Single or Repeat Dose of G03-52-01 in Adult Subjects

U.S. Army Medical Research and Development Command622 enrolled

Overview

A Phase 2, randomized, double-blind, placebo-controlled single or repeat dose trial

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

PREVENTION

Masking

QUADRUPLE

Enrollment

622

Conditions

Healthy Botulinum Toxin

Interventions

G03-52-01DRUG

G03-52-01 administered intramuscularly

PlaceboDRUG

placebo

Eligibility

Sex: ALLMin age: 18 YearsMax age: 65 YearsHealthy volunteers:

Medical Language ↔ Plain English

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 exclusion criteria. 9. Breathalyzer test is negative. 10. Available for follow-up for the duration of the study. 11. Agrees not to participate in vigorous activity 2 days prior to dosing and 2 days post-dose Day 1 and Day 45 for Cohorts 1-3 and Day 1 for Cohort 4, per Investigator discretion. Exclusion Criteria: 1. History of a chronic medical condition that would either interfere with the accurate assessment of the objectives of the study or increase the risk profile of the subject. \- Chronic medical conditions include but are not limited to diabetes; Asthma requiring use of medication in the year before screening; Autoimmune disorder such as lupus, Wegener's, rheumatoid arthritis, thyroid disease; coronary artery disease; chronic hypertension; History of malignancy except low-grade (squamous and basal cell) skin cancer thought to be cured; chronic renal, hepatic, pulmonary, or endocrine disease (except previous asthma which has required no treatment for the past year). 2. Known history of severe allergic reaction of any type to medications, bee stings, food, or environmental factors or hypersensitivity or reaction to immunoglobulins. \- Severe allergic reactions are defined as any of the following: anaphylaxis, urticaria, or angioedema. 3. Known allergic reactions to any of the study product components present in the formulation or in the processing. 4. A marked baseline prolongation of QT/QTc interval (e.g., repeated demonstration of a QTc interval \>450 milliseconds). 5. Clinically significant abnormal electrocardiogram (ECG) at screening. \- Clinically significant abnormal ECG results include but are not limited to: complete left or right bundle branch block; other ventricular conduction block except for incomplete RBB; 2nd degree or 3rd degree atrioventricular (AV) block; sustained ventricular arrhythmia; sustained atrial arrhythmia; two Premature Ventricular Contractions in a row; pattern of ST elevation felt consistent with cardiac ischemia; or any condition deemed clinically significant by a study investigator. 6. Positive serology results for human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg), or hepatitis C virus (HCV) antibodies. 7. Febrile illness with temperature ≥38°C within 7 days of dosing. Subjects with acute febrile illness within 7 days of dosing may be rescreened no earlier than 7 days following resolution of symptoms. 8. Female subjects that are pregnant or breastfeeding or intending to become pregnant within the projected duration of the trial starting from the Screening visit until last dose. 9. Donation of blood or blood product within 56 days of enrollment. 10. Is currently participating or has participated in a study with an investigational product (IP) within 28 days preceding Day 1 (documented receipt of placebo in a previous trial would be permissible for trial eligibility) 11. Plans to enroll in another clinical trial that could interfere with safety assessment of the IP at any time during the study period. \- Includes trials that have a study intervention such as a drug, biologic, or device only 12. Treatment with a mAB within 3 months of Day 1. 13. Receipt of antibody (e.g., tetanus immune globulin \[TIG\], varicella zoster immune globulin \[VZIG\], intravenous immunoglobulin \[IVIG\], IM gamma globulin) or blood transfusion within 6 months or within 5 half-lives of the specific product given. 14. Reported active drug or alcohol or substance abuse/independence or illicit drug use that, in the opinion of the Investigator, would interfere with adherence to study requirements. 15. Use of H1 antihistamines or beta-blockers within 5 days of dosing Day 1 and Day 45 for Cohorts 1-3 and Day 1 for Cohort 4 (PRN use could be allowed with MM approval). 16. Use of any prohibited medication within 28 days prior to study entry or planned use during the study period. \- Note: Prohibited medications include immunosuppressives (except nonsteroidal anti-inflammatory drugs \[NSAIDs\]); immune modulators; oral corticosteroids (topical/intranasal steroids are acceptable); anti-neoplastic agents. 17. Previous exposure to botulinum toxin, receipt of antibodies against botulinum toxin, or previous treatment with equine antitoxin. 18. Any previous injection or any planned injection within 4 months after enrollment of botulinum toxin for cosmetic reasons, spastic dysphonia, torticollis, or any other reason. 19. Any illness or condition that in the judgment of the Investigator may affect the safety of the subject or the evaluation of any study endpoint. 20. Is a study site employee, staff, or close relative as defined. * PIs and Sub-Investigators * Staff who are supervised by the PI, Sub-Investigators * Member of the team conducting this clinical trial * Children, spouse, partners, siblings, and parents of site staff

Locations (15)

AMR Mobile

Mobile, Alabama, United States

AMR Tempe

Tempe, Arizona, United States

AMR Fort Myers

Fort Myers, Florida, United States

Outcomes

Primary Outcomes

Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)

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.

Time frame: Cohorts 1-3: 240 days; Cohort 4: 120 days

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

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.

Time frame: Day 45 and Day 90

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

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.

Time frame: 4 and 8 hours post dose on Day 1

Secondary Outcomes

Data from ClinicalTrials.gov

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AMR Miami

Miami, Florida, United States

AMR El Dorado

El Dorado, Kansas, United States

AMR Newton

Newton, Kansas, United States

AMR Wichita West

Wichita, Kansas, United States

AMR Wichita East

Wichita, Kansas, United States

AMR Lexington

Lexington, Kentucky, United States

AMR New Orleans

New Orleans, Louisiana, United States

...and 5 more locations

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

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

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.

Time frame: Day 1 pre-dose, 24 hours post dose, and on Days 8, 15, 45 (prior to dosing), 49, 90, and 120

Cohorts 1-2 Only: Terminal Half-life (t1/2) for Serotypes BoNT/A and BoNT/B

Time frame: Day 1 pre-dose, 24 hours post dose, and on Days 8, 15 and 45 (prior to dosing)

Cohorts 1-2 Only: Maximum Observed Concentration (Cmax) for Serotypes BoNT/A and BoNT/B

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.

Time frame: Day 1 pre-dose, 24 hours post dose, and on Days 8, 15, 45 (prior to dosing), 49, 90, and 120

Cohorts 1-2 Only: Time of Maximum Observed Concentration (Tmax) for Serotypes BoNT/A and BoNT/B

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.

Time frame: Day 1 pre-dose, 24 hours post dose, and on Days 8, 15, 45 (prior to dosing), 49, 90, and 120

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

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.

Time frame: Day 1 pre-dose and Days 15, 45 (prior to dosing), 60, 90, 120, 150, 180, and 240

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

Time frame: 2 hours post dose on Day 1

Cohort 4 Only: Area Under the Concentration-time Curve Extrapolated to Infinity (AUC(0-inf)) of Each Component of the G03-52-01 DP

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.