A Phase I Study to Evaluate the Safety and PK of ND-340 in Healthy Volunteers

Study Overview
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Brief Summary
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This study focuses on ND-340 extended release injection suspension for healthy volunteers with a one-time nerve blockade to determine the safety, tolerability, and pharmacokinetic profile.

Detailed Description
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The current investigational product, ND-340, is a bupivacaine microsphere injection with an extended release profiling. Lipid microsphere, or liposphere, has been proposed as new type of lipid-based encapsulation system for drug delivery of bioactive compounds especially lipophilic compound. ND-340 has not been studied in human before. However, MARCAINE® and EXPAREL® are both FDA-approved drugs, which contain the same active pharmaceutical ingredient (API) as ND-340, which is bupivacaine. MARCAINE® is indicated for the production of local or regional anesthesia or analgesia for surgery, dental and oral surgery procedures, diagnostic and therapeutic procedures, and for obstetrical procedures. In this study, Investigators will focus on determining the safety, tolerability, and pharmacokinetic profile of ND-340.

Official Title
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A Phase I Dose-escalation Study, Randomized Comparison With Active Control to Evaluate the Safety and Pharmacokinetics of a Single Administration of ND-340 Via Adductor Canal Block (ACB) and IPACK Block in Healthy Volunteers

Conditions
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Pain, Postoperative

Intervention / Treatment
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* Drug: Marcaine® 100mg/20mL (0.5%) bupivacaine solution for Injection
* Drug: ND-340 (Bupivacaine Microsphere), 300 mg/vial bupivacaine for extended-release injectable suspension


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 20 - 45 year-old healthy male subjects or female subjects who are in non-lactating and non-pregnant status. Subjects must have a Body Mass Index (BMI) of 18.5 to 30.0 Kg/m², inclusive. For male subjects, body weight must be above 50 kg; for female subjects, body weight must be above 45 kg. BMI = Weight (kg)/Height (m2). Female subject with childbearing potential must have a negative serum pregnancy test at the screening visit. Able and willing to comply with all study visits and procedures. The informed consent form has been read, signed and dated by the subject. Able to communicate well with the investigator, comply with study questionnaires, and other instruments used for collecting subject-reported outcomes. Exclusion Criteria: Subject has a sitting pulse rate outside the reference range of 50 to 90 beats per minute or an ear temperature outside the reference range of 35.0 to 37.5°C or a sitting blood pressure less than 90/50 mmHg or more than 140/90 mmHg at screening visit. Subject has clinically significant results of physical examination, laboratory tests, electrocardiogram, or chest X-ray as judged by the investigator at the screening visit. With abnormal results of sensory and neurological assessment as judged by the investigator at the screening visit. Presence of liver disease or liver injury as indicated by an abnormal liver function profile such as alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkalinephosphatase (ALP), or total bilirubin, if any one of them is out of the reference range. Presence of impaired renal function as indicated by abnormal creatinine or blood urea nitrogen values or abnormal urinary constituents, if any one of them is out of the reference range. Known of active infection with HIV, HBV, or HCV as defined by blood tests at the screening visit. Presence of clinically significant illness, such as cardiovascular disease, cerebrovascular disease, metabolic disease, respiratory disease, neurological disease, psychiatric disease, cancers or immunological disease, may increase the risk of study as judged by the investigator at the screening visit. Subject does not agree not to take any prescription, over-the-counter medication, herbal medicine and dietary supplement (including multivitamins) within two weeks before hospital admission and until the end of the study. Subject does not agree not to consume any beverage or food that might affect the drug metabolism, such as pomelo, grapefruit or related products within one week before hospital admission and until the end of the study. Subject does not agree not to consume any caffeine-containing product (e.g., tea, coffee, coke, or chocolate) 3 days prior to hospital admission and until the end of the study. Subject does not agree not to consume any product containing tobacco, nicotine (such as e-cigarettes, nicotine gum), and alcohol 3 days prior to hospital admission and until the end of the study. Administration of an investigational drug within 2 months or 5 elimination half-lives of such investigational drug, whichever is longer, prior to study drug administration; or planned administration of another investigational product or procedure during the study period. Donation or loss of more than 500 mL and 250 mL of blood within 3 months and 2 months before the screening visit, respectively. Known with a history of allergy or hypersensitivity to medicine as judged by the investigator at the screening visit. Female subject who is breast-feeding, pregnant, or planning to become pregnant. Subject does not agree to use effective non-hormonal contraception method to prevent from pregnancy ('double barrier method': condoms used concomitantly with vaginal sponge, diaphragm or intra-uterine contraceptive device) or abstain from sexual behavior with his/her partner from screening until the end of the study. Individual is not eligible to be a subject for other reasons based on the judgment of investigator.

Ages Eligible for Study
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Minimum Age: 20 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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: The subjects of each cohort will be randomly arranged to receive ND-340 or control drug (Marcaine® Injection 0.5%, equal to bupivacaine base 5 mg/mL) in the ratio of 3:1.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Marcaine® 100mg/20mL (0.5%) bupivacaine solution for Injection<br>Marcaine® at 150 mg in each cohort. | Drug: Marcaine® 100mg/20mL (0.5%) bupivacaine solution for Injection<br>* Subjects in this arm will receive a single administration of Marcaine® at the 150 mg. Marcaine® will be administered under ultrasound guidance with a total volume of 40 mL, of which 20 mL will be used via adductor canal block (ACB) and the other 20 mL will be used as IPACK block (interspace between the popliteal artery and the capsule of the posterior knee).<br>|
| Experimental: ND-340 (Bupivacaine Microsphere), 300 mg/vial bupivacaine for extended-release injectable suspension<br>ND-340(90-320 mg) at dose escalations | Drug: ND-340 (Bupivacaine Microsphere), 300 mg/vial bupivacaine for extended-release injectable suspension<br>* Subjects in this arm will receive a single administration of ND-340 at the specified dose (90-320 mg). ND-340 will be administered under ultrasound guidance with a total volume of 40 mL, of which 20 mL will be used via adductor canal block (ACB) and the other 20 mL will be used as IPACK block (interspace between the popliteal artery and the capsule of the posterior knee).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse events as assessed by CTCAE v 5.0 | Treatment-related adverse events will be analyzed by cohort | From administration of ND-340 to 140 hours | 
| Changes in 12-lead ECG and Holter monitor | To definition safety profile in cardiac events, vent. rate, PR interval, QRS duration, QT interval, QTc interval | Pre-dose, 0.25, 0.5, 1, 1.5, 2, 4, 8, 18, 24, 32, 44, 56, 68, 80, 92,104,116,128,140 hour | 
| Changes in Laboratory test - hematology | Hemoglobin, Hct, RBC count, WBC count, Neutrophils, Lymphocytes, Monocytes, Eosinophils, Basophils, Platelet count | Pre-dose, 140 hour | 
| Changes in Laboratory tests - biochemistry | Albumin, Total protein, ALT, AST, ALP, Total bilirubin, BUN, Serum creatinine, K, Na, Mg, Ca, P, Uric acid, Total cholesterol, HbA1c | Pre-dose, 140 hour | 
| Changes in Laboratory tests - urinalysis | pH, Specific gravity, Leukocyte, Erythrocyte, Protein, Glucose | Pre-dose, 140 hour | 
| Changes in vital signs | To definition safety profile including body temperature,blood pressure, respiratory rate, pulse rate | Screening visit, day 0 (Pre-dose, 60 mins), Day 1, Day 2, Day 3, Day 4, Day 5, Day 6 | 
| Changes in physical examination | To definition safety profile including general appearance, HEENT, neck, Lymph nodes, skin, cardiovascular, pulmonary, abdomen, neurological system, musculoskeletal/joints | Screening visit, day -1, Day 6 | 
| The tolerability and maximal tolerated dose (MTD) of ND-340 by dose-limiting toxicities (DLTs) | The incidence of DLT will be summarized by each cohort. The number of subject who has DLT will be summarized by cohorts. and the determination of MTD in this study will be provided. | Pre-dose, 0.25, 0.5, 1, 1.5, 2, 4, 8, 18, 24, 32, 44, 56, 68, 80, 92,104,116,128,140 hour | 
| Cmax | Maximum Plasma Concentration of ND-340 | Pre-dose, 0.25, 0.5, 1, 1.5, 2, 4, 8, 18, 24, 32, 44, 56, 68, 80, 92,104,116,128,140 hours | 
| Tmax | Time of peak concentration of ND-340 | Pre-dose, 0.25, 0.5, 1, 1.5, 2, 4, 8, 18, 24, 32, 44, 56, 68, 80, 92,104,116,128,140 hours | 
| AUC 0-t | Area under the plasma concentration versus time curve from zero to t of ND-340 | Pre-dose, 0.25, 0.5, 1, 1.5, 2, 4, 8, 18, 24, 32, 44, 56, 68, 80, 92,104,116,128,140 hours | 
| AUC 0-∞ | Area under the plasma concentration versus time curve from zero to infinity of ND-340 | Pre-dose, 0.25, 0.5, 1, 1.5, 2, 4, 8, 18, 24, 32, 44, 56, 68, 80, 92,104,116,128,140 hours | 
| T1/2 | Terminal half life of ND-340 | Pre-dose, 0.25, 0.5, 1, 1.5, 2, 4, 8, 18, 24, 32, 44, 56, 68, 80, 92,104,116,128,140 hours | 
| CL/F | Clearance/Bioavailability of ND-340 | Pre-dose, 0.25, 0.5, 1, 1.5, 2, 4, 8, 18, 24, 32, 44, 56, 68, 80, 92,104,116,128,140 hours | 
| λz | Terminal elimination rate constant | Pre-dose, 0.25, 0.5, 1, 1.5, 2, 4, 8, 18, 24, 32, 44, 56, 68, 80, 92,104,116,128,140 hours | 
| Vz/F | Apparent volume of distribution during terminal phase after non-intravenous administration | Pre-dose, 0.25, 0.5, 1, 1.5, 2, 4, 8, 18, 24, 32, 44, 56, 68, 80, 92,104,116,128,140 hours | 
| MRT 0-∞ | Mean residence time from zero to infinity of ND-340 | Pre-dose, 0.25, 0.5, 1, 1.5, 2, 4, 8, 18, 24, 32, 44, 56, 68, 80, 92,104,116,128,140 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Range of motion of knee | The range of motion (ROM) of knee as measured by knee flexion and extension at baseline and subsequent visits, and the change from baseline will be summarized descriptively by cohorts and drugs(ND-340 or Marcaine®). | Pre-dose, 1, 2, 4, 8, 18, 24, 32, 44, 56, 68, 80, 92,104,116,128,140 hours | 
| The ambulation distance | The ambulation distance as measured by six-minute walk test (6MWT) at baseline and subsequent visits, and the change from baseline will be summarized descriptively by cohorts and drugs (ND-340 or Marcaine®). | Once a day on Pre-dose, Day 1 and Day 2 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Bupivacaine, Pharmacokinetics, Analgesics