A Study to Evaluate the Safety and Pharmacokinetics of NTM-1633 vs Placebo Administered Intravenously in Healthy Adults

NCT03603665 | Completed Phase 1 FDA Drug

• 2 other identifiers: 14-0023HHSN272201300017I
• Study Type: interventional
• Target: 24
• Locations: 1 country
• Sites: 1

Brief Summary

This is a Phase I, single-center, double-blind, placebo-controlled dose escalation trial of three dose cohorts (A: 0.033 mg/kg, B: 0.165 mg/kg, and C: 0.33 mg/kg). The purpose of this study is to evaluate the safety and tolerability of NTM-1633 in healthy adults. This is a first-in-human study consisting of three cohorts of eight subjects each. Dosing for each cohort is as follows: Two sentinel subjects will be administered a single 1-hour infusion (one NTM-1633, one placebo). No more than two subjects per day thereafter (at least 24 hrs will elapse between the dosing of each two subjects) will be dosed in the same manner until all subjects are dosed. Dose escalation will not occur until safety data through Day 8 is reviewed by the Safety Review Committee (SRC). Objective dose-escalation criteria and safety evaluations will be utilized. The study duration will be for approximately 8 months. Subjects in Cohort A will participate for approximately 17 weeks and Subjects in Cohorts B and C will participate approximately 21 weeks. Primary Objective: To assess the safety and tolerability of escalating doses of NTM-1633 administered intravenously in healthy adults.

Conditions

Botulism

Keywords

Botulism; Dose Escalation; Double-Blind; NTM-1633; Pharmacokinetics; Phase I; Safety

Outcome Measures

Primary Outcomes (35)

• The occurrence of AEs

  From Day 1 through Day 57

• The occurrence of changes in absolute neutrophil count

  From Day -1 through Day 91

• The occurrence of changes in alanine transaminase (ALT) level

  From Day -1 through Day 91

• The occurrence of changes in aldolase level

  From Day -1 through Day 91

• The occurrence of changes in alkaline phosphatase level

  From Day -1 through Day 91

• The occurrence of changes in aspartate transaminase (AST) level

  From Day -1 through Day 91

• The occurrence of changes in blood urea nitrogen (BUN) level

  From Day -1 through Day 91

• The occurrence of changes in calcium level

  From Day -1 through Day 91

• The occurrence of changes in Complete Blood Count (CBC) with differential

  From Day -1 through Day 91

• The occurrence of changes in diastolic blood pressure in arm A

  From Day -1 through Day 91

• The occurrence of changes in diastolic blood pressure in arms B and C

  From Day -1 through Day 121

• The occurrence of changes in direct bilirubin level

  From Day -1 through Day 91

• The occurrence of changes in heart rate in arm A

  From Day -1 through Day 91

• The occurrence of changes in heart rate in arms B and C

  From Day -1 through Day 121

• The occurrence of changes in hemoglobin level

  From Day -1 through Day 91

• The occurrence of changes in indirect bilirubin level

  From Day -1 through Day 91

• The occurrence of changes in oral temperature in arm A

  From Day -1 through Day 91

• The occurrence of changes in oral temperature in arms B and C

  From Day -1 through Day 121

• The occurrence of changes in physical examination in arm A

  From Day -1 through Day 91

• The occurrence of changes in physical examination in arms B and C

  From Day -1 through Day 121

• The occurrence of changes in platelet count

  From Day -1 through Day 91

• The occurrence of changes in potassium level

  From Day -1 through Day 91

• The occurrence of changes in prothrombin time/international normalized ratio (INR)

  From Day -1 through Day 91

• The occurrence of changes in serum creatinine level

  From Day -1 through Day 91

• The occurrence of changes in sodium level

  From Day -1 through Day 91

• The occurrence of changes in systolic blood pressure in arm A

  From Day -1 through Day 91

• The occurrence of changes in systolic blood pressure in arms B and C

  From Day -1 through Day 121

• The occurrence of changes in total bilirubin level

  From Day -1 through Day 91

• The occurrence of changes in total creatine kinase (CK) level

  From Day -1 through Day 91

• The occurrence of changes in White Blood Cell (WBC) count

  From Day -1 through Day 91

• The occurrence of clinically significant ECG abnormalities

  From Day -28 through Day 1

• The occurrence of QT interval abnormalities

  From Day -28 through Day 1

• The occurrence of SAEs in arm A

  From Day 1 through Day 91

• The occurrence of SAEs in arms B and C

  From Day 1 through Day 121

• The presence of protein, blood, or glucose in urine

  From Day -1 through Day 91

Secondary Outcomes (23)

• Area under the plasma concentration-time curve (AUC) from time 0 up to the last observed concentration at time t (AUC0-t) for XE02 in arm A

  From Day 1 through Day 91

• Area under the plasma concentration-time curve (AUC) from time 0 up to the last observed concentration at time t (AUC0-t) for XE02 in arms B and C

  From Day 1 through Day 121

• Area under the plasma concentration-time curve (AUC) from time 0 up to the last observed concentration at time t (AUC0-t) for XE06 in arm A

  From Day 1 through Day 91

• Area under the plasma concentration-time curve (AUC) from time 0 up to the last observed concentration at time t (AUC0-t) for XE06 in arms B and C

  From Day 1 through Day 121

• Area under the plasma concentration-time curve (AUC) from time 0 up to the last observed concentration at time t (AUC0-t) for XE17 in arm A

  From Day 1 through Day 91

Study Arms (3)

Arm A

EXPERIMENTAL

Single intravenous (IV) infusion of 0.033 mg/kg NTM-1633 (N=6) or matching Placebo (N=2) using an infusion pump over 60 minutes

Biological: NTM-1633; Other: Placebo

Arm B

EXPERIMENTAL

Single IV infusion of 0.165 mg/kg NTM-1633 (N=6) or matching Placebo (N=2) using an infusion pump over 60 minutes

Biological: NTM-1633; Other: Placebo

Arm C

EXPERIMENTAL

Single IV infusion of 0.330 mg/kg NTM-1633 (N=6) or matching Placebo (N=2) using an infusion pump over 60 minutes

Biological: NTM-1633; Other: Placebo

Interventions

NTM-1633 BIOLOGICAL

NTM-1633 is an equimolar mixture of three IgG1 monoclonal antibodies (mAb), referred to as XE02, XE06, and XE17 which bind to non-overlapping epitopes on Botulinum Neurotoxin (BoNT/E). Administered as a single intravenous infusion of NTM-1633 over one hour.

Arm A; Arm B; Arm C

Placebo OTHER

0.9% Sodium Chloride Injection administered as a single intravenous infusion over one hour.

Arm A; Arm B; Arm C

Eligibility Criteria

• Age: 18 Years - 45 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Informed consent understood and signed.
• Healthy male or healthy, non-pregnant, non-lactating female.
• Willingness to comply and be available for all protocol procedures including inpatient confinement for 36 - 48 hours.
• Age between 18 and 45 years, inclusive on the day of infusion.
• Body Mass Index (BMI) of \> / =18.5 and \< 35 kg/m\^2.
• 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 infusion.
• 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 up to visit 12 of the study.
• Acceptable contraception methods are restricted to effective devices (Intrauterine Contraceptive Devices, NuvaRing(R)) or licensed hormonal products with use of method for a minimum of 28 days prior to dosing, condoms or diaphragm with spermicidal agents, monogamous relationship with a vasectomized partner
• The hemoglobin, platelet count, white blood cell count and absolute neutrophil count are within normal limits at the screening visit.
• The urine dipstick results on protein, glucose and blood are negative or trace.
• Chemistry screening laboratory tests are in the normal reference range.
• 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 400mg/ml; 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.
• Has adequate venous access for the infusion.

You may not qualify if:

• 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 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.
• Clinically significant abnormal ECG results include: 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 \> 37.6 degrees Celsius within 7 days of dosing
• Pregnant or breastfeeding
• Donated blood within 56 days of enrollment (day -1)
• 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 at any time in the past
• 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

Sponsors & Collaborators

• National Institute of Allergy and Infectious Diseases (NIAID): lead

Study Sites (1)

Duke University School of Medicine - Duke Clinical Research Institute - Duke Clinical Research Unit

Durham, North Carolina, 27710-4000, United States

Location

MeSH Terms

Conditions

Botulism

Condition Hierarchy (Ancestors)

Clostridium Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections; Neuromuscular Junction Diseases; Neuromuscular Diseases; Nervous System Diseases; Neurotoxicity Syndromes; Foodborne Diseases; Poisoning; Chemically-Induced Disorders

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 19, 2018
• First Posted: July 27, 2018
• Study Start: September 25, 2018
• Primary Completion: June 11, 2019
• Study Completion: June 11, 2019
• Last Updated: June 22, 2022

Record last verified: 2018-07-17

Locations

US (1)