Dose Escalation, Maximum Tolerated Dose
Conditions
Keywords
Healthy volunteers, Dose toxicity, Monoclonal antibody
Brief summary
This is a Phase 1 single-blind, placebo-controlled, dose-escalation study designed to evaluate the safety of AD-NP1, a humanized monoclonal antibody targeting human ectonucleotide pyrophosphatase/phosphodiesterase-1 (ENPP1). The study aims to assess the maximum tolerated dose (MTD), pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity of AD-NP1 in healthy volunteers. Participants will be randomized to receive either AD-NP1 or placebo, with safety and efficacy monitored in accordance with Good Clinical Practice (GCP) guidelines. The study also seeks to explore changes in health-related quality of life (HRQOL) during the trial.
Interventions
DRUGAD-NP1
AD-NP1 is a humanized monoclonal antibody targeting the catalytic domain of human ENPP1. It is administered intravenously at escalating doses (30 mg/kg, 40 mg/kg, 60 mg/kg, and 100 mg/kg).
DRUGPlacebo
Placebo is a normal saline solution administered intravenously in volumes matched to the corresponding AD-NP1 doses (30 mg/kg, 40 mg/kg, 60 mg/kg, and 100 mg/kg)
Sponsors
Arjun Deb, MD
United States Department of Defense
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
BASIC_SCIENCE
Masking
SINGLE (Subject)
Eligibility
Sex/Gender
ALL
Age
21 Years to 65 Years
Healthy volunteers
Yes
Inclusion criteria
* Body weight ≤ 90kg * Ability to understand and the willingness to sign a written informed consent document * Study subject must have read, understood, and provided written informed consent and HIPAA authorization after the nature of the study has been fully explained * Be in general good health without history of any of the conditions listed in
Exclusion criteria
* No use of any tobacco products for at least 6 months * Woman/women of childbearing potential (WOCBP) must agree not to become pregnant from the time of study enrollment until at least 6 months after the completion of the monoclonal antibody infusion. If a WOCBP is sexually active and has no history of hysterectomy or tubal ligation, she must agree to use hormonal or barrier birth control with spermicidal gel * Sexually active male subjects must use a barrier method of contraception during the study * Screening laboratory values must meet the following criteria: * WBC (\>3,000 - \<11,000/mm\^3) * Platelets (\>100,000/mm\^3) * Hemoglobin (\>10.5 gm/dl) * Creatinine (\<1.1 x upper limit of normal \[ULN\]) * BUN (\<1.25 x ULN) * AST (\<1.1 x ULN) * ALT (\<1.1 x ULN) * Alkaline Phosphatase (\<1.1 x ULN) * Bilirubin (\<1.1 x ULN) * Glucose-non-fasting (\> 60 mg/dl and \< 115 mg/dl) * Human immunodeficiency virus (HIV)-infected individuals on effective antiretroviral therapy with undetectable viral load within 6 months are eligible for this trial * For subjects with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated * Individuals with a history of hepatitis C virus (HCV) infection must have been treated and cured. For individuals with HCV infection who are currently on treatment are eligible if they have an undetectable HCV viral load
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Safety and tolerability of escalating doses of a single IV dose of AD-NP1 | Day of infusion (Day 0) to 28 days post-dose | Assessed by the incidence of treatment-related Adverse Events (AEs) using the Common Terminology Criteria for Adverse Events (CTCAE) v5.0. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Immunogenicity of a single IV dose of AD-NP1 | Baseline (pre-dose) and Days 1, 7, 14, 28, 90, and 180 post-dose | Determined by measuring levels of circulating anti-drug antibody in blood samples |
| Plasma Adenine Concentration | Baseline (pre-dose), and Days 1, 3, 7, 14, and 28 post-dose. | Plasma concentrations of adenine will be quantified using Liquid Chromatography-Mass Spectrometry (LC/MS) |
| Maximum Tolerated Dose of AD-NP1 | Day of infusion (Day 0) to 28 days post-dose | To be determined based on dose limiting toxicities (DLTs) and adverse events |
| Maximum Plasma Concentration (Cmax) as a pharmacokinetics (PK) parameter | Baseline (pre-dose) up to Day 60 post-dose | Peak plasma concentration obtained directly from the experimental data points, to be measured in Nanograms per milliliter (ng/mL) |
| Time to Maximum Plasma Concentration (Tmax) as a pharmacokinetics (PK) parameter | Baseline (pre-dose) up to Day 60 post-dose | Tmax presents the time at which Cmax is observed, to be measured in hours (h) and minutes (m) |
| Apparent Volume of Distribution (Vd) as a pharmacokinetics (PK) parameter | Baseline (pre-dose) up to Day 60 post-dose | Volume of distribution calculated during the terminal elimination phase following administration, to be measured in Liters (L) or Liters per kilogram (L/kg) |
| Area Under the Plasma Concentration-Time Curve (AUC) as a pharmacokinetics (PK) parameter | Baseline (Pre-dose), 30 minutes, 1, 2, 4, 6 hours, and Days 1, 3, 7, 14, 28, 60 post-dose. | AUC calculated using the linear-log trapezoidal rule from time zero (pre-dose) to the last quantifiable concentration point to be measured in Nanogram x hours per milliliter (ng \* h/mL) |
| Terminal Elimination Half-life (T(1/2)) as a pharmacokinetics (PK) parameter | Baseline (pre-dose) up to Day 60 post-dose | The rate at which Ad-NP1 is cleared from the systemic plasma circulation, to be measured in Liters per hour (L/h) or Milliliters per minute per kilogram (mL/min/kg) |
| Total Body Clearance (CL) as a pharmacokinetics (PK) parameter | Baseline (pre-dose) up to Day 60 post-dose | The rate at which AD-NP1 is cleared from the systemic plasma circulation, to be measured in Liters per hour (L/h) or Milliliters per minute per kilogram (mL/min/kg) |
| Plasma Uridine Concentration | Baseline (pre-dose), and Days 1, 3, 7, 14, and 28 post-dose. | Plasma concentrations of uridine will be quantified using Liquid Chromatography-Mass Spectrometry (LC/MS). |
| Plasma Cytidine Concentration | Baseline (pre-dose), and Days 1, 3, 7, 14, and 28 post-dose. | Plasma concentrations of cytidine will be quantified using Liquid Chromatography-Mass Spectrometry (LC/MS) |
| Plasma Carbamoyl Aspartate Concentration | Baseline (pre-dose), and Days 1, 3, 7, 14, and 28 post-dose. | Plasma concentrations of carbamoyl aspartate will be quantified using Liquid Chromatography-Mass Spectrometry (LC/MS). |
| Plasma Orotidine Concentration | Baseline (pre-dose), and Days 1, 3, 7, 14, and 28 post-dose. | Plasma concentrations of orotidine will be quantified using Liquid Chromatography-Mass Spectrometry (LC/MS) |
Countries
United States
Outcome results
None listed