Anthrax
Conditions
Keywords
Anthrax, Human Anthrax Immune Globulin Intravenous, Safety, Pharmacokinetics
Brief summary
The purpose of this study is to: * evaluate the safety profile of a single intravenous administration of AIGIV (containing either 3.5 mg/kg, 7.0 mg/kg or 14.0 mg/kg anti-PA IgG) as compared with either 90 mg/kg, 180 mg/kg or 360 mg/kg total IgG, GAMUNEX® (immune globulin intravenous (human) 10% caprylate/chromatography purified). GAMUNEX is a trademark of Talecris Biotherapeutics. * evaluate the pharmacokinetic (PK) profile of a single intravenous administration of AIGIV (containing either 3.5 mg/kg, 7.0 mg/kg or 14.0 mg/kg anti-PA IgG) as measured by lethal toxin neutralizing antibody (TNA).
Interventions
BIOLOGICALAIGIV 3.5 mg/kg
AIGIV containing 3.5 mg/kg anti-PA IgG as a single intravenous infusion.
BIOLOGICALGamunex 90 mg/kg
Gamunex 90 mg/kg total IgG as a single intravenous infusion.
BIOLOGICALAIGIV 7.0 mg/kg
AIGIV containing 7.0 mg/kg anti-PA IgG as a single intravenous infusion.
BIOLOGICALGamunex 180 mg/kg
Gamunex 180 mg/kg total IgG as a single intravenous infusion.
BIOLOGICALAIGIV 14.0 mg/kg
AIGIV containing 14.0 mg/kg anti-PA IgG as a single intravenous infusion.
BIOLOGICALGamunex 360 mg/kg
Gamunex 360 mg/kg total IgG as a single intravenous infusion.
Sponsors
National Institutes of Health (NIH)
Emergent BioSolutions
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
Yes
Inclusion criteria
* Between 18 and 65 years of age, inclusive. * Have a minimal weight of 110 lbs and a body mass index (BMI) between 17 and 35. * In good health. * For pre-menopausal female subjects, using acceptable methods of birth control. * Willing and capable of complying with all aspects of the protocol through completion of the program period. * No blood donation in the preceding 8 weeks; willing to not donate whole blood or plasma during the clinical trial; and willing to not donate whole blood or plasma for up to one year following the last infusion. * Has read and signed an informed consent form. * Adequate venous access and can receive intravenous infusion.
Exclusion criteria
* Previously intolerant of immune globulin or blood product preparations or known immunodeficiency. * Previous treatment with immune globulin products or blood products within three months of study. * Previous receipt of anthrax vaccine, known exposure to anthrax organisms, or previously enlisted in the military. * Receipt of any live vaccine within three months or inactivated vaccine within 2 weeks prior to study; plans to receive any vaccine at any time during the study. * Participation in any investigational clinical trial within one month prior to study. * Positive serology for human immunodeficiency virus (HIV), hepatitis B virus, or hepatitis C virus. * Receipt of chemotherapy, radiation therapy, immunosuppressive therapy, or high-dose corticosteroid therapy within five years of study. * Use of prohibited medications as defined in the protocol. * History of drug or alcohol abuse within 1 year of study. * History of IgA deficiency. * Pregnancy. * Positive Coombs test at screening. * Males with a hemoglobin value less than 13.2 gm/dL and females less than 10.9 gm/dL. * Absolute eosinophil counts greater than 600 cells/mm3 or Absolute lymphocyte counts less than 1000 cells/mm3. * Aspartate aminotransferase (AST) \>55 U/L or alanine aminotransferase (ALT) \>60 U/L. * Hyperglycemia with random blood glucose \>141 mg/dL, fasting blood glucose \>112 mg/dL, or urine glucose \>50 mg/dL; or hypoglycemia with a blood glucose \<65 mg/dL. * BUN \>25 mg/dL or creatinine, for males \>1.4 mg/dL and, for females \>1.2 mg/dL. * Creatinine clearance \<80 mL/min. * Urine protein \>15 mg/dL for males and non-menstruating females, or \>30 mg/dL for menstruating females. * Febrile illness within three days prior to infusion. * History of significant medical or psychiatric condition or abnormal laboratory tests indicating possible underlying medical condition. * An opinion of the investigator that a condition exists that would preclude compliance with protocol-specified procedures. * Absolute neutrophil count is less than 3000 cells/mm3 as defined by the central lab (screening) or local lab (pre-infusion) for cohort B. Absolute neutrophil count is less than 2500 cells/mm3 as defined by the central lab (screening) or local lab (pre-infusion) for cohort C. * White blood cell counts are less than 3500 cells/mm3 as defined by the central lab (screening) or local lab (pre-infusion) for cohorts B and C. * History of a severe or anaphylactic reaction to quinolone or penicillin antibiotics.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Reporting Adverse Events (AEs) | From the time of infusion through Day 90. | Any untoward medical occurrence reported to or observed by the principal investigator (PI), including as identified from other safety assessments (eg, vital signs, clinical laboratory testing, electrocardiogram). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time of Cmax | From the time of infusion through Day 90 postinfusion. | Blood samples for TNA analysis collected at pre-infusion; 5 minutes postinfusion; 8, 24, and 48 hours postinfusion; and Days 3, 5, 10, 14, 21, 30, 45, 60, and 90 postinfusion. |
| Area Under the Curve to the Last Time With a Measurable TNA Titer (AUC[0-t]) | From the time of infusion through Day 90 postinfusion. | Blood samples for TNA analysis collected at pre-infusion; 5 minutes postinfusion; 8, 24, and 48 hours postinfusion; and Days 3, 5, 10, 14, 21, 30, 45, 60, and 90 postinfusion. |
| Area Under the Curve to Infinity (AUC[0-inf]) | From the time of infusion through Day 90 postinfusion. | Blood samples for TNA analysis collected at pre-infusion; 5 minutes postinfusion; 8, 24, and 48 hours postinfusion; and Days 3, 5, 10, 14, 21, 30, 45, 60, and 90 postinfusion. |
| Maximum Plasma Titer/Concentration of TNA (Toxin Neutralizing Antibody) (Cmax) | From the time of infusion through Day 90 postinfusion. | Blood samples for TNA analysis collected at pre-infusion; 5 minutes postinfusion; 8, 24, and 48 hours postinfusion; and Days 3, 5, 10, 14, 21, 30, 45, 60, and 90 postinfusion. Assay results are reported as the 50% neutralization factor, TNA NF50: the ED50 of the test sample (ie, effective dilution of test sample that neutralized 50% of toxin) divided by the ED50 of the reference standard. |
| Elimination Half-life (t½) | From the time of infusion through Day 90 postinfusion. | Blood samples for TNA analysis collected at pre-infusion; 5 minutes postinfusion; 8, 24, and 48 hours postinfusion; and Days 3, 5, 10, 14, 21, 30, 45, 60, and 90 postinfusion. |
| Mean Residence Time (MRT) | From the time of infusion through Day 90 postinfusion. | Blood samples for TNA analysis collected at pre-infusion; 5 minutes postinfusion; 8, 24, and 48 hours postinfusion; and Days 3, 5, 10, 14, 21, 30, 45, 60, and 90 postinfusion. |
| Elimination Rate Constant | From the time of infusion through Day 90 postinfusion. | Blood samples for TNA analysis collected at pre-infusion; 5 minutes postinfusion; 8, 24, and 48 hours postinfusion; and Days 3, 5, 10, 14, 21, 30, 45, 60, and 90 postinfusion. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| AIGIV 3.5 mg/kg (Cohort A) AIGIV containing 3.5 mg/kg anti-PA IgG as a single intravenous infusion. | 31 |
| Gamunex 90 mg/kg (Cohort A) Gamunex 90 mg/kg total IgG as a single intravenous infusion. | 5 |
| AIGIV 7.0 mg/kg (Cohort B) AIGIV containing 7.0 mg/kg anti-PA IgG as a single intravenous infusion. | 31 |
| Gamunex 180 mg/kg (Cohort B) Gamunex 180 mg/kg total IgG as a single intravenous infusion. | 14 |
| AIGIV 14.0 mg/kg (Cohort C) AIGIV containing 14.0 mg/kg anti-PA IgG as a single intravenous infusion. | 31 |
| Gamunex 360 mg/kg (Cohort C) Gamunex 360 mg/kg total IgG as a single intravenous infusion. | 17 |
| Total | 129 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Overall Study | Lost to Follow-up | 0 | 0 | 3 | 1 | 0 | 1 |
| Overall Study | Sponsor hold on dosing | 0 | 0 | 0 | 0 | 1 | 1 |
| Overall Study | Unable to access IV line | 1 | 0 | 0 | 0 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 0 | 0 | 2 | 0 |
Baseline characteristics
| Characteristic | AIGIV 7.0 mg/kg (Cohort B) | Gamunex 180 mg/kg (Cohort B) | AIGIV 3.5 mg/kg (Cohort A) | Gamunex 90 mg/kg (Cohort A) | AIGIV 14.0 mg/kg (Cohort C) | Gamunex 360 mg/kg (Cohort C) | Total |
|---|---|---|---|---|---|---|---|
| Age, Continuous | 32.1 years STANDARD_DEVIATION 10.6 | 37.1 years STANDARD_DEVIATION 9.4 | 35.1 years STANDARD_DEVIATION 10.3 | 35.2 years STANDARD_DEVIATION 13.8 | 33.3 years STANDARD_DEVIATION 9.1 | 36.6 years STANDARD_DEVIATION 9.8 | 34.3 years STANDARD_DEVIATION 10 |
| Age, Customized 18 to < 30 years | 16 Participants | 3 Participants | 12 Participants | 2 Participants | 13 Participants | 4 Participants | 50 Participants |
| Age, Customized 30 to < 40 years | 7 Participants | 6 Participants | 7 Participants | 1 Participants | 7 Participants | 8 Participants | 36 Participants |
| Age, Customized 40 to < 50 years | 6 Participants | 3 Participants | 9 Participants | 1 Participants | 11 Participants | 3 Participants | 33 Participants |
| Age, Customized ≥ 50 years | 2 Participants | 2 Participants | 3 Participants | 1 Participants | 0 Participants | 2 Participants | 10 Participants |
| Body Mass Index < 25 kg/m^2 | 11 Participants | 3 Participants | 10 Participants | 1 Participants | 9 Participants | 7 Participants | 41 Participants |
| Body Mass Index ≥ 25 kg/m^2 | 20 Participants | 11 Participants | 21 Participants | 4 Participants | 22 Participants | 10 Participants | 88 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 2 Participants | 1 Participants | 0 Participants | 3 Participants | 2 Participants | 8 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 31 Participants | 12 Participants | 30 Participants | 5 Participants | 28 Participants | 15 Participants | 121 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 16 Participants | 7 Participants | 26 Participants | 2 Participants | 16 Participants | 9 Participants | 76 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 2 Participants | 0 Participants | 0 Participants | 1 Participants | 2 Participants | 5 Participants |
| Race (NIH/OMB) White | 14 Participants | 5 Participants | 5 Participants | 3 Participants | 12 Participants | 6 Participants | 45 Participants |
| Sex: Female, Male Female | 13 Participants | 5 Participants | 10 Participants | 2 Participants | 17 Participants | 10 Participants | 57 Participants |
| Sex: Female, Male Male | 18 Participants | 9 Participants | 21 Participants | 3 Participants | 14 Participants | 7 Participants | 72 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 30 | 0 / 5 | 0 / 31 | 0 / 14 | 0 / 29 | 0 / 16 |
| other Total, other adverse events | 28 / 30 | 5 / 5 | 29 / 31 | 11 / 14 | 29 / 29 | 15 / 16 |
| serious Total, serious adverse events | 1 / 30 | 0 / 5 | 1 / 31 | 1 / 14 | 0 / 29 | 0 / 16 |
Outcome results
Primary
Number of Participants Reporting Adverse Events (AEs)
Any untoward medical occurrence reported to or observed by the principal investigator (PI), including as identified from other safety assessments (eg, vital signs, clinical laboratory testing, electrocardiogram).
Time frame: From the time of infusion through Day 90.
Population: Safety Population: all subjects who received any infusion of AIGIV or Gamunex.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| AIGIV 3.5 mg/kg (Cohort A) | Number of Participants Reporting Adverse Events (AEs) | 28 Participants |
| Gamunex 90 mg/kg (Cohort A) | Number of Participants Reporting Adverse Events (AEs) | 5 Participants |
| AIGIV 7.0 mg/kg (Cohort B) | Number of Participants Reporting Adverse Events (AEs) | 29 Participants |
| Gamunex 180 mg/kg (Cohort B) | Number of Participants Reporting Adverse Events (AEs) | 11 Participants |
| AIGIV 14.0 mg/kg (Cohort C) | Number of Participants Reporting Adverse Events (AEs) | 29 Participants |
| Gamunex 360 mg/kg (Cohort C) | Number of Participants Reporting Adverse Events (AEs) | 15 Participants |
Secondary
Area Under the Curve to Infinity (AUC[0-inf])
Blood samples for TNA analysis collected at pre-infusion; 5 minutes postinfusion; 8, 24, and 48 hours postinfusion; and Days 3, 5, 10, 14, 21, 30, 45, 60, and 90 postinfusion.
Time frame: From the time of infusion through Day 90 postinfusion.
Population: Pharmacokinetic ITT population: all subjects who received any infusion of AIGIV, had sufficient data for PK analysis, and had no specified protocol violations known before database lock that would be expected to affect the titer.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AIGIV 3.5 mg/kg (Cohort A) | Area Under the Curve to Infinity (AUC[0-inf]) | 329.01 h*NF50 | Standard Deviation 51.04 |
| Gamunex 90 mg/kg (Cohort A) | Area Under the Curve to Infinity (AUC[0-inf]) | 698.26 h*NF50 | Standard Deviation 117.61 |
| AIGIV 7.0 mg/kg (Cohort B) | Area Under the Curve to Infinity (AUC[0-inf]) | 1401.08 h*NF50 | Standard Deviation 216.62 |
Secondary
Area Under the Curve to the Last Time With a Measurable TNA Titer (AUC[0-t])
Blood samples for TNA analysis collected at pre-infusion; 5 minutes postinfusion; 8, 24, and 48 hours postinfusion; and Days 3, 5, 10, 14, 21, 30, 45, 60, and 90 postinfusion.
Time frame: From the time of infusion through Day 90 postinfusion.
Population: Pharmacokinetic ITT population: all subjects who received any infusion of AIGIV, had sufficient data for PK analysis, and had no specified protocol violations known before database lock that would be expected to affect the titer.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AIGIV 3.5 mg/kg (Cohort A) | Area Under the Curve to the Last Time With a Measurable TNA Titer (AUC[0-t]) | 323.03 h*NF50 | Standard Deviation 312.94 |
| Gamunex 90 mg/kg (Cohort A) | Area Under the Curve to the Last Time With a Measurable TNA Titer (AUC[0-t]) | 636.31 h*NF50 | Standard Deviation 115.17 |
| AIGIV 7.0 mg/kg (Cohort B) | Area Under the Curve to the Last Time With a Measurable TNA Titer (AUC[0-t]) | 1277.30 h*NF50 | Standard Deviation 186.41 |
Secondary
Elimination Half-life (t½)
Blood samples for TNA analysis collected at pre-infusion; 5 minutes postinfusion; 8, 24, and 48 hours postinfusion; and Days 3, 5, 10, 14, 21, 30, 45, 60, and 90 postinfusion.
Time frame: From the time of infusion through Day 90 postinfusion.
Population: Pharmacokinetic ITT population: all subjects who received any infusion of AIGIV, had sufficient data for PK analysis, and had no specified protocol violations known before database lock that would be expected to affect the titer.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| AIGIV 3.5 mg/kg (Cohort A) | Elimination Half-life (t½) | 489.36 hours |
| Gamunex 90 mg/kg (Cohort A) | Elimination Half-life (t½) | 526.36 hours |
| AIGIV 7.0 mg/kg (Cohort B) | Elimination Half-life (t½) | 569.98 hours |
Secondary
Elimination Rate Constant
Blood samples for TNA analysis collected at pre-infusion; 5 minutes postinfusion; 8, 24, and 48 hours postinfusion; and Days 3, 5, 10, 14, 21, 30, 45, 60, and 90 postinfusion.
Time frame: From the time of infusion through Day 90 postinfusion.
Population: Pharmacokinetic ITT population: all subjects who received any infusion of AIGIV, had sufficient data for PK analysis, and had no specified protocol violations known before database lock that would be expected to affect the titer.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AIGIV 3.5 mg/kg (Cohort A) | Elimination Rate Constant | 0.0014 /h | Standard Deviation 0.0004 |
| Gamunex 90 mg/kg (Cohort A) | Elimination Rate Constant | 0.0013 /h | Standard Deviation 0.0003 |
| AIGIV 7.0 mg/kg (Cohort B) | Elimination Rate Constant | 0.0012 /h | Standard Deviation 0.0004 |
Secondary
Maximum Plasma Titer/Concentration of TNA (Toxin Neutralizing Antibody) (Cmax)
Blood samples for TNA analysis collected at pre-infusion; 5 minutes postinfusion; 8, 24, and 48 hours postinfusion; and Days 3, 5, 10, 14, 21, 30, 45, 60, and 90 postinfusion. Assay results are reported as the 50% neutralization factor, TNA NF50: the ED50 of the test sample (ie, effective dilution of test sample that neutralized 50% of toxin) divided by the ED50 of the reference standard.
Time frame: From the time of infusion through Day 90 postinfusion.
Population: Pharmacokinetic (PK) intent-to-treat (ITT) population: all subjects who received any infusion of AIGIV, had sufficient data for PK analysis, and had no specified protocol violations known before database lock that would be expected to affect the titer.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AIGIV 3.5 mg/kg (Cohort A) | Maximum Plasma Titer/Concentration of TNA (Toxin Neutralizing Antibody) (Cmax) | 1.07 NF50 (50% neutralization factor) | Standard Deviation 0.26 |
| Gamunex 90 mg/kg (Cohort A) | Maximum Plasma Titer/Concentration of TNA (Toxin Neutralizing Antibody) (Cmax) | 2.21 NF50 (50% neutralization factor) | Standard Deviation 0.48 |
| AIGIV 7.0 mg/kg (Cohort B) | Maximum Plasma Titer/Concentration of TNA (Toxin Neutralizing Antibody) (Cmax) | 4.31 NF50 (50% neutralization factor) | Standard Deviation 0.98 |
Secondary
Mean Residence Time (MRT)
Blood samples for TNA analysis collected at pre-infusion; 5 minutes postinfusion; 8, 24, and 48 hours postinfusion; and Days 3, 5, 10, 14, 21, 30, 45, 60, and 90 postinfusion.
Time frame: From the time of infusion through Day 90 postinfusion.
Population: Pharmacokinetic ITT population: all subjects who received any infusion of AIGIV, had sufficient data for PK analysis, and had no specified protocol violations known before database lock that would be expected to affect the titer.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AIGIV 3.5 mg/kg (Cohort A) | Mean Residence Time (MRT) | 679.67 hours | Standard Deviation 178.07 |
| Gamunex 90 mg/kg (Cohort A) | Mean Residence Time (MRT) | 694.68 hours | Standard Deviation 184.39 |
| AIGIV 7.0 mg/kg (Cohort B) | Mean Residence Time (MRT) | 724.82 hours | Standard Deviation 175.58 |
Secondary
Time of Cmax
Blood samples for TNA analysis collected at pre-infusion; 5 minutes postinfusion; 8, 24, and 48 hours postinfusion; and Days 3, 5, 10, 14, 21, 30, 45, 60, and 90 postinfusion.
Time frame: From the time of infusion through Day 90 postinfusion.
Population: Pharmacokinetic ITT population: all subjects who received any infusion of AIGIV, had sufficient data for PK analysis, and had no specified protocol violations known before database lock that would be expected to affect the titer.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AIGIV 3.5 mg/kg (Cohort A) | Time of Cmax | 4.49 hours | Standard Deviation 13.65 |
| Gamunex 90 mg/kg (Cohort A) | Time of Cmax | 7.81 hours | Standard Deviation 23.06 |
| AIGIV 7.0 mg/kg (Cohort B) | Time of Cmax | 7.35 hours | Standard Deviation 22.53 |