Clinical trial NCT04515953: A Phase I Dose-escalation Study of a Single Administration of Extended-Release Injectable Suspension (ND-340)
Official title: 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)
Study type: INTERVENTIONAL
Overall status: SUSPENDED
Phase: PHASE1
Conditions: Pain, Postoperative
Lead sponsor: Nang Kuang Pharmaceutical Co., Ltd.
Sponsor class: INDUSTRY
First posted: 2020-08-17
Enrollment: 36
Sex: ALL
Minimum age (years): 20
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention 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.
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: Inclusion Criteria:

1. Subject with age between 20 and 80 (inclusive) years old at the screening visit
2. With physician's order to undergo scheduled primary unilateral TKA
3. Female subject with childbearing potential must have a negative serum pregnancy test at the screening visit
4. 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).
5. Able and willing to comply with all study visits and procedures
6. 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
7. Willing and capable of providing written informed consent

Exclusion Criteria:

1. Body weight \< 50 kilograms or a morbidly obese (body mass index ≥ 35kg/m2)
2. Subject with American Society of Anesthesiologists (ASA) physical status \> 3 at the screening visit
3. Undergoing or is plan to undergo bilateral or revision total knee replacement
4. 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.
5. 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
6. 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)
7. 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
8. Pre-operative renal insufficiency (creatinine clearance \< 60 mL/min) at the screening visit
9. Known of active infection with HIV, HBV, or HCV at the screening visit
10. With abnormal ECG at screening and admission, which is not suitable to participate into this study as judged by the investigator before TKA
11. With abnormal results of sensory examination as judged by the investigator before TKA
12. 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
13. Receiving other surgeries within 30 days prior to screening
14. Receiving blood transfusion within 30 days prior to screening
15. With a history of allergy or hypersensitivity to local anesthetics
16. 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)
17. 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
18. Uncontrolled anxiety, schizophrenia, or other psychiatric disorder that could interfere with study assessments or compliance in the opinion of the investigator
19. 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
20. 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
21. With pre-existed psychiatric or neurological deficits, which may compromise the neurological toxicity evaluations in this study by the investigator's judgment
22. With stroke within 1 year prior to screening
23. With bone cancer within 5 years prior to screening
24. Inability to understand or operate the PCA machine
25. Female subject who is breast-feeding, pregnant, or planning to become pregnant

Primary outcomes:
measure: Number of participants with treatment-related adverse events as assessed by CTCAE v5.0
timeFrame: up to 3 months
measure: Cmax
timeFrame: 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
measure: Tmax
timeFrame: 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
measure: AUC 0-t
timeFrame: 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
measure: AUC 0-∞
timeFrame: 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
measure: T1/2
timeFrame: 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
measure: CL/F
timeFrame: 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
measure: λz
timeFrame: 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
measure: Vz/F
timeFrame: 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
measure: MRT 0-∞
timeFrame: 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 outcomes:
measure: Pain intensity
timeFrame: up to 1 week
measure: The requirement for rescue pain medication
timeFrame: up to 1 week
measure: The ambulation distance
timeFrame: up to 3 months
measure: Range of motion of knee
timeFrame: up to 3 months
measure: WOMAC
timeFrame: up to 3 months
Other outcomes:
Locations:
city: Tainan City
country: Taiwan
facility: Nang Kuang Pharmaceutical Co., LTD
state: Taiwan (台灣)
Study officials:
affiliation: National Taiwan University Hospital
name: Chih-Peng Lin
role: PRINCIPAL_INVESTIGATOR
References: