Botulinum Toxin, Healthy
Conditions
Brief summary
A Phase 2, randomized, double-blind, placebo-controlled single or repeat dose trial
Detailed description
A Phase 2, multicenter, randomized, double-blinded, placebo-controlled study to evaluate a single (100 mg) or repeat dose (50 mg and 100 mg) of G03-52-01 administered by IM injection(s) in adult subjects. Approximately 625 subjects will be enrolled in this study.
Interventions
DRUGG03-52-01
G03-52-01 administered intramuscularly
DRUGPlacebo
placebo
Sponsors
U.S. Army Medical Research and Development Command
United States Department of Defense
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
randomized, double-blind, placebo-controlled
Intervention model description
Single dose of G03-52-01 100 mg or placebo or a repeat dose of G03-52-01 (50mg or 100mg) or placebo on days 1 and 45
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
Yes
Inclusion criteria
1. Informed consent understood and signed prior to screening procedures. 2. Assessed by the Investigator to be a healthy male or healthy, non-pregnant, non-lactating female between the ages of 18 and 65 inclusive on the day of dosing. 3. Able and willing to comply and be available for all protocol procedures and follow-up for the duration of the study. 4. Body Mass Index (BMI) of ≥18.5 and ≤35 kg/m2. 5. Females of child-bearing potential must have a negative serum pregnancy test at screening and negative urine pregnancy test on Day 1 prior to dosing. \- A woman is considered of childbearing potential unless post-menopausal (≥ 1 year without menses) or surgically sterilized via bilateral oophorectomy, or hysterectomy or bilateral tubal ligation. 6. If the subject is female and of childbearing potential, she agrees to practice abstinence from sexual intercourse with men or use medically effective contraception (methods with a failure rate of \< 1% per year when used consistently and correctly) during participation in the study. Acceptable methods include: * Hormonal contraception including implants, injections or oral * Two barrier methods, e.g., condom and cervical cap (with spermicide) or diaphragm (with spermicide) * Intrauterine device (IUD) or intrauterine system 7. Screening clinical laboratory results within normal ranges or are no greater than a Grade 1 and deemed not clinically significant by Medical Monitor (MM) and Principal Investigator (PI). Any subjects with results that are Grade 2 or above according to Appendix B will be excluded. \- Laboratory values that are outside the range of eligibility but are thought to be due to an acute condition or due to laboratory error may be repeated once. 8. The urine drug screen is negative. * For Cohorts 1-3, if a subject has a positive urine drug screen that the PI believes is caused by a currently prescribed medication, (except for THC), the PI may enroll the subject if they meet all inclusion criteria, and none of the
Exclusion criteria
. * For Cohort 4, if a subject has a positive urine drug screen that the PI believes is caused by a currently prescribed medication or positive for THC, the PI may enroll the subject if they meet all other inclusion criteria and none of the
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Cohorts 1-3: 240 days; Cohort 4: 120 days | An AE was any unfavourable and unintended sign, symptom, or disease temporarily associated with the use of investigational product (IP), whether or not related to the IP. A SAE was any untoward medical occurrence that at any dose: resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in a congenital abnormality/birth defect, or caused any persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions. Clinically significant changes in physical examination, vital signs, and clinical safety laboratory values were included as AEs. |
| Cohorts 1-2 Only: Percentage of Participants With Target Protective Concentration Neutralizing Antibody Concentration (NAC) Value > 0.02 U/mL (Botulinum Neurotoxin [BoNT]/A) or > 0.03 U/mL (BoNT/B) at Day 45 and Day 90 | Day 45 and Day 90 | Pharmacodynamic (PD) samples were tested using the Battelle Mouse Neutralization Assay (MNA) for serotypes A and B. The MNA was used to determine the concentration of functional antibodies in a sample capable of neutralizing BoNT (i.e., amount of BoNT/A or BoNT/B toxin neutralization afforded by the combination of antibodies). NAC, as measured by the MNA, is proposed to bridge efficacy between animal models and humans. |
| Cohort 4 Only: Percentage of Participants With Target Protective Concentration NAC Value > 0.02 U/mL (BoNT/A) or > 0.03 U/mL (BoNT/B) at 4 and 8 Hours Post Dose | 4 and 8 hours post dose on Day 1 | PD samples were tested using the MNA for serotypes A and B. The MNA was used to determine the concentration of functional antibodies in a sample capable of neutralizing BoNT (i.e., amount of BoNT/A or BoNT/B toxin neutralization afforded by the combination of antibodies). NAC, as measured by the MNA, is proposed to bridge efficacy between animal models and humans. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Cohorts 1-2 Only: Percentage of Participants With Target Protective Concentration NAC Value > 0.02 U/mL (BoNT/A) or > 0.03 U/mL (BoNT/B) at Day 120 | Day 120 | PD samples were tested using the MNA for serotypes A and B. The MNA was used to determine the concentration of functional antibodies in a sample capable of neutralizing BoNT (i.e., amount of BoNT/A or BoNT/B toxin neutralization afforded by the combination of antibodies). NAC, as measured by the MNA, is proposed to bridge efficacy between animal models and humans. |
| Cohorts 1-2 Only: Area Under the Concentration-time Curve to the Last Concentration Above the Lower Limit of Quantitation (AUC(0-t)) for Serotypes BoNT/A and BoNT/B | Day 1 pre-dose, 24 hours post dose, and on Days 8, 15, 45 (prior to dosing), 49, 90, and 120 | PD samples were tested by MNA for serotypes BoNT/A and BoNT/B. The MNA was used to determine the concentration of functional antibodies in a sample capable of neutralizing BoNT (i.e., amount of BoNT/A or BoNT/B toxin neutralization afforded by the combination of antibodies). NAC, as measured by the MNA, is proposed to bridge efficacy between animal models and humans. If pre-dose concentration was inconclusive, not tested, or missing, or if there were fewer than two measurable concentrations in the participant's profile, the parameters were not determined and the participant was excluded from MNA analysis. In the calculation of PD parameters, below limit of quantitation (BLQ) values were treated as zero prior to the first measurable concentration. After the first measurable concentration, subsequent BLQ values were treated as missing. Values that were above the upper limit of quantitation were set to the ULQ (upper limit of quantitation) of the assay for analysis. |
| Cohorts 1-2 Only: Terminal Half-life (t1/2) for Serotypes BoNT/A and BoNT/B | Day 1 pre-dose, 24 hours post dose, and on Days 8, 15 and 45 (prior to dosing) | PD samples were tested by MNA for serotypes BoNT/A and BoNT/B. The MNA was used to determine the concentration of functional antibodies in a sample capable of neutralizing BoNT (i.e., amount of BoNT/A or BoNT/B toxin neutralization afforded by the combination of antibodies). NAC, as measured by the MNA, is proposed to bridge efficacy between animal models and humans. t1/2 was determined after the first dose on Day 1. This value was calculated as t1/2 = ln(2)/ λz where λz is the elimination rate constant. Only samples up to Day 45 predose were used in these calculations, however the above equation allows a half life greater than the sampling interval. |
| Cohorts 1-2 Only: Maximum Observed Concentration (Cmax) for Serotypes BoNT/A and BoNT/B | Day 1 pre-dose, 24 hours post dose, and on Days 8, 15, 45 (prior to dosing), 49, 90, and 120 | PD samples were tested by MNA for serotypes BoNT/A and BoNT/B. The MNA was used to determine the concentration of functional antibodies in a sample capable of neutralizing BoNT (i.e., amount of BoNT/A or BoNT/B toxin neutralization afforded by the combination of antibodies). NAC, as measured by the MNA, is proposed to bridge efficacy between animal models and humans. If pre-dose concentration was inconclusive, not tested, or missing, or if there were fewer than two measurable concentrations in the participant's profile, the parameters were not determined and the participant was excluded from MNA analysis. In the calculation of PD parameters, BLQ values were treated as zero prior to the first measurable concentration. After the first measurable concentration, subsequent BLQ values were treated as missing. Values that were above the upper limit of quantitation were set to the upper limit of quantitation of the assay for analysis. |
| Cohorts 1-2 Only: Time of Maximum Observed Concentration (Tmax) for Serotypes BoNT/A and BoNT/B | Day 1 pre-dose, 24 hours post dose, and on Days 8, 15, 45 (prior to dosing), 49, 90, and 120 | PD samples were tested by MNA for serotypes BoNT/A and BoNT/B. The MNA was used to determine the concentration of functional antibodies in a sample capable of neutralizing BoNT (i.e., amount of BoNT/A or BoNT/B toxin neutralization afforded by the combination of antibodies). NAC, as measured by the MNA, is proposed to bridge efficacy between animal models and humans. If pre-dose concentration was inconclusive, not tested, or missing, or if there were fewer than two measurable concentrations in the participant's profile, the parameters were not determined and the participant was excluded from MNA analysis. In the calculation of PD parameters, BLQ values were treated as zero prior to the first measurable concentration. After the first measurable concentration, subsequent BLQ values were treated as missing. Values that were above the upper limit of quantitation were set to the upper limit of quantitation of the assay for analysis. |
| Cohorts 1-2 Only: Number of Participants With Anti-drug Antibodies (ADA) to Each Component of the G03-52-01 Drug Product (DP) at Each Timepoint Tested | Day 1 pre-dose and Days 15, 45 (prior to dosing), 60, 90, 120, 150, 180, and 240 | The presence of ADA was determined using a validated electrochemiluminescence assay (ECLA) that measured total ADA in serum. Detected and Not Detected results correspond to samples that were potential positive during screening testing. No Recorded Result (NRR) results correspond to samples that were NRR during screening testing. Percentages are based on n, the number of participants in each treatment group with a non-missing result at each time point for the given analyte. |
| Cohort 4 Only: Percentage of Participants With Target Protective NAC Value > 0.02 U/mL (BoNT/A) or > 0.03 U/mL (BoNT/B) at 2 Hours Post Dose | 2 hours post dose on Day 1 | PD samples were tested using the MNA for serotypes A and B. The MNA was used to determine the concentration of functional antibodies in a sample capable of neutralizing BoNT (i.e., amount of BoNT/A or BoNT/B toxin neutralization afforded by the combination of antibodies). NAC, as measured by the MNA, is proposed to bridge efficacy between animal models and humans. |
| Cohort 4 Only: Area Under the Concentration-time Curve Extrapolated to Infinity (AUC(0-inf)) of Each Component of the G03-52-01 DP | Day 1 pre-dose, 2 hours, 4 hours, 8 hours, 24 hours, 72 hours post dose, and on Days 8, 15, 30, 45, 90, and 120 | PK parameters were measured by enzyme-linked immunosorbent assay (ELISA) or ECLA for each of the monoclonal antibodies (mAb) of G03-52-01, and PK parameters were estimated for each of the six mAbs separately using noncompartmental methods in WinNonlin or a similar software package. |
| Cohort 4 Only: AUC(0-t) of Each Component of the G03-52-01 DP | Day 1 pre-dose, 2 hours, 4 hours, 8 hours, 24 hours, 72 hours post dose, and on Days 8, 15, 30, 45, 90, and 120 | PK parameters were measured by ELISA or ECLA for each of the mAb of G03-52-01, and PK parameters were estimated for each of the six mAbs separately using noncompartmental methods in WinNonlin or a similar software package. |
| Cohort 4 Only: Total Body Clearance (CL/F) of Each Component of the G03-52-01 DP | Day 1 pre-dose, 2 hours, 4 hours, 8 hours, 24 hours, 72 hours post dose, and on Days 8, 15, 30, 45, 90, and 120 | PK parameters were measured by ELISA or ECLA for each of the monoclonal antibodies (mAb) of G03-52-01, and PK parameters were estimated for each of the six mAbs separately using noncompartmental methods in WinNonlin or a similar software package. |
| Cohort 4 Only: Cmax of Each Component of the G03-52-01 DP | Day 1 pre-dose, 2 hours, 4 hours, 8 hours, 24 hours, 72 hours post dose, and on Days 8, 15, 30, 45, 90, and 120 | PK parameters were measured by ELISA or ECLA for each of the mAb of G03-52-01, and PK parameters were estimated for each of the six mAbs separately using noncompartmental methods in WinNonlin or a similar software package. |
| Cohort 4 Only: t1/2 of Each Component of the G03-52-01 DP | Day 1 pre-dose, 2 hours, 4 hours, 8 hours, 24 hours, 72 hours post dose, and on Days 8, 15, 30, 45, 90, and 120 | PK parameters were measured by ELISA or ECLA for each of the monoclonal antibodies (mAb) of G03-52-01, and PK parameters were estimated for each of the six mAbs separately using noncompartmental methods in WinNonlin or a similar software package. |
| Cohort 4 Only: Tmax of Each Component of the G03-52-01 DP | Day 1 pre-dose, 2 hours, 4 hours, 8 hours, 24 hours, 72 hours post dose, and on Days 8, 15, 30, 45, 90, and 120 | PK parameters were measured by ELISA or ECLA for each of the mAb of G03-52-01, and PK parameters were estimated for each of the six mAbs separately using noncompartmental methods in WinNonlin or a similar software package. |
| Cohort 4 Only: Volume of Distribution (Vz/F) of Each Component of the G03-52-01 DP | Day 1 pre-dose, 2 hours, 4 hours, 8 hours, 24 hours, 72 hours post dose, and on Days 8, 15, 30, 45, 90, and 120 | PK parameters were measured by ELISA or ECLA for each of the mAb of G03-52-01, and PK parameters were estimated for each of the six mAbs separately using noncompartmental methods in WinNonlin or a similar software package. |
| Cohort 4 Only: AUC(0-t) for Serotypes BoNT/A and BoNT/B | Day 1 pre-dose, 2, 4, 8 and 24 hours post-dose, and on Days 30, 45, and 90 | PD samples were tested by MNA for serotypes BoNT/A and BoNT/B. The MNA was used to determine the concentration of functional antibodies in a sample capable of neutralizing BoNT (i.e., amount of BoNT/A or BoNT/B toxin neutralization afforded by the combination of antibodies). NAC, as measured by the MNA, is proposed to bridge efficacy between animal models and humans. If pre-dose concentration was inconclusive, not tested, or missing, or if there were fewer than two measurable concentrations in the participant's profile, the parameters were not determined and the participant was excluded from MNA analysis. In the calculation of PD parameters, BLQ values were treated as zero prior to the first measurable concentration. After the first measurable concentration, subsequent BLQ values were treated as missing. Values that were above the upper limit of quantitation were set to the upper limit of quantitation of the assay for analysis. |
| Cohort 4 Only: t1/2 for Serotypes BoNT/A and BoNT/B | Day 1 pre-dose, 2, 4, 8 and 24 hours post-dose, and on Days 30 and 45 | PD samples were tested by MNA for serotypes BoNT/A and BoNT/B. The MNA was used to determine the concentration of functional antibodies in a sample capable of neutralizing BoNT (i.e., amount of BoNT/A or BoNT/B toxin neutralization afforded by the combination of antibodies). NAC, as measured by the MNA, is proposed to bridge efficacy between animal models and humans. t1/2 was determined after the first dose on Day 1. This value was calculated as t1/2 = ln(2)/ λz where λz is the elimination rate constant. Only samples up to Day 45 were used in these calculations, however the above equation allows a half life greater than the sampling interval. |
| Cohort 4 Only: Cmax for Serotypes BoNT/A and BoNT/B | Day 1 pre-dose, 2, 4, 8 and 24 hours post-dose, and on Days 30, 45, and 90 | PD samples were tested by MNA for serotypes BoNT/A and BoNT/B. The MNA was used to determine the concentration of functional antibodies in a sample capable of neutralizing BoNT (i.e., amount of BoNT/A or BoNT/B toxin neutralization afforded by the combination of antibodies). NAC, as measured by the MNA, is proposed to bridge efficacy between animal models and humans. If pre-dose concentration was inconclusive, not tested, or missing, or if there were fewer than two measurable concentrations in the participant's profile, the parameters were not determined and the participant was excluded from MNA analysis. In the calculation of PD parameters, BLQ values were treated as zero prior to the first measurable concentration. After the first measurable concentration, subsequent BLQ values were treated as missing. Values that were above the upper limit of quantitation were set to the upper limit of quantitation of the assay for analysis. |
| Cohort 4 Only: Tmax for Serotypes BoNT/A and BoNT/B | Day 1 pre-dose, 2, 4, 8 and 24 hours post-dose, and on Days 30, 45, and 90 | PD samples were tested by MNA for serotypes BoNT/A and BoNT/B. The MNA was used to determine the concentration of functional antibodies in a sample capable of neutralizing BoNT (i.e., amount of BoNT/A or BoNT/B toxin neutralization afforded by the combination of antibodies). NAC, as measured by the MNA, is proposed to bridge efficacy between animal models and humans. If pre-dose concentration was inconclusive, not tested, or missing, or if there were fewer than two measurable concentrations in the participant's profile, the parameters were not determined and the participant was excluded from MNA analysis. In the calculation of PD parameters, BLQ values were treated as zero prior to the first measurable concentration. After the first measurable concentration, subsequent BLQ values were treated as missing. Values that were above the upper limit of quantitation were set to the upper limit of quantitation of the assay for analysis. |
| Cohort 4 Only: Number of Participants With ADA to Each Component of the G03-52-01 DP at Each Timepoint Tested | Day 1 pre-dose and Days 90 and 120 | The presence of ADA was determined using a validated ECLA that measured total ADA in serum. Detected and Not Detected results correspond to samples that were potential positive during screening testing. NRR results correspond to samples that were NRR during screening testing. Percentages are based on n, the number of participants in each treatment group with a non-missing result at each time point for the given analyte. |
Countries
United States
Participant flow
Recruitment details
A total of 622 participants were enrolled into this trial in the United States between June 2022 and February 2025.
Pre-assignment details
The total duration of this trial was up to approximately 254 days for cohorts 1-3 and up to approximately 134 days for cohort 4. The screening period was up to 14 days for all cohorts, and the treatment/follow-up period was 240 days for cohorts 1-3 and 120 days for cohort 4.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 75 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 9 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 62 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 122 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) White | 50 Participants |
| Sex: Female, Male Female | 27 Participants |
| Sex: Female, Male Male | 23 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 | EG006 affected / at risk |
|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 75 | 0 / 75 | 0 / 74 | 0 / 73 | 0 / 74 | 0 / 200 | 0 / 50 |
| other Total, other adverse events | 61 / 75 | 61 / 75 | 61 / 74 | 56 / 73 | 47 / 74 | 105 / 200 | 21 / 50 |
| serious Total, serious adverse events | 2 / 75 | 0 / 75 | 1 / 74 | 0 / 73 | 0 / 74 | 1 / 200 | 0 / 50 |
Outcome results
None listed