Post-operative Analgesia

This study focused on ND-340 extended release injection suspension for patients undergoing total knee arthroplasty with a one-time nerve blockade to assess drug side effects, pharmacokinetics and the effect of pain relief after surgery.

ND-340

Bupivacaine base

IVT

300 mg

Primary Outcome Measures :

Number of participants with treatment-related adverse events as assessed by CTCAE v5.0 [ Time Frame: up to 3 months ]
The AEs of special interest, including any symptom of local anesthetic systemic toxicity (LAST), cardiac events, neurologic events, and falls, will be analyzed by cohort.

Cmax [ Time Frame: 0(Pre-dose), 0.25, 0.5, 1, 1.5, 2, 4, 8, 18, 24, 32, 44, 56, 68, 80, 92,104,116,128,140,164 hour ]
Maximum Plasma Concentration of ND-340

Tmax [ Time Frame: 0(Pre-dose), 0.25, 0.5, 1, 1.5, 2, 4, 8, 18, 24, 32, 44, 56, 68, 80, 92,104,116,128,140,164 hour ]
Time of peak concentration of ND-340

AUC 0-t [ Time Frame: 0(Pre-dose), 0.25, 0.5, 1, 1.5, 2, 4, 8, 18, 24, 32, 44, 56, 68, 80, 92,104,116,128,140,164 hour ]
Area under the plasma concentration versus time curve from zero to t of ND-340

AUC 0-∞ [ Time Frame: 0(Pre-dose), 0.25, 0.5, 1, 1.5, 2, 4, 8, 18, 24, 32, 44, 56, 68, 80, 92,104,116,128,140,164 hour ]
Area under the plasma concentration versus time curve from zero to infinity of ND-340

T1/2 [ Time Frame: 0(Pre-dose), 0.25, 0.5, 1, 1.5, 2, 4, 8, 18, 24, 32, 44, 56, 68, 80, 92,104,116,128,140,164 hour ]
Terminal half life of ND-340

CL/F [ Time Frame: 0(Pre-dose), 0.25, 0.5, 1, 1.5, 2, 4, 8, 18, 24, 32, 44, 56, 68, 80, 92,104,116,128,140,164 hour ]
Clearance/Bioavailability of ND-340

λz [ Time Frame: 0(Pre-dose), 0.25, 0.5, 1, 1.5, 2, 4, 8, 18, 24, 32, 44, 56, 68, 80, 92,104,116,128,140,164 hour ]
Terminal elimination rate constant

Vz/F [ Time Frame: 0(Pre-dose), 0.25, 0.5, 1, 1.5, 2, 4, 8, 18, 24, 32, 44, 56, 68, 80, 92,104,116,128,140,164 hour ]
Apparent volume of distribution during terminal phase after non-intravenous administration

MRT 0-∞ [ Time Frame: 0(Pre-dose), 0.25, 0.5, 1, 1.5, 2, 4, 8, 18, 24, 32, 44, 56, 68, 80, 92,104,116,128,140,164 hour ]
Mean residence time

Secondary Outcome Measures :

Pain intensity [ Time Frame: up to 1 week ]
The pain assessment in subjects will be analyzed by each cohort. The AUC of NRS-R or NRS-A within 24 hours (AUCNRS-R, 0-24 or AUCNRS-A, 0-24), 56 hours (AUCNRS-R, 0-56 or AUCNRS-A, 0-56), 80 hours (AUCNRS-R, 0-80 or AUCNRS-A, 0-80), 104 hours (AUCNRS-R, 0-104 or AUCNRS-A, 0-104), 128 hours (AUCNRS-R, 0-128 or AUCNRS-A, 0-128), and 164 hours (AUCNRS-R, 0-164 or AUCNRS-A, 0-164) after TKA will be analyzed and score-time curves will be plotted graphically.

The requirement for rescue pain medication [ Time Frame: up to 1 week ]
The requirement for rescuing pain medication will be analyzed by each cohort. Descriptive statistics will be used to analyze the percentage of subjects who use all IV-PCA morphine dose within 48 hours post-TKA or the percentage of subjects who use ULTRACET® within 7 days post-TKA, time period from the end of TKA to the first bolus dose of IV-PCA morphine or to the first use of ULTRACET® by cohort, the total amount of IV-PCA morphine administered within 48 hours post-TKA or the total amount of ULTRACET® administered within 7 days post-TKA.

The ambulation distance [ Time Frame: up to 3 months ]
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.

Range of motion of knee [ Time Frame: up to 3 months ]
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.

WOMAC [ Time Frame: up to 3 months ]
The quality of life (QoL) as measured by WOMAC Index at baseline and subsequent visits, and the change from baseline will be summarized descriptively by cohorts.

Inclusion Criteria:

Subject with age between 20 and 80 (inclusive) years old at the screening visit
With physician's order to undergo scheduled primary unilateral TKA
Female subject with childbearing potential must have a negative serum pregnancy test at the screening visit
Both male and female subjects with childbearing potential must agree to use 2 medically accepted methods of contraception (e.g., barrier contraceptives [male condom, female condom, or diaphragm with a spermicidal gel], hormonal contraceptives [implants, injectables, combination oral contraceptives, transdermal patches, or contraceptive rings], and intrauterine devices) during the course of the study with their partners (excluding women who are not of childbearing potential and men who have been sterilized).
Able and willing to comply with all study visits and procedures
Able to speak, read, and understand the language of the informed consent form (ICF), study questionnaires, and other instruments used for collecting subject-reported outcomes, in order to enable accurate and appropriate responses to pain scales and other required study assessments
Willing and capable of providing written informed consent

Exclusion Criteria:

Body weight < 50 kilograms or a morbidly obese (body mass index ≥ 35kg/m2)
Subject with American Society of Anesthesiologists (ASA) physical status > 3 at the screening visit
Undergoing or is plan to undergo bilateral or revision total knee replacement
Previous contralateral TKA or open knee surgery on the knee being considered for TKA in this study within 1 year prior to screening. Prior arthroscopy at least 1 week prior to TKA is permitted.

Use of any of the following medications within the time specified before TKA
Use of any opioid within 24 hours or long-acting opioid within 3 days
Use of any NSAID including selective COX-2 inhibitor within 3 days
Use of any selective serotonin reuptake inhibitors (SSRIs), gabapentin, pregabalin (LYRICA®), or duloxetine (CYMBALTA®) within 3 days
Use of monoamine oxidase inhibitors (MAOIs) within 14 days
Concurrent painful physical condition, diseases or concurrent surgery that may require analgesic treatment (such as NSAIDs or opioids) in the post-operative period for pain that is not strictly related to the surgery, and which may confound the post-operative assessments (e.g., significant pain from other joints including the non-index knee joint, chronic neuropathic pain, concurrent or prior contralateral TKA, concurrent foot surgery)
Pre-operative liver insufficiency as defined by liver function tests [i.e. alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), or total bilirubin] ≥ 1.5 times the upper limit of normal (ULN) at the screening visit
Pre-operative renal insufficiency (creatinine clearance < 60 mL/min) at the screening visit
Known of active infection with HIV, HBV, or HCV at the screening visit
With abnormal ECG at screening and admission, which is not suitable to participate into this study as judged by the investigator before TKA
With abnormal results of sensory examination as judged by the investigator before TKA
Administration of an investigational drug within 30 days 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
Receiving other surgeries within 30 days prior to screening
Receiving blood transfusion within 30 days prior to screening
With a history of allergy or hypersensitivity to local anesthetics
Previous hypersensitivity to or contraindication to any of the pain-control agents planned for surgical or post-operative use in this study (i.e., morphine, bupivacaine, tramadol, and acetaminophen)
History of, suspected, or known addiction to or abuse of illicit drug(s), prescription medicine(s), or alcohol within the past 2 years prior to screening
Uncontrolled anxiety, schizophrenia, or other psychiatric disorder that could interfere with study assessments or compliance in the opinion of the investigator
Current or historical evidence of any clinically significant disease or condition, especially terminal stage cancer, poorly controlled diabetic mellitus (i.e., HbA1c > 8%), or neurological disease that, in the opinion of the investigator, may increase the risk of study treatment and TKA, or complicate the subject's post-operative course or interfere with the determination of pain intensity related solely to the TKA
Subject with severe heart diseases (NYHA class-III and IV), with ischemic heart diseases (angina pectoris and myocardial infarction) and subject who underwent percutaneous transluminal coronary angioplasty (PTCA) or had treatments for coronary artery bypass graft within 6 months prior to screening
With pre-existed psychiatric or neurological deficits, which may compromise the neurological toxicity evaluations in this study by the investigator's judgment
With stroke within 1 year prior to screening
With bone cancer within 5 years prior to screening
Inability to understand or operate the PCA machine
Female subject who is breast-feeding, pregnant, or planning to become pregnant