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

Pain, Postoperative Clinical Trial

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05588557
• Other study ID #: NKC340-202101
• Status: Recruiting
• Phase: Phase 1
• Start date: July 8, 2022
• Est. completion date: December 2024

Study information

• Verified date: October 2023
• Source: Nang Kuang Pharmaceutical Co., Ltd.
• Contact: Cindy Hsu, Manager
• Phone: +886-6-598-4121
• Email: cindy[@]nangkuang.com.tw
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 40
• Est. completion date: December 2024
• Est. primary completion date: December 2024
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 20 Years to 45 Years

Eligibility

Inclusion Criteria:

1. 20 - 45 year-old healthy male subjects or female subjects who are in non-lactating and non-pregnant status.

2. 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).

3. Female subject with childbearing potential must have a negative serum pregnancy test at the screening visit.

4. Able and willing to comply with all study visits and procedures.

5. The informed consent form has been read, signed and dated by the subject.

6. Able to communicate well with the investigator, comply with study questionnaires, and other instruments used for collecting subject-reported outcomes.

Exclusion Criteria:

1. 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.

2. Subject has clinically significant results of physical examination, laboratory tests, electrocardiogram, or chest X-ray as judged by the investigator at the screening visit.

3. With abnormal results of sensory and neurological assessment as judged by the investigator at the screening visit.

4. 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.

5. 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.

6. Known of active infection with HIV, HBV, or HCV as defined by blood tests at the screening visit.

7. 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.

8. 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.

9. 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.

10. 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.

11. 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.

12. 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.

13. Donation or loss of more than 500 mL and 250 mL of blood within 3 months and 2 months before the screening visit, respectively.

14. Known with a history of allergy or hypersensitivity to medicine as judged by the investigator at the screening visit.

15. Female subject who is breast-feeding, pregnant, or planning to become pregnant.

16. 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.

17. Individual is not eligible to be a subject for other reasons based on the judgment of investigator.

Related Conditions & MeSH terms

• Pain, Postoperative

Intervention

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

Locations

Country	Name	City	State
Taiwan	National Taiwan University Hospital	Taipei city

Sponsors (1)

Lead Sponsor	Collaborator
Nang Kuang Pharmaceutical Co., Ltd.

Country where clinical trial is conducted

Taiwan, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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
Primary	Changes in Laboratory test - hematology	Hemoglobin, Hct, RBC count, WBC count, Neutrophils, Lymphocytes, Monocytes, Eosinophils, Basophils, Platelet count	Pre-dose, 140 hour
Primary	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
Primary	Changes in Laboratory tests - urinalysis	pH, Specific gravity, Leukocyte, Erythrocyte, Protein, Glucose	Pre-dose, 140 hour
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	AUC 0-8	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
Primary	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
Primary	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
Primary	?z	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
Primary	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
Primary	MRT 0-8	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	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
Secondary	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