day 85 | Number of subjects with of adverse events by severity. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Assessment of Zika Virus Immune Globulin (ZIKV-IG) Time to Maximum Concentration (Tmax) | 0-2 hours predose up to Day 85 postdose | Time at which maximum serum concentration of Zika Virus Immune Globulin (ZIKV-IG) occurs. |
| Assessment of Zika Virus Immune Globulin (ZIKV-IG) Area Under the Curve Up to Last Quantifiable Concentration (AUC0-t) | 0-2 hours predose to Day 85 postdose | Area under the concentration-time curve from time 0 to the last quantifiable serum Zika Virus Immune Globulin (ZIKV-IG) concentration. |
| Assessment of Zika Virus Immune Globulin (ZIKV-IG) Area Under the Curve Extrapolated to Infinity (AUC0-inf) | 0-2 hours predose up to Day 85 postdose | Area under the concentration-time curve from time 0 to the last quantifiable serum Zika Virus Immune Globulin (ZIKV-IG) concentration, plus the area extrapolated to infinity. |
| Assessment of Zika Virus Immune Globulin (ZIKV-IG) Maximum Concentration (Cmax) | 0-2 hours predose to Day 85 postdose | Maximum observed serum concentration of Zika Virus Immune Globulin (ZIKV-IG) |
| Assessment of Zika Virus Immune Globulin (ZIKV-IG) Half-Life (t1/2) | 0-2 hours predose up to Day 85 postdose | Apparent first order terminal elimination half-life of Zika Virus Immune Globulin (ZIKV-IG). |
| Assessment of Zika Virus Immune Globulin (ZIKV-IG) Volume of Distribution (Vz) | 0-2 hours predose up to Day 85 postdose | Volume of distribution of Zika Virus Immune Globulin (ZIKV-IG) following IV administration. |
| Assessment of Zika Virus Immune Globulin (ZIKV-IG) Clearance (CL) | 0-2 hours predose up to Day 85 postdose | Total body clearance of Zika Virus Immune Globulin (ZIKV-IG) following IV administration. |
Countries
Canada
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Zika Virus Immune Globulin (ZIKV-IG) Single dose of 50 mL Zika Virus Immune Globulin (ZIKV-IG) will be administered intravenously over 33 minutes.
Zika Virus Immune Globulin (ZIKV-IG): Zika Virus Immune Globulin (ZIKV-IG) is a human immune globulin preparation containing neutralizing antibodies to Zika virus. | 19 |
| Placebo (Saline Solution) Single dose of 50 mL placebo will be administered intravenously over 33 minutes.
Placebo: Placebo is a normal saline solution (0.9% sodium chloride). | 11 |
| Total | 30 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 0 | 1 |
Baseline characteristics
| Characteristic | Zika Virus Immune Globulin (ZIKV-IG) | Placebo (Saline Solution) | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 19 Participants | 11 Participants | 30 Participants |
| Age, Continuous | 35 years | 30 years | 33.5 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 3 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 18 Participants | 8 Participants | 26 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 3 Participants | 2 Participants | 5 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) White | 14 Participants | 8 Participants | 22 Participants |
| Region of Enrollment Canada | 19 participants | 11 participants | 30 participants |
| Sex: Female, Male Female | 4 Participants | 4 Participants | 8 Participants |
| Sex: Female, Male Male | 15 Participants | 7 Participants | 22 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 19 | 0 / 11 |
| other Total, other adverse events | 12 / 19 | 8 / 11 |
| serious Total, serious adverse events | 0 / 19 | 0 / 11 |
Outcome results
Primary
Number of Subjects With Adverse Events.
Number of subjects with of adverse events by severity.
Time frame: Up to Day 85
Population: Safety population includes all subjects who received any amount of study treatment (ZIKV-IG or placebo).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Zika Virus Immune Globulin (ZIKV-IG) | Number of Subjects With Adverse Events. | Subjects with an adverse event | 12 participants |
| Zika Virus Immune Globulin (ZIKV-IG) | Number of Subjects With Adverse Events. | Subjects with a severe adverse event | 0 participants |
| Zika Virus Immune Globulin (ZIKV-IG) | Number of Subjects With Adverse Events. | Subjects with an adverse event assessed as related | 8 participants |
| Zika Virus Immune Globulin (ZIKV-IG) | Number of Subjects With Adverse Events. | Subjects with a serious adverse event | 0 participants |
| Placebo (Saline Solution) | Number of Subjects With Adverse Events. | Subjects with a serious adverse event | 0 participants |
| Placebo (Saline Solution) | Number of Subjects With Adverse Events. | Subjects with an adverse event | 8 participants |
| Placebo (Saline Solution) | Number of Subjects With Adverse Events. | Subjects with an adverse event assessed as related | 3 participants |
| Placebo (Saline Solution) | Number of Subjects With Adverse Events. | Subjects with a severe adverse event | 0 participants |
Secondary
Assessment of Zika Virus Immune Globulin (ZIKV-IG) Area Under the Curve Extrapolated to Infinity (AUC0-inf)
Area under the concentration-time curve from time 0 to the last quantifiable serum Zika Virus Immune Globulin (ZIKV-IG) concentration, plus the area extrapolated to infinity.
Time frame: 0-2 hours predose up to Day 85 postdose
Population: PK population included all subjects who received ZIKV-IG with adequate number of PK samples (a suitable pre-dose sample and at least one measurable post-dose sample) and PK population with subject 01-127 removed to permit comparison of the concentrations with and without the outlying subject.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Zika Virus Immune Globulin (ZIKV-IG) | Assessment of Zika Virus Immune Globulin (ZIKV-IG) Area Under the Curve Extrapolated to Infinity (AUC0-inf) | 76170 h*U/mL | Geometric Coefficient of Variation 18.4 |
| Placebo (Saline Solution) | Assessment of Zika Virus Immune Globulin (ZIKV-IG) Area Under the Curve Extrapolated to Infinity (AUC0-inf) | 77224 h*U/mL | Geometric Coefficient of Variation 17.9 |
Secondary
Assessment of Zika Virus Immune Globulin (ZIKV-IG) Area Under the Curve Up to Last Quantifiable Concentration (AUC0-t)
Area under the concentration-time curve from time 0 to the last quantifiable serum Zika Virus Immune Globulin (ZIKV-IG) concentration.
Time frame: 0-2 hours predose to Day 85 postdose
Population: PK population included all subjects who received ZIKV-IG with adequate number of PK samples (a suitable pre-dose sample and at least one measurable post-dose sample) and PK population with subject 01-127 removed to permit comparison of the concentrations with and without the outlying subject.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Zika Virus Immune Globulin (ZIKV-IG) | Assessment of Zika Virus Immune Globulin (ZIKV-IG) Area Under the Curve Up to Last Quantifiable Concentration (AUC0-t) | 66304 h*U/mL | Geometric Coefficient of Variation 19.2 |
| Placebo (Saline Solution) | Assessment of Zika Virus Immune Globulin (ZIKV-IG) Area Under the Curve Up to Last Quantifiable Concentration (AUC0-t) | 67221 h*U/mL | Geometric Coefficient of Variation 18.8 |
Secondary
Assessment of Zika Virus Immune Globulin (ZIKV-IG) Clearance (CL)
Total body clearance of Zika Virus Immune Globulin (ZIKV-IG) following IV administration.
Time frame: 0-2 hours predose up to Day 85 postdose
Population: PK population included all subjects who received ZIKV-IG with adequate number of PK samples (a suitable pre-dose sample and at least one measurable post-dose sample) and PK population with subject 01-127 removed to permit comparison of the concentrations with and without the outlying subject.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Zika Virus Immune Globulin (ZIKV-IG) | Assessment of Zika Virus Immune Globulin (ZIKV-IG) Clearance (CL) | 6.966 mL/h | Geometric Coefficient of Variation 18.4 |
| Placebo (Saline Solution) | Assessment of Zika Virus Immune Globulin (ZIKV-IG) Clearance (CL) | 6.871 mL/h | Geometric Coefficient of Variation 17.9 |
Secondary
Assessment of Zika Virus Immune Globulin (ZIKV-IG) Half-Life (t1/2)
Apparent first order terminal elimination half-life of Zika Virus Immune Globulin (ZIKV-IG).
Time frame: 0-2 hours predose up to Day 85 postdose
Population: PK population included all subjects who received ZIKV-IG with adequate number of PK samples (a suitable pre-dose sample and at least one measurable post-dose sample) and PK population with subject 01-127 removed to permit comparison of the concentrations with and without the outlying subject.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Zika Virus Immune Globulin (ZIKV-IG) | Assessment of Zika Virus Immune Globulin (ZIKV-IG) Half-Life (t1/2) | 674.3 hours | Geometric Coefficient of Variation 15.9 |
| Placebo (Saline Solution) | Assessment of Zika Virus Immune Globulin (ZIKV-IG) Half-Life (t1/2) | 674.7 hours | Geometric Coefficient of Variation 16.4 |
Secondary
Assessment of Zika Virus Immune Globulin (ZIKV-IG) Maximum Concentration (Cmax)
Maximum observed serum concentration of Zika Virus Immune Globulin (ZIKV-IG)
Time frame: 0-2 hours predose to Day 85 postdose
Population: PK population included all subjects who received ZIKV-IG with adequate number of PK samples (a suitable pre-dose sample and at least one measurable post-dose sample) and PK population with subject 01-127 removed to permit comparison of the concentrations with and without the outlying subject.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Zika Virus Immune Globulin (ZIKV-IG) | Assessment of Zika Virus Immune Globulin (ZIKV-IG) Maximum Concentration (Cmax) | 171.8 U/mL | Geometric Coefficient of Variation 33.9 |
| Placebo (Saline Solution) | Assessment of Zika Virus Immune Globulin (ZIKV-IG) Maximum Concentration (Cmax) | 182.3 U/mL | Geometric Coefficient of Variation 21.3 |
Secondary
Assessment of Zika Virus Immune Globulin (ZIKV-IG) Time to Maximum Concentration (Tmax)
Time at which maximum serum concentration of Zika Virus Immune Globulin (ZIKV-IG) occurs.
Time frame: 0-2 hours predose up to Day 85 postdose
Population: PK population included all subjects who received ZIKV-IG with adequate number of PK samples (a suitable pre-dose sample and at least one measurable post-dose sample) and PK population with subject 01-127 removed to permit comparison of the concentrations with and without the outlying subject.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Zika Virus Immune Globulin (ZIKV-IG) | Assessment of Zika Virus Immune Globulin (ZIKV-IG) Time to Maximum Concentration (Tmax) | 6.1 hours | Standard Deviation 16.4 |
| Placebo (Saline Solution) | Assessment of Zika Virus Immune Globulin (ZIKV-IG) Time to Maximum Concentration (Tmax) | 2.3 hours | Standard Deviation 1 |
Secondary
Assessment of Zika Virus Immune Globulin (ZIKV-IG) Volume of Distribution (Vz)
Volume of distribution of Zika Virus Immune Globulin (ZIKV-IG) following IV administration.
Time frame: 0-2 hours predose up to Day 85 postdose
Population: PK population included all subjects who received ZIKV-IG with adequate number of PK samples (a suitable pre-dose sample and at least one measurable post-dose sample) and PK population with subject 01-127 removed to permit comparison of the concentrations with and without the outlying subject.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Zika Virus Immune Globulin (ZIKV-IG) | Assessment of Zika Virus Immune Globulin (ZIKV-IG) Volume of Distribution (Vz) | 6776.8 mL | Geometric Coefficient of Variation 20.4 |
| Placebo (Saline Solution) | Assessment of Zika Virus Immune Globulin (ZIKV-IG) Volume of Distribution (Vz) | 6687.7 mL | Geometric Coefficient of Variation 20.1 |