Evaluate the Analgesic Efficacy and Safety of VVZ-149 Injection for Post-operative Pain Following Gastrectomy

A Randomized, Double-Blind, Parallel Group, Placebo-Controlled Study to Evaluate the Analgesic Efficacy and Safety of VVZ-149 Injection for Post-operative Pain Following Laparoscopic-assisted Gastrectomy in Early Gastric Cancer Patients

VVZ-149 is a novel analgesic drug candidate that shows a potential analgesic activity inhibiting GlyT2 and 5HT2A simultaneously. These target receptors have been known to play important roles in induction and transmission of pain signals. There have been many efforts to develop selective drugs to treat pain, but usually unsuccessful due to the lack of efficacy or limitations of single-target approach for new drug discovery. VVZ-149 is expected to be a dual-target drug, demonstrated having a potential synergism between GlyT2 and 5HT2A to maximize an antinociceptive effect in the in vivo animal models. In Phase 1 conducted among healthy subjects, safety and tolerability were confirmed. Phase 2 was designed as a randomized, double-blind, parallel-group, placebo-controlled trial to evaluate the efficacy and safety of the analgesic drug VVZ-149 injection.

Study Overview

• Status: Completed
• Conditions: Post-Operative Pain
• Intervention / Treatment: Drug: VVZ-149 injections; Drug: Placebo

Detailed Description

VVZ-149 is a dual antagonist of GlyT2 and 5HT2A. GlyT2 blockage increases inhibitory synaptic transmission by glycine in the spinal cord, resulting in a reduction of pain transmissions to the brain. 5HT2A blockage decreases descending serotonergic facilitatory modulation on pain transmission by the brain and reduces nociceptor activation in peripheral nerves, which are primary sources of pain in post-surgical pain. VVZ-149 has been shown to have comparable efficacy to morphine in well controlled (blind, complete randomization with a positive control) animal studies using rat models of post-operative pain and formalin-induced pain. The PK/PD study in animals indicates that therapeutic plasma concentration in human subjects will be 600-1,900 ng/ml. A clinical Phase 1 study performed in healthy subjects has shown no clinically significant adverse events up to a plasma concentration level of 3,261 ng/ml other than brief symptoms of mild nausea or dizziness, and mild somnolence when the plasma exposure level is more than 2,000 ng/ml.

• Study Type: Interventional
• Enrollment (Actual): 38
• Phase: Phase 2

Contacts and Locations

Study Locations

• Korea, Republic of
  • Seoul, Korea, Republic of
    • Yonsei University Health System, Severance Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 25 years to 70 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Patient between the ages of 25 and 70 years old
2. Male patient, in the case of female patient, postmenopausal women, or women physically incapable of childbearing
3. Minimal pain intensity (NRS) of ≥5 at initial post-operative measurement.
4. Subject who underwent surgery specially for the clinical study
5. Ability to provide written informed consent prior to any study procedures.
6. Ability to understand study procedures and communicate clearly with the investigator and staff.
7. Subjects with body weight under 100kg and body mass index (BMI) level lower than 35 kg/m2, inclusive

Exclusion Criteria:

< Surgical Factors >

1. Emergency or unplanned surgery.
2. Repeat operation (e.g., previous surgery within 30 days for same condition).

3. Cancer-related condition causing preoperative pain in site of surgery.

   < Subject Characteristics >

4. Women with childbearing potential, Women who are pregnant or breastfeeding.
5. Chronic pain diagnosis (e.g., ongoing pain at baseline with NRS ≥ 4/10).
6. Unstable or poorly controlled psychiatric condition (e.g., untreated PTSD, anxiety, or depression). Subjects who take stable doses (same dose >30 days) of antidepressants and anti-anxiety drugs may be included.
7. Unstable or acute medical condition (e.g., unstable angina, congestive heart failure, renal failure, hepatic failure, AIDS).

8. Subjects who have long PR (>200msec) or prolonged QTc (> 450msec) at Screening

   < Drug, Alcohol, and Pharmacological Considerations >

9. History of alcohol, opiate or other drug abuse or dependence within 12 months prior to Screening .
10. Ongoing or recent (within 30 days prior to surgery) use of steroids, opioids, or antipsychotics.
11. Alcohol consumption within 24 hours of surgery.
12. Use of nonsteroidal anti-inflammatory drugs (NSAIDs) or acetaminophen within 24 hours of surgery.

13. Use of herbal agents or nutraceuticals (i.e., chaparral, comfrey, germander, jin bu huan, kava, pennyroyal, skullcap, St. John's wort, or valerian) within 7 days prior to surgery.

    < Anesthetic and Other Exclusion Considerations >

14. Use of neuraxial or regional anesthesia related to the surgery.
15. Use of ketamine, gabapentin, pregabalin, or lidocaine (>1 mg/kg) intra or peri-operatively, or within 24 hours of surgery.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: TRIPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: VVZ-149 injection; VVZ-149 Injections will be mixed with saline,then intravenous infusion for 8hr. The drug product will be administered with a loading dose of 1.8 mg/kg for 0.5 hour followed by a maintenance dose of 1.3 mg/kg/h for 7.5 hours.	Drug: VVZ-149 injections; Colorless, transparent liquid in water for injection; Other Names: VVZ-149 injection or water for injection
Placebo Comparator: Placebo; placebo group will receive an water for injection the same volume and period of experimental group.	Drug: Placebo; water for injection; Other Names: VVZ-149 injection or water for injection

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Change of Numerical Rating Scale using(NRS) a 10-point scale upto 24hr	prior to administration, at 15 min, 30 min, 1, 2, 4, 6, 8, 10, 24 hours post-dose

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Difference of Opioid Consumption between Study Groups		0-2, 2-4, 4-6, 6-8, 8-12, 12-16, 16-24 hours post-dose
Change of Pain Relief (PR) using a 6-point categorical scale upto 24hours		15min, 30 min, 1, 2, 4, 6, 8, 10, 20, 24 hours post-dose
Pain Intensity Difference (PID) upto 24hours	Pain Intensity using a 10-point categorical scale	pre-administration of investigational drug and at 15 min, 30 min, 1, 2, 4, 6, 8, 10, 24 hr post dosing
Sum Pain Intensity Difference over 8hr post- dose (SPID-8)		pre-administration of investigational drug and at 15 min, 30 min, 1, 2, 4, 6, 8, 10, 24 hr post dosing
global measurement of patient satisfaction		8, 24 hours after dosing
Change of Incidence of Postoperative Nausea and Vomiting(PONV) upto 24hr		pre-administration of investigational drug and at 15 min, 30 min, 1, 2, 4, 6, 8, 10, 24 hours post dosing
Change of Richmond Agitation-Sedation Scale(RASS) upto 24hr		pre-administration of investigational drug and at 15 min, 30 min, 1, 2, 4, 6, 8, 10, 24 hours post dosing

Collaborators and Investigators

• Sponsor: Vivozon, Inc.

Study record dates

Study Major Dates

• Study Start: August 1, 2015
• Primary Completion (Actual): February 1, 2016
• Study Completion (Actual): February 1, 2016

Study Registration Dates

• First Submitted: August 5, 2015
• First Submitted That Met QC Criteria: August 10, 2015
• First Posted (Estimate): August 13, 2015

Study Record Updates

• Last Update Posted (Estimate): September 29, 2016
• Last Update Submitted That Met QC Criteria: September 28, 2016
• Last Verified: September 1, 2016

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Postoperative Complications; Pain; Neurologic Manifestations; Pain, Postoperative
• Other Study ID Numbers: PT-VVZ149-04