A Phase I Dose-escalation Study of a Single Administration of Extended-Release Injectable Suspension (ND-340)

Study Overview
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Brief Summary
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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.

Official Title
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A Phase I Dose-escalation Study to Evaluate the Safety, Pharmacokinetics, and Efficacy of a Single Administration of Extended-Release Injectable Suspension (ND-340) as Post-operative Analgesia in Patients With Total Knee Arthroplasty (TKA)

Conditions
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Pain, Postoperative

Intervention / Treatment
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* Drug: ND-340
* Drug: IV-PCA


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

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 first two arms of the placebo control and the 1st dose level ND-340 were randomly paralleled and then subsequently arms for ND-340 dose escalations.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Control<br>Standard practice of pain management for post-TKA | Drug: IV-PCA<br>* IV-PCA: Intravenous patient-controlled analgesia (IV-PCA), morphine, will be administered in subjects of control group after TKA for postoperative pain management as standard practice.<br>|
| Experimental: ND-340<br>ND-340 90mg 320mg at dose escalations | Drug: ND-340<br>* ND-340: Subjects will receive a single administration of ND-340 at the specified dose in each arm after TKA.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with treatment-related adverse events as assessed by CTCAE v5.0 | 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. | up to 3 months | 
| Cmax | Maximum Plasma Concentration of ND-340 | 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 | 
| Tmax | Time of peak concentration of ND-340 | 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 | 
| AUC 0-t | Area under the plasma concentration versus time curve from zero to t of ND-340 | 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 | 
| AUC 0-∞ | Area under the plasma concentration versus time curve from zero to infinity of ND-340 | 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 | 
| T1/2 | Terminal half life of ND-340 | 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 | 
| CL/F | Clearance/Bioavailability of ND-340 | 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 | 
| λz | Terminal elimination rate constant | 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 | 
| Vz/F | Apparent volume of distribution during terminal phase after non-intravenous administration | 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 | 
| MRT 0-∞ | Mean residence time | 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 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pain intensity | 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. | up to 1 week | 
| The requirement for rescue pain medication | 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. | up to 1 week | 
| 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. | up to 3 months | 
| 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. | up to 3 months | 
| WOMAC | 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. | up to 3 months |