Study to Evaluate Safety and PK of a Single IM Dose of G03-52-01 vs Placebo in Adult Subjects

Study Overview
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Brief Summary
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A Phase 1, randomized, double-blind, placebo-controlled dose escalation trial of four dose cohorts of 10 subjects (A: 10mg, B: 25mg, C: 50mg, D: 100mg).

Detailed Description
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A Phase 1, randomized, double-blind, placebo-controlled dose escalation trial of four dose cohorts of 10 subjects (A: 10mg, B: 25mg, C: 50mg, D: 100mg). Dose escalation will not occur until safety data through Day 8 is reviewed by the Safety Review Committee (SRC). The study will consist of a twenty-eight day screening period, 12-hour clinic stay, and 120-day (Cohorts A-C) or 180-day (Cohort D) outpatient follow-up. The primary objective of this study is to assess the safety and tolerability of escalating doses of G03-52-01 administered intramuscularly (IM) in healthy adult subjects. The secondary objectives are to evaluate the pharmacokinetics (PK) and immunogenicity of escalating IM doses of G03-52-01.

Official Title
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A Phase 1, Randomized, Double-Blind, Dose Escalation Study to Evaluate the Safety and Pharmacokinetics of a Single IM Dose of G03-52-01 vs Placebo in Adult Subjects

Conditions
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Healthy

Intervention / Treatment
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* Drug: G03-52-01
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Informed consent understood and signed Healthy male or healthy, non-pregnant, non-lactating female Willingness to comply and be available for all protocol procedures Between 18 and 45 years of age on the day of IM injection Body Mass Index (BMI) of ≥18.5 and ≤35 kg/m2 If the subject is female and of childbearing potential, she has a negative serum pregnancy test at screening and negative urine test within 24 hours prior to IM injection • Note: 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 or successful Essure placement with documented confirmation test at least 3 months after the procedure. If the subject is female and of childbearing potential, she agrees to practice abstinence from sexual intercourse with men or use acceptable contraception during participation in the study • Note: Acceptable contraception methods are restricted to effective devices (Intrauterine Contraceptive Devices) The hemoglobin, platelet count, white blood cell count and absolute neutrophil count are not below the LLN and ≤ULN x 10% • Abnormalities in mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), red cell distribution width (RDW), mean platelet volume (MPV), and nucleated red blood cell count (NRBC CT), which are included in a complete blood count with differential, will not be exclusions. The urine dipstick results on protein, glucose and blood are negative or trace Note: Menstruating females failing inclusion criteria due to a positive blood on urine dipstick may be retested following cessation of menses. Note: When a urine dipstick is more than trace positive for blood (whether a menstruating female or other subjects), that subject would not be excluded if the urine microscopic exam shows <5 rbcs/hpf. Chemistry screening laboratory tests as outlined in Section 7.5.1.4 are in the normal reference range Note: The following exceptions to laboratory normal reference ranges are allowed: Creatinine, Blood Urea Nitrogen (BUN), total bilirubin, AST, ALT, lipase, amylase, Prothrombin Time (PT), Partial Thromboplastin Time (PTT) below the lower limit of normal (LLN); CK less than 400U/L; Glucose, potassium, total protein, and alkaline phosphatase with a toxicity grade of 1 is allowable; albumin above the upper limit of normal (ULN). 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. The urine drug screen is negative Breathalyzer test is negative Available for follow-up for the duration of the study Agrees not to participate in vigorous activity 72 hours prior to dosing through day 15 post dosing Exclusion Criteria: 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. • Note: Chronic medical conditions include but 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); History of severe allergic reaction of any type to medications, bee stings, food, or environmental factors or hypersensitivity or reaction to immunoglobulins. • Note: Severe allergic reaction is defined as any of the following: anaphylaxis, urticaria, or angioedema A marked baseline prolongation of QT/QTc interval (e.g., repeated demonstration of a QTc interval >450 milliseconds) Clinically significant abnormal electrocardiogram at screening. • Note: Clinically significant abnormal ECG results include but not limited to: complete left or right bundle branch block; other ventricular conduction block; 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 Positive serology results for HIV, HBsAg, or HCV antibodies Febrile illness with temperature ≥38°C within 7 days of dosing Pregnant or breastfeeding Donated blood within 56 days of enrollment Known allergic reactions to any of the study product components present in the formulation or in the processing, as listed in the Investigator Brochure Treatment with another investigational drug within 28 days of dosing Treatment with a monoclonal antibody within 3 months of enrollment. Receipt of antibody (e.g. TIG, VZIG, IVIG, IM gamma globulin) or blood transfusion within 6 months or within 5 half-lives of the specific product given Active drug or alcohol use or dependence that, in the opinion of the investigator, would interfere with adherence to study requirements Use of H1 antihistamines or beta-blockers within 5 days of dosing 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; any vaccine (licensed or investigational). Subjects will be eligible to receive any authorized COVID-19 vaccine after they complete Study Day 8 Previous exposure to botulinum toxin, receipt of antibodies against botulinum toxin, or previous treatment with equine antitoxin Any previous injection or planned injection within 4 months after enrollment of botulinum toxin for cosmetic reasons, spastic dysphonia, torticollis, or any other reason Any specific condition that in the judgment of the investigator precludes participation because it could affect subject safety Plans to enroll or is already enrolled in another clinical trial* that could interfere with safety assessment of the investigational product at any time during the study period • Note: Includes trials that have a study intervention such as a drug, biologic, or device Is a study site employee or staff • Note: Site employees or staff include the PIs and sub-investigators or staff who are supervised by the PI or Sub-Investigators Systolic blood pressure >140mm Hg or diastolic blood pressure >90 mm Hg Resting hear rate <50 or >100 beats per minute Oral temperature ≥ 38°C (100.4°F) Subjects with NX02 antibody levels present at screening will be excluded from Cohort 4.

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

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: dose escalation trial of four dose cohorts of 10 subjects (A: 10mg, B: 25mg, C: 50mg, D: 100 mg)
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 10mg of G03-52-01<br>8 subjects randomized to 10 mg of G03-52-01 and 2 subjects randomized to placebo | Drug: G03-52-01<br>* G03-52-01 administered intramuscularly<br>Drug: Placebo<br>* Placebo administered intramuscularly<br>|
| Experimental: 25mg of G03-52-01<br>8 subjects randomized to 25 mg of G03-52-01 and 2 subjects randomized to placebo | Drug: G03-52-01<br>* G03-52-01 administered intramuscularly<br>Drug: Placebo<br>* Placebo administered intramuscularly<br>|
| Experimental: 50 mg of G03-52-01<br>8 subjects randomized to 50 mg of G03-52-01 and 2 subjects randomized to placebo | Drug: G03-52-01<br>* G03-52-01 administered intramuscularly<br>Drug: Placebo<br>* Placebo administered intramuscularly<br>|
| Experimental: 100 mg of G03-52-01<br>8 subjects randomized to 100 mg of G03-52-01 and 2 subjects randomized to placebo | Drug: G03-52-01<br>* G03-52-01 administered intramuscularly<br>Drug: Placebo<br>* Placebo administered intramuscularly<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The occurrence of Serious Adverse Events (SAE) following administration of G03-52-01 to the final follow-up visit. | Determine number of SAEs after dosing (Cohorts A-C) | day 0 to day 120 | 
| The occurrence of Serious Adverse Events (SAE) following administration of G03-52-01 to the final follow-up visit. | Determine number of SAEs after dosing (Cohort D) | day 0 to day 180 | 
| The occurrence of Adverse Events (AE) following administration of G03-52-01 to the final follow-up visit | Determine number of AEs after dosing (Cohorts A-C) | day 0 to day 120 | 
| The occurrence of Adverse Events (AE) following administration of G03-52-01 to the final follow-up visit | Determine number of AEs after dosing (Cohort D) | day 0 to day 180 | 
| The occurrence of changes from baseline in physical examination, vital signs and clinical safety laboratory values following administration of G03-52-01 to the final follow-up visit. | Determine number of changes from baseline (Cohorts A-C) | day 0 to day 120 | 
| The occurrence of changes from baseline in physical examination, vital signs and clinical safety laboratory values following administration of G03-52-01 to the final follow-up visit. | Determine number of changes from baseline (Cohort D) | day 0 to day 180 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Peak plasma concentration (Cmax) | MNA assessment of PK (Cohorts A-C) | pre-dose, days 4, 30, 60, 90, and 120 | 
| Peak plasma concentration (Cmax) | MNA assessment of PK (Cohort D) | pre-dose, 2 hours post-dose, days 4, 30, 45, 60, 90, and 120 | 
| Time to achieve peak concentration of the drug after administration (Tmax) | MNA assessment of PK (Cohorts A-C) | pre-dose, days 4, 30, 60, 90, and 120 | 
| Time to achieve peak concentration of the drug after administration (Tmax) | MNA assessment of PK (Cohort D) | pre-dose, 2 hours post-dose, days 4, 30, 45, 60, 90, and 120 | 
| Area under the plasma concentration versus time curve (AUC) | MNA assessment of PK (Cohorts A-C) | pre-dose, days 4, 30, 60, 90, and 120 | 
| Area under the plasma concentration versus time curve (AUC) | MNA assessment of PK (Cohort D) | pre-dose, 2 hours post-dose, days 4, 30, 45, 60, 90, and 120 | 
| Peak plasma concentration (Cmax) | ELISA/ECLA assessment of PK (Cohorts A-C) | pre-injection, 2, 4, 8, 24, 48, and 72 hours post injection, and on days 4, 8, 15, 30, 45, 60, 90, and 120 | 
| Peak plasma concentration (Cmax) | ELISA/ECLA assessment of PK (Cohort D) | pre-injection, 6 hours post injection, and on days 1, 2, 4, 8, 15, 30, 45, 60, 90, 120, and 180 | 
| Time to achieve peak concentration of the drug after administration (Tmax) | ELISA/ECLA assessment of PK (Cohorts A-C) | pre-injection, 2, 4, 8, 24, 48, and 72 hours post injection, and on days 4, 8, 15, 30, 45, 60, 90, and 120 | 
| Time to achieve peak concentration of the drug after administration (Tmax) | ELISA/ECLA assessment of PK (Cohort D) | pre-injection, 6 hours post injection, and on days 1, 2, 4, 8, 15, 30, 45, 60, 90, 120, and 180 | 
| Area under the plasma concentration versus time curve (AUC) | ELISA/ECLA assessment of PK (Cohorts A-C) | pre-injection, 2, 4, 8, 24, 48, and 72 hours post injection, and on days 4, 8, 15, 30, 45, 60, 90, and 120 | 
| Area under the plasma concentration versus time curve (AUC) | ELISA/ECLA assessment of PK (Cohort D) | pre-injection, 6 hours post injection, and on days 1, 2, 4, 8, 15, 30, 45, 60, 90, 120, and 180 | 
| Anti-drug antibodies (ADA) | To assess the anti-drug antibody levels (Cohorts A-C) | pre-dose, days 15, 30, 45, 60, 90, and 120 | 
| Anti-drug antibodies (ADA) | To assess the anti-drug antibody levels (Cohort D) | pre-dose, days 45, 60, 90, 120, and 180 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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botulinum toxin, botulism