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Study Protocol – A Randomized, Double-Blind, Parallel Group, Placebo-Controlled Study to Evaluate the Analgesic

Efficacy and Safety of VVZ-149 Injections for Post-Operative Pain Following Laparoscopic Colorectal Surgery

Journal: BMJ Open

Manuscript ID bmjopen-2016-011035

Article Type: Protocol

Date Submitted by the Author: 13-Jan-2016

Complete List of Authors: Nedeljkovic, Srdjan; Brigham and Women\'s Hospital, Department of Anesthesiology, Perioperative and Pain Medicine Correll, Darin; Brigham and Women\'s Hospital, Department of Anesthesiology, Perioperative and Pain Medicine Bao, Xiaodong; Massachusetts General Hospital, Department of Anesthesia, Critical Care and Pain Medicine Zamor, Natacha ; Beth Israel Deaconess Medical Center, Department of Anesthesia, Critical Care and Pain Medicine Zeballos, Jose; Brigham and Women\'s Hospital, Department of Anesthesiology, Perioperative and Pain Medicine

Zhang, Yi; Massachusetts General Hospital, Department of Anesthesia, Critical Care and Pain Medicine Young, Mark; Beth Israel Deaconess Medical Center, Department of Anesthesia, Critical Care and Pain Medicine Ledley, Johanna; Brigham and Women\'s Hospital, Department of Anesthesiology, Perioperative and Pain Medicine Sorace, Jessica; Brigham and Women\'s Hospital, Department of Anesthesiology, Perioperative and Pain Medicine Eng, Kristen; Massachusetts General Hospital, Department of Anesthesia, Critical Care and Pain Medicine Hamsher, Carlyle; Brigham and Women\'s Hospital, Department of Anesthesiology, Perioperative and Pain Medicine

Maniam, Rajivan; Brigham and Women\'s Hospital, Department of Anesthesiology, Perioperative and Pain Medicine Chin, Jonathan; Brigham and Women\'s Hospital, Department of Anesthesiology, Perioperative and Pain Medicine Tsui, Becky; Massachusetts General Hospital, Department of Anesthesia, Critical Care and Pain Medicine Cho, Sunyoung; Vivozon, Inc, Research Director Lee, Doo; Vivozon, Inc., Chief Executive Officer

<b>Primary Subject Heading</b>:

Pharmacology and therapeutics

Secondary Subject Heading: Anaesthesia

Keywords: Pain management < ANAESTHETICS, PAIN MANAGEMENT, CLINICAL PHARMACOLOGY, Clinical trials < THERAPEUTICS

For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml

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FIGURE 1: CONSORT diagram for VVZ-149 study flow

Recruitment: 1-4 wks prior

to surgery

Enrollment: Day of surgery

Allocation: Postoperative

Time 0

1º Analysis: Postoperative

Time 8 hrs

2º Analysis: Postoperative Time 24 hrs

Adult patients undergoing laparoscopic

colorectal surgery at 3 hospitals

120 subjects Fulfilling inclusion and exclusion

criteria as per Table 1

80 subjects Randomized to intervention group VVZ-149 + IV hydromorphone PCA

40 subjects Randomized to control group

Placebo + IV hydromorphone PCA

Safety Analysis: 2-4 wks after

surgery

Primary endpoint: Sum of Pain Intensity Difference over

8 hrs (SPID-8)

Secondary endpoints: Opioid consumption, Pain Intensity (NRS), Pain relief, Subject satisfaction,

RASS score, Respiratory depression, PONV score, pK analysis

Safety evaluation: EKG, blood chemistry and hematology,

adverse events

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Study Protocol – A Randomized, Double-Blind, Parallel Group, Placebo-Controlled Study to Evaluate the Analgesic Efficacy and Safety of VVZ-149 Injections for Post-Operative Pain Following Laparoscopic Colorectal Surgery Srdjan S. Nedeljkovic MD1, Darin J. Correll MD1, Xiaodong Bao MD PhD2, Natacha Zamor MD3, Jose L. Zeballos MD1, Yi Zhang MD PhD2, Mark J. Young MD3, Johanna Ledley BA MS1, Jessica Sorace BS1, Kristen Eng BS2, Carlyle P. Hamsher MD1, Rajivan Maniam MD1, Jonathan W. Chin MD1, Becky Tsui MD2, Sunyoung Cho PhD4, Doo H. Lee PhD4. Corresponding author: Dr. Srdjan S. Nedeljkovic <[email protected]> 1. Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women’s Hospital,

Boston, MA, USA

2. Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Boston, MA, USA

3. Department of Anesthesia, Critical Care and Pain Medicine, Beth Israel Deaconess Medical Center,

Boston, MA, USA

4. Vivozon, Inc. Seoul, South Korea

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ABSTRACT Introduction: In spite of advances in understanding and technology, postoperative pain remains poorly treated for a significant number of patients. In colorectal surgery, the need for developing novel analgesics is especially important. Patients after bowel surgery are assessed for rapid return of bowel function and opioids worsen ileus, nausea, and constipation. We describe a prospective, double-blind, parallel group, placebo-controlled randomized controlled trial testing the hypothesis that a novel analgesic drug, VVZ-149, is safe and effective in improving pain compared to providing opioid analgesia alone among adults undergoing laparoscopic colorectal surgery. Methods and analysis: Based on sample size calculations for primary outcome, we plan to enroll 120 adult patients undergoing laparoscopic colorectal surgery who are without significant medical comorbidities. Participants are randomly assigned to receive either VVZ-149 with IV hydromorphone PCA or the control intervention (IV PCA alone) in the postoperative period. The primary outcome is the SPID-8 (Sum of Pain Intensity Difference over 8 hours post-dose). Subjects receive VVZ-149 for 8 hours postoperatively to the primary study endpoint, after which they continue to be assessed for up to 24 hrs. We measure opioid consumption, record pain intensity and pain relief, and evaluate the number of rescue doses and requests for opioid. To assess safety, we record sedation, nausea and vomiting, respiratory depression, laboratory tests and EKG readings after study drug administration. We evaluate for possible confounders of analgesic response, such as anxiety, depression, and catastrophizing behaviors. The study will also collect blood sample data and evaluate for pharmacokinetic and pharmacodynamic relationships. Ethics and dissemination: Ethical approval of the study protocol has been obtained from Institutional Review Boards at the participating institutions. Trial results will be disseminated through scientific conference presentations and by publication in scientific journals. Trial Registration: Clinicaltrials.gov NCT02489526 STRENGTHS AND LIMITATIONS

• This is a prospective, randomized, double blind design that will evaluate for a clinically meaningful response to a novel analgesic agent. The new drug could broadly expand treatment options for postoperative pain for patients.

• The trial assesses for many of the common potential confounders of analgesic response, including perioperative anxiety, depression, and catastrophizing behaviors that may influence reporting of pain levels and affect use of opioids in the postoperative period.

• The protocol includes an assessment of perception of treatment both on the part of subjects and investigators, which will help evaluate the effectiveness of blinding to treatment allocation.

• A potential limitation is that a diverse and heterogenous group of patients may be enrolled, potentially confounding the results.

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INTRODUCTION Although there have been numerous studies published regarding the use of existing drugs classes for analgesia, manuscripts related to opioid-type drugs dominate (1). In spite of significant research efforts, novel non-opioid or non-NSAID drugs have been found to have questionable efficacy in the treatment of postoperative pain, and are not in routine clinical use. As noted by Kissin in 2010, there has been no new analgesic drug based on a novel pain mechanism introduced to the market in more than a generation (2). Therefore, there is an unmet need for such research to come to fruition, especially since postoperative pain continues to be inadequately managed in some patients even with full availability of existing therapies. The currently available analgesic therapies for acute postoperative pain based on providing opioid analgesics often lead to unsatisfactory pain relief or excessive side effects (3). Providing additional opioids can result in intolerable side effects such as nausea, pruritis, constipation, respiratory depression, and may induce tolerance, rendering the analgesic treatment less effective. In addition, opioid management can lead to the development of hyperalgesia (increased pain sensitivity) in some patients in the postoperative period (4). Furthermore, the use of NSAIDs can be linked to the development of gastrointestinal complications and renal injury, especially in patients who have altered fluid shifts in the perioperative period (5)(6). Although patients may benefit from perioperative use of drugs like gabapentin, non-opioid, non-NSAID drugs are poorly effective as stand-alone agents for acute postoperative pain management (7). Finally, regional anesthetic techniques, although useful for many patients, also have limitations, side effects, and can still be poorly effective (8). In colorectal surgery, the need for novel analgesics is especially important. Patients after bowel surgery are assessed for rapid return of bowel function and opioids can worsen or prolong ileus, nausea, and constipation – which are highly undesirable outcomes in this patient population. Excessive pain and use of opioids not only delays return of normal gastrointestinal function, but patients may require prolonged stays in the hospital – increasing the risk of iatrogenic infections. Prolonged immobility due to pain can increase the risk of thromboembolic events and result in muscle wasting and debilitation, which may have an overall adverse effect on patients’ outcomes, satisfaction, and quality of life. Therefore, the need to develop alternate and novel analgesics is desirable for improving management of postoperative pain, being specifically desirable and needed in managing patients postoperatively who have undergone bowel surgery. VVZ-149 is a small molecular compound in the benzamide family that has been developed as an injectable product to improve postoperative pain control. A novel analgesic drug, VVZ-149 is a dual antagonist of GlyT2 (glycine transporter type 2) and 5HT2A (serotonin receptor 2A). GlyT2 blockage increases inhibitory synaptic transmission by glycine in the spinal cord, resulting in a reduction of pain transmissions to the brain (9)(10)(11)(12)(13)(14). 5HT2A blockage decreases descending serotonergic facilitatory modulation on pain transmission by the brain and reduces nociceptor activation in peripheral nerves, both of which are primary sources of post-surgical pain (15)(16)(17)(18)(19). There is good rationale for developing drugs that act on multiple targets, as this may improve therapeutic benefit while reducing side effects of therapy (20). VVZ-149 has 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. A clinical Phase 1 study performed in healthy subjects has shown no clinically significant adverse events. Laparoscopic colorectal surgery is typically associated with a burst of moderate to severe pain (NRS ≥4, scale 0-10) in the immediate postoperative period (21). Because of the significant analgesic requirements for patients who undergo this type of surgery, using this postoperative pain model is an appropriate

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condition under which to study VVZ-149. In addition, due to potentially undesirable effects that opioids often have upon bowel function and recovery, studying the efficacy and side effect profile of VVZ-149 is ideally suited to the colorectal surgery patient population. In summary, VVZ-149 is potentially a favorable non-opioid and non-NSAID analgesic candidate with comparable efficacy to morphine that may be able to provide superior analgesia and reduce side effects for patients who are recovering from laparoscopic colorectal surgery. OBJECTIVES The overall objective of this multi-center, double-blind RCT is to evaluate the safety and efficacy of VVZ-149 for treating postoperative pain in patients who undergo laparoscopic colorectal surgery. When compared to providing patients with intravenous opioids alone (hydromorphone PCA), we hypothesize that patients randomized to receive VVZ-149 with hydromorphone PCA will show significantly greater improvement in pain with an acceptable side effect profile compared to patients randomized to receive IV hydromorphone PCA only. We are also examining whether VVZ-149 is effective in reducing opioid consumption, as well as its side effect and safety profile (e.g. nausea and vomiting, sedation, EKG changes, other laboratory parameters, and respiratory depression). We are examining potential confounders, such as pre-existing anxiety, depression, and catastrophizing behaviors, and reporting on overall patient satisfaction with this novel therapy. Finally, we are also evaluating the robustness of our blinding by assessing expectation of treatment in study participants and perception of treatment in both study personnel and patients. METHODS AND STUDY DESIGN The VVZ-149 study is a randomized, double-blind, parallel group, placebo-controlled study to evaluate the efficacy and safety of the analgesic drug candidate VVZ-149 for subjects with pain following laparoscopic colorectal surgery. Patients, study investigators, and the research team collecting data are blind to patient treatment allocation. Subjects of age 18 to 70 undergoing laparoscopic colorectal surgery are screened within 30 days prior to the day of the surgery. After completion of the surgery, subjects are transferred to the post-operative anesthesia care unit (PACU), where the study drug is initiated as soon as possible once the subject is admitted. During surgery, eligible subjects are randomized in a 2:1 ratio to one of two study groups, VVZ-149 Injections or placebo. Then, subjects who have a pain score of at least 4 on the 11-point NRS are administered the study drug. Subjects who are deemed ineligible have no further data collected and receive routine postoperative care. A randomized subject receives a dosing regimen of VVZ-149 injections or placebo via IV infusion for 8 hours. In addition to receiving the study drug or placebo, all subjects receive IV patient-controlled analgesia (PCA) with hydromorphone on demand to facilitate achieving adequate pain relief. Subjects are evaluated per the study protocol through 24 hours after dosing. A follow-up assessment is performed 14-30 days following the treatment. Please refer to FIGURE 1 (Consort Flow Diagram). Setting and Recruitment Patients are being recruited from three academic medical centers: Brigham and Women’s Hospital, Beth Israel Deaconess Medical Center, and Massachusetts General Hospital. All three hospitals are located in Boston, Massachusetts and are teaching affiliates of Harvard Medical School. The study was approved by the local IRBs in July 2015 and enrollment is expected to conclude by December 2016.

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Patients undergoing planned laparoscopic colorectal surgery are informed about the study at their local surgeon’s office or at the facility’s preoperative test center, where they are asked if they would like to participate in the VVZ-149 trial. Prior to recruitment, members of the research team evaluate whether the patient is potentially an appropriate candidate for enrollment into the study based on diagnosis, age, and the nature of the planned procedure. The physician or study representative introduces the study during the patient’s planned visit to their surgeon or the preoperative test center, or by telephone call for those patients who do not require pre-hospital evaluation within the facility. Each potential patient is given detailed information about the procedures involved with the study protocol as well as the IRB-approved consent form to review prior to agreeing to participate in the study. All patients are required to provide written informed consent when enrolling in the study. Eligibility Criteria Inclusion and exclusion criteria for patients to participate in the study are listed in Table 1. Inclusion criteria were developed to allow enrollment of adult patients age 70 or lower who are without high anesthetic risk classification (ASA 1-III) and who are scheduled to undergo laparoscopic colorectal surgery. Patients must have the ability to understand study procedures and communicate in English. To be enrolled in the study, a patient must have minimal pain intensity of ≥4 (on a 0-10 scale) at the time of their initial pain measurement after surgery in the PACU. Patients may be excluded from participation in the study due to certain surgical factors, subject characteristics, anesthetic factors, or pharmacological considerations. Many of the exclusion factors were chosen to reduce or eliminate possible confounders that could affect study outcomes, like the use of neuraxial, regional, or local anesthesia or the use of certain analgesic drugs such as NSAIDs, anticonvulsants, ketamine, acetaminophen, or herbal agents. Other exclusion factors were chosen to maintain safety of study participants, such as exclusion of patients who have prolonged QTc on their EKG, those with unstable or acute medical conditions, or those who have clinically important renal or hepatic impairment. To avoid the confounder of ongoing pain and opioid use, subjects with a chronic pain diagnosis or those taking opioids on regular basis preoperatively were excluded. To ensure that treatment results are not affected by recent prior surgery or use of analgesics, we are excluding patients who have a cancer related condition causing preoperative pain, those who are having a repeat operation within 30 days, and those who are having emergency surgery. Baseline Assessments, Treatment Phase, and Post-treatment Follow-up Patients scheduled to undergo laparscopic colorectal surgery are invited to participate in the study by the treating physician, research physicians, and/or research staff. Potentially eligible and interested patients are then screened for eligibility by research staff at each of the sites. If a patient is eligible, the potential subject is asked to complete the informed consent process. A physician investigator reviews each potential patient’s eligibility and pre-operative test results (laboratory tests, EKG, and response to questionnaires) to confirm the eligibility of the subject for enrollment into the study protocol. On screening, questionnaires are administered to assess demographic and clinical factors, including medical and surgical history (Charlson-Katz questionnaire) (22), medication history, vital signs, cognitive impairment (Six-item Cognitive Screening questionnaire) (23), alcohol/drug use (TICS questionnaire) (24), EKG, and blood samples are obtained to assess baseline hematologic, coagulation, renal, hepatic, thyroid, and metabolic parameters. Patients are asked to complete self-report questionnaires to assess for anxiety, depression, and pain catastrophizing behaviors (25)(26). Subjects who meet eligibility criteria based on assessments done at screening check-in 2-4 hours prior to the scheduled surgery. At that time, any changes in medications are recorded and the eligibility of the

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subject is confirmed. Patients complete an “Expectations of Treatment” questionnaire. Randomization of eligible subjects occurs during the time of surgery. After completion of surgery, subjects are transferred to the PACU. There, it is confirmed that the subject continues to meet inclusion/exclusion criteria. An EKG is done to ensure that there has been no significant increase in QTc interval that would otherwise render the patient ineligible. Pain intensity (NRS), level of sedation (RASS), presence of postoperative nausea and vomiting (PONV), and level of respiratory depression are assessed. Upon regaining alertness, subjects are asked to report a pre-dose pain intensity score. Subjects who indicate a pain score of at least 4 on the 11-point NRS are dosed with the study medication within 30 minutes of measuring the pre-dose pain intensity score. The experimental group receives a 1.8 mg/kg VVZ-149 intravenous infusion for 0.5 hour. This loading dose is followed by a maintenance dose of an intravenous VVZ-149 infusion of 1.3 mg/kg/hr for 7.5 hours.

A PCA pump containing hydromorphone (1 mg/ml) is connected to an intravenous infusion line and programmed to deliver 0.2-0.3 mg boluses of hydromorphone on demand by the subject, with a lockout time interval of 6 minutes. If adequate pain relief is not achieved with the IV PCA titration (pain score NRS ≥6), a mandatory “rescue” dose of 0.5 mg IV hydromorphone is administered as needed at a time interval of every 5 minutes to achieve a pain score of NRS ≤5, but total number of rescue doses cannot be more than 3 times per hour. Subjects who no longer require IV PCA can be transitioned to oral hydromorphone (4 mg q 3-4 hours as needed) after 12 or more hours post-dosing. Once the treatment infusion has been initiated, subjects are observed for 24 hours. Patients are placed on centrally monitored continuous pulse oximetry for up to 12 hours post-dosing of VVZ-149 or during IV PCA use up to 24 hours. In addition, respiratory depression assessments are done at pre-dose and each post-baseline time point and prior to administering any rescue doses of hydromorphone. Subjects complete the treatment phase of the study on post-operative Day 1 after a 24-hour post-dose assessment has been completed. In subjects who receive rescue dosing, the pain intensity (NRS) rating that is measured immediately before the dose is documented to replace the closest measurement scheduled to be recorded as part of the study protocol. If the number of rescue doses exceeds 3 times per hour, the subject is withdrawn from the study and allowed additional boluses of opioid and other analgesic treatments that are deemed clinically appropriate. During the drug infusion phase (0 to 8 hours) and treatment assessment phase (8 to 24 hours), patients are periodically assessed for pain intensity at rest and with movement, pain relief, RASS (Richmond Agitation and Sedation Scale) (27), PONV (Post operative Nausea and Vomiting scale) (28), opioid consumption, respiratory depression, adverse events, and concomitant use of medications. Vital signs are recorded and EKG’s are obtained at several time points. Blood samples for pharmacokinetic analysis are also obtained. At 8 hr and 24 hr post-dose, patient satisfaction with treatment is evaluated using the “Global Measure of Subject Satisfaction Scale.” At 24 hours post-dosing, a blood sample to evaluate hematologic, coagulation, renal, hepatic, thyroid, and metabolic parameters is collected. To assess the robustness of blinding, a “Perception of Treatment” questionnaire is administered to both study subjects and to the study personnel who most closely observed the subject during the treatment phase of the protocol. Subject expectation of treatment and overall satisfaction with the study drug is evaluated to see if these parameters are associated with treatment outcomes.

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Randomization and Blinding In this double-blind study, the investigator, research assistants involved in obtaining data, the treating clinicians, and the study subjects are blinded to the treatment assignment of the study subjects while the site pharmacist and study project manager remain unblinded. After confirming the initial eligibility of subjects, the randomization is requested by the site project team during the time of surgery. The site pharmacist is 1) notified of the randomization code generated via the electronic data capture (EDC) system, 2) confirms which group the subject is assigned through the list of randomization code and group provided to only the site pharmacist, 3) mixes VVZ-149 Injections or placebo in a 500mL saline IV bag after calculating the dosing volume according to the subject’s weight, and 4) dispenses the IV bag to the nurse for the dosing. The list of randomization codes and group assignment lists are securely retained by the site pharmacist. The randomization information of each subject can be disclosed to the investigator in an emergency situation only. If unblinding occurs, the study medication for the subject is discontinued and a written explanation of the event is prepared immediately. Treatment Administered and Selection of Doses in the Study The treatment consists of a loading dose of 1.8 mg/kg VVZ-149 Injections administered by intravenous infusion for 0.5 hour, followed by a maintenance dose of 1.3 mg/kg/h VVZ-149 Injections for 7.5 hours. The placebo group receives the corresponding volume of placebo for the proscribed time of the study. The estimated therapeutic range of targeted pooled plasma concentration has been determined to be 600-1900 ng/mL, which corresponds to 2-6 mg/kg in a 4-h infusion as the Cmax of the dose in a Phase 1 study (PT-VVZ149-01). Using NONMEM (Non-linear Mixed Effects Modeling) with individual PK data from the Phase 1 study, the expected plasma concentration and individual variability of an initial loading dose followed by a maintenance dose were simulated. The results suggest that a loading dose of 1.5 mg/kg of 0.5 hour followed by a maintenance dose of 1.1 mg/kg/h for 7.5 hours will achieve a similar level of pooled plasma concentration at a steady state with Cmax of 5 mg/kg in a 4-h IV infusion, a level within the range where VVZ-149 Injections is expected to demonstrate its maximum efficacy. However, actual plasma concentration in a Phase 1 study with elderly subjects (PT-VVZ149-02) appeared to be about 20% less than the expected level by the simulation. Thus, the doses used for this protocol have been adjusted to 1.8 mg/kg of 0.5 hour for a loading dose followed by a maintenance dose of 1.3 mg/kg/h for 7.5 hours to increase the plasma exposure level by about 20% of the level of maximally efficacious analgesic effect without adverse side effects. Anesthesia Protocol All subjects have general anesthesia without any regional or neuraxial anesthesia, and subjects do not receive ketamine or lidocaine > 1 mg/kg. Only IV hydromorphone, fentanyl, or morphine are administered as opioids during anesthesia. The dose and type of IV opioid given intraoperatively is recorded as one of the variables that can affect treatment outcome. No more than the following doses are given intraoperatively: IV morphine 10 mg, IV fentanyl 500 mcg total during entire anesthetic, and IV hydromorphone 2 mg. Within 1 hour of expected surgical completion, only IV fentanyl up to 200 mcg is administered. No NSAID, gabapentin, pregabalin, or acetaminophen is provided intraoperatively or during the postoperative study period. No more than 20 ml of 1% lidocaine anesthetic wound infiltration may be given. At the discretion of the anesthesiologist, subjects may receive standard doses of intra-operative prophylactic anti-emetics (dexamethasone ≤10 mg, haloperidol ≤1 mg, ondansetron ≤4 mg) and the use of these drugs is recorded.

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After the completion of surgery, subjects will be transferred to the PACU within 30 minutes of emergence from anesthesia. In the PACU, the study protocol and the IV PCA pump will be ready to initiate as soon as possible once the anesthesiologist delivers the subject to the PACU. If there is a need to administer IV opioid from the time of emergence of the subject from general anesthesia to the time they are transferred to the PACU and therefore before the study protocol is initiated, fentanyl up to 3 µg/kg may be administered incrementally as needed and the dose recorded.

Use of Opioid PCA An opioid PCA pump containing hydromorphone (0.5-1.0 mg/mL) is connected to an intravenous infusion line and programmed to deliver 0.2-0.3 mg boluses of hydromorphone on demand by the subject, with a lockout time interval of 6 minutes. If adequate pain relief is not achieved with the IV hydromorphone PCA (if pain score NRS is ≥6), a “rescue” bolus of 0.5 mg/bolus IV hydromorphone may be administered as needed at a time interval of every 5 minutes to achieve a pain score of NRS ≤5, but the total number of rescue doses may not be given over 3 times per hour. In subjects who receive rescue dosing, the pain intensity (NRS) rating that is measured immediately before the dose and the measurement is documented to replace the closest measurement scheduled to be recorded as part of the study protocol. If the number of rescue doses exceeds 3 times per hour, the subject is withdrawn from the study and allowed additional boluses and analgesic treatments that are deemed clinically appropriate. Subjects who are withdrawn continue to be monitored as part of the study protocol and safety and efficacy data continues to be collected and recorded for future analysis. Subjects who no longer require IV PCA may be transitioned to oral hydromorphone (2-4 mg q 3-4 hours prn) to replace IV PCA 12 hours or longer post-dosing. The amount and frequency of oral hydromorphone used by the subject 12-24 hours post-dosing is recorded, as well as any IV rescue dosing necessary during this time.

OUTCOMES The primary outcome is the Sum of Pain Intensity Difference over 8 hours post dosing of the study drug (SPID-8) (29). This is assessed using an 11-point Numerical Pain Rating Scale pain scores (NRS, 0-10) measured up to 8 hours post-dose. Pain intensity difference is calculated by subtracting each subject’s baseline score of pain with movement minus post-dosing pain scores so that positive differences indicated decreased pain. Pain intensity difference (PID) scores are evaluated using pre-dose scores, and then at 0.25 hr, 0.50 hr, 1 hr, 2 hr, 4 hr, 6 hr, and 8 hrs post dosing. A number of secondary outcome measures are being analyzed. Opioid consumption up to 24 hours post-dosing of study drug during multiple time segments is assessed while also evaluating the total number of PCA demands for opioid, the total number of rescue doses given, and the time to the first rescue dose. Pain Intensity at rest and with movement is assessed as recorded on the 11-point numerical rating scale (NRS). Categorical Pain Relief scores are assessed using a 6-point scale (0: worse, 1: none, 2: a little relief, 3: some relief, 4: a lot of relief, 5: complete relief) up to 24 hours post-dose). Using this data, Total Pain Relief (TOTPAR) over the 8-hour and 24-hour time points is calculated (30). Global Measurement of Subjects Satisfaction with the study medication is assessed using a 5-point scale (extremely dissatisfied, 1: dissatisfied, 2: neutral, 3: satisfied, 4: extremely satisfied) at 8 and 24 hours post-dose. Finally, side effects of the study medication are evaluated by analyzing results of the Richmond Agitation Sedation Scale (RASS), Post-operative Nausea and Vomiting scale (PONV), and by reviewing the Respiratory Depression Assessments for up to 24 hours post-dose.

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As part of this efficacy and safety study, blood samples are collected from patients at various time points pre- and post-dosing to perform pharmacokinetic evaluation of the study product. A pharmacokinetic to pharmacodynamic correlation assessment will eventually be performed. Subjects are assessed at one additional time point after discharge from the hospital, 14-30 days after surgery. At that time, vital signs are measured, an EKG is performed, and any adverse events or changes in medications are noted. A blood sample to evaluate hematologic, coagulation, renal, hepatic, thyroid, and metabolic parameters is collected.

SAMPLE SIZE CALCULATION The sample size for this study was determined based on the conjectures for the primary endpoint of SPID. Specifically, a minimum clinically important difference between group means of 5, with a maximum standard deviation of 7 were conjectured. A statistical power of 90% with an overall alpha-level of 5% (4.5% for the final analysis and 0.5% for the interim analysis) was assumed in the calculations. In addition, a maximum attrition rate of 15% is incorporated. With all the above specifications, 120 subjects with a 2:1 ratio will be enrolled into the study (n=80) and control (n=40) groups. STATISTICAL METHODS Unless otherwise specified, standard descriptive statistics will be computed for all endpoints and other observed values. The standard descriptive statistics for continuous variables include: number of observations analyzed, mean, standard deviation, median, minimum, and maximum. The standard descriptive statistics for categorical variables include: frequency distribution with the number and percent of subjects included in each category. Calculation of percentage will use the denominator of the total number of subjects in the particular group of analysis population used in the data display unless otherwise specified. All observed data will be summarized and analyzed. No imputations are planned for missing data. Analysis of Primary Endpoint SPID-8 will be summarized descriptively for each of the two groups. Groups will be compared using a t-test if the endpoint is approximately normally distributed, or using a Wilcoxon rank sum test if the endpoint is markedly non-normally distributed. Analysis of Secondary Endpoints Opioid consumption, NRS, PID, RASS, respiratory depression assessment, Pain Relief, TOPAR, global assessment of satisfaction, intensity, and number and duration of PONV will be summarized and analyzed using the same methodology as described for the primary endpoint, SPID. The time to first rescue hydromorphone dose will be summarized with Kaplan-Meier estimates and groups will be compared with a log-rank test.

Safety Analyses Adverse events will be compared between groups using chi-square tests or Fisher’s exact tests, as appropriate. The remaining safety endpoints will either be analyzed using the same methodology as

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described for the primary endpoint, if continuous, or using chi-square tests or Fisher’s exact tests, as appropriate, if categorical. Pharmacokinetic Analyses The actual sampling time for each subject will be used in the PK analysis. Drug concentrations under lower limit of quantification (LLOQ), not applicable or not sampled will be recorded as < LLOQ, NA, or ND, respectively. PK parameters will be calculated from the data from individual plasma concentration times of VVZ-149 Injections using non-compartmental methods. PK calculations will be performed using WinNonlin®. The PK parameters of VVZ-149 Injections will be calculated as per TABLE 2. PK parameters will be summarized using descriptive statistics (e.g. mean, SD, median, minimum, maximum and coefficient of variation). Plasma drug-concentration time curves will be expressed as linear or log/linear graphs for each subject, and the mean of the plasma drug-concentration time curve for each dose level will be used in the same manner. Linearity and dose proportionality will be evaluated using linear regressions of AUClast, AUCinf, AUCτ,ss, Cmax and Cmax,ss to the dose and of log-transformed AUClast, AUCinf, AUCτ,ss, Cmax and Cmax,ss to the log-transformed dose. A graphical presentation of the linearity and dose proportionality will also be provided. Interim Analyses When 60 subjects complete the study, there will be a single blinded interim analysis planned. The main purpose of this blinded interim analysis will be futility (Go / No Go). The details of this interim analysis will be presented in the statistical analysis plan which will be finalized before the interim analysis. ETHICS AND DISSEMINATION Institutional Review Board Approval The trial has been approved by the IRB at the participating institutions. Two of the three participating clinical sites (BWH and MGH) are under the auspices of a single Institutional Review Board (IRB), the Partners Human Research Committee, and the third site (BIDMC) is under review by its own IRB, the Committee on Clinical Investigations. The study is being conducted in accordance with Declaration of Helsinki standards and FDA regulations regarding Good Clinical Practice. Informed Consent All participants will have been provided with information about the possible risks and benefits of participating in this clinical trial. After being given time and opportunity to ask questions, subjects will be provided an informed consent form approved by the local IRB. A signed copy of the consent form will be maintained with the study records. Subject Confidentiality and Dissemination of Results Trial participants will be given a unique subject identification number to maintain confidentiality, and no Protected Health Information will be disseminated. Study results will be published in a scientific journal upon study completion.

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DISCUSSION Although significant strides have been made in treating postoperative pain, there continue to be patients in whom the level of pain creates dissatisfaction and impedes recovery. In colorectal surgery, the use of standard analgesics such as opioids is problematic due to the desire for a rapid return of bowel function and the tendency of these drugs to worsen or prolong ileus (31). NSAIDs can lead to bleeding problems, renal dysfunction, or thrombotic events, which may have adverse effects on patient recovery (5)(6). For those reasons, many surgeons have begun to adapt ERAS protocols (Enhanced Recovery After Surgery). These protocols involve early mobilization of patients after surgery, maintaining a euvolemic state by avoiding overhydration, and optimizing pain management through multimodal techniques while minimizing opioid use. Data on outcomes of ERAS protocols in patients undergoing colorectal surgery have been favorable (32).

Various in vivo pharmacological studies with laboratory animals have consistently demonstrated dose-dependent analgesic or anti-allodynic effects of VVZ-149 in rat models of post-operative pain, formalin-induced nociceptive/inflammatory pain and neuropathic pain. The analgesic effect of VVZ-149 has been shown to be due to a non-opioid mechanism and was not blocked by pre-treatment with naloxone, an opioid-receptor antagonist, in the formalin model. VVZ-149 did not inhibit cyclooxygenase activity in an in vitro assay. These results suggest that the analgesic effect of VVZ-149 is neither based on opioid nor non-steroidal anti-inflammatory-based mechanisms. VVZ-149 is thus a non-opioid and non-NSAID analgesic candidate with morphine-comparable efficacy that may be able to provide analgesic benefits to patients. Consistent with the implementation of ERAS protocols, we anticipate that the use of this novel non-opioid analgesic VVZ-149 will provide an alternate and novel method of reducing post-operative pain in patients undergoing laparoscopic colorectal surgery. We have developed a study protocol that evaluates the efficacy and safety of using VVZ-149 in this surgical population and our research will determine if the use of this drug leads to the improved management of postoperative pain. In addition to evaluating the primary endpoint of pain intensity difference over time, we are assessing secondary outcomes such as opioid use, pain relief, sedation, nausea, and overall levels of patient satisfaction with treatment. We have implemented recruitment strategies and engaged in collaborative relationships at three academic hospitals and we believe that we have a successful strategy that will improve our ability to recruit patients who fulfill inclusion and exclusion criteria into our trial. It is our hope that this study will provide high quality data to show whether VVZ-149 is safe and efficacious for use as an analgesic for postoperative pain in this study population.

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TABLE 1: Inclusion and Exclusion Criteria for Phase II VVZ-149 Study Inclusion Criteria • Men and women age between 18-70, inclusive.

• Pain intensity (NRS) ≥4 at initial post-operative measurement in PACU • Subjects undergoing planned laparoscopic colorectal surgery • Ability to provide written informed consent • Ability to understand study procedures and communicate clearly with the

investigator and staff • American Society of Anesthesiologists (ASA) risk class of I to III

Exclusion Criteria Surgical factors

• Emergency or unplanned surgery • Repeat operation (e.g., previous surgery within 30 days for same

condition) • Cancer-related condition causing preoperative pain in site of surgery

Exclusion Criteria Subject criteria

• Women with childbearing potential (Women age 18-55 must undergo pregnancy test)

• Women who are pregnant or breastfeeding • Chronic pain diagnosis (e.g., ongoing pain at baseline with NRS ≥ 4/10). • 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

• Unstable or acute medical condition (e.g., unstable angina, congestive heart failure, renal failure, hepatic failure, AIDS)

Exclusion Criteria Pharmacologic considerations

• Renal or hepatic impairment • History of alcohol, opiate or other drug abuse or dependence within 12

months prior to Screening (TICS alcohol/drug screen will be performed at Screening)

• Ongoing or recent (within 30 days prior to surgery) use of steroids, opioids, or antipsychotics

• Alcohol consumption within 24 hours of surgery • Use of nonsteroidal anti-inflammatory drugs (NSAIDs) or acetaminophen

within 24 hours of surgery • 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

Exclusion Criteria Anesthetic considerations

• Use of neuraxial or regional anesthesia related to the surgery • Use of local anesthetic wound infiltration > 20 ml of 1% lidocaine • Use of ketamine, gabapentin, pregabalin, or lidocaine (>1 mg/kg) intra or

peri-operatively, or within 24 hours of surgery • Subjects with known allergies to hydromorphone • Subjects who received another investigational drug within 30 days of

scheduled surgery • Subjects who have long PR (>200 msec) or prolonged QTc (> 450 msec

for males and > 470 msec for females) at screening or clinically significant prolonged QTc (> 500 msec or change in baseline of > 60 msec) on an ECG done immediately prior to dosing

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TABLE 2: Pharmacokinetic parameters collected in the VVZ-149 protocol Cmax Maximum plasma concentration over the time span specified Cmax,ss Maximum plasma concentration at steady-state Ctrough,ss Plasma concentration at a dosing interval after the treatment at steady-state

(trough concentration at steady-state) Cav,ss Average plasma concentration during a dosing interval at steady-state,

calculated as AUCτ,ss/τt Clast Area under the plasma concentration versus time curve, from time 0 to the last

measurable concentration, calculated by the linear/log trapezoidal method AUCinf The area under the plasma concentration versus time curve from time 0 to

infinity. AUCinf is calculated as the sum of AUClast plus the ratio of the last measurable plasma concentration to the elimination rate constant; AUCinf = AUClast+Clast/λZ

AUCτ,sst Area under the plasma concentration versus time curve during a dosing interval (τ) at steady-state, calculated by the linear/log trapezoidal method.

CL (VVZ-149 Injection) The total body clearance after IV administration, calculated as Dose/AUCinf

CL/F (VVZ-368) Apparent total body clearance after IV administration, calculated as Dose/AUCinf

MRT Mean residence time from the time of dosing to the time of the last measurable concentration. MRT = AUMClast/AUClast

PTF Peak-trough fluctuation, calculated as [(Cmax,ss - Ctrough,ss)/Cav,ss] x 100 (%) Tmax Time of the maximum measured plasma concentration Tmax,ss Time of the maximum measured plasma concentration at steady-state t1/2 Terminal half-life, calculated as ln(2)/λz R Accumulation ratio, AUCτ,ss/AUC0-τt Vd (VVZ-149 Injection) The total volume of distribution after IV administration,

calculated as Dose/(AUCss × λ) Metabolic Ratio

Metabolic Ratio, AUClast of VVZ-368 / AUClast of VVZ-149 Injection

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FIGURE 1: CONSORT diagram for VVZ-149 study flow

Recruitment: 1-4 wks prior

to surgery

Enrollment: Day of surgery

Allocation: Postoperative

Time 0

1º Analysis: Postoperative

Time 8 hrs

2º Analysis: Postoperative Time 24 hrs

Adult patients undergoing laparoscopic

colorectal surgery at 3 hospitals

120 subjects Fulfilling inclusion and exclusion

criteria as per Table 1

80 subjects Randomized to intervention group VVZ-149 + IV hydromorphone PCA

40 subjects Randomized to control group

Placebo + IV hydromorphone PCA

Safety Analysis: 2-4 wks after

surgery

Primary endpoint: Sum of Pain Intensity Difference over

8 hrs (SPID-8)

Secondary endpoints: Opioid consumption, Pain Intensity (NRS), Pain relief, Subject satisfaction,

RASS score, Respiratory depression, PONV score, pK analysis

Safety evaluation: EKG, blood chemistry and hematology,

adverse events

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ABBREVIATIONS: PACU: Postoperative Anesthesia Care Unit; PCA: Patient-controlled Analgesia; HADS: Hospital Anxiety and Depression Scale; PONV: Post Operative Nausea and Vomiting Scale; RASS: Richmond Agitation and Sedation Scale; NSAIDs: Non-Steroidal Anti-Inflammatory Drugs; IV: Intravenous; AEs: Adverse Events; PID: Pain Intensity Differences; SPID: Sum of Pain Intensity Differences; TOTPAR: Total Pain Relief; ERAS: Enhanced Recovery After Surgery; NRS: Numeric Rating Scale; EKG: Electrocardiogram; RCT: Randomized Controlled Trial; IRB: Institutional Review Board; Pharmacokinetic analysis abbreviations noted in Table 2. COMPETING INTERESTS: The following authors confirm that research grant funding has been assigned by the study sponsor, Vivozon Inc., to Brigham and Women’s Hospital, Massachusetts General Hospital, and Beth Israel Deaconess Medical Center, which are the employing institutions of authors SSN, DJC, XB, JLZ, YZ, MJY, JL, JS, KE, CPH, RM, JWC, and BT. In addition, the authors noted below report the following potential competing interests: SSN: consulting fees (Vivozon Inc); DJC: none declared; XB: none declared; JLZ: none declared; YZ: none declared; MJY: none declared; JL: none declared; JS: none declared; KE: none declared; CPH: none declared; RM: none declared; JWC: none declared; BT: none declared. SC and DHL are employees of Vivozon Company, the sponsor of this study, and have received funding from the South Korean Ministry of Health & Welfare for R&D support for pharmaceutical development of the product that is described in this manuscript. AUTHOR CONTRIBUTIONS: Srdjan S. Nedeljkovic: Provided advice on designing and drafting the protocol, edited and approved the final version. Prepared the protocol for manuscript submission and is the lead author for this paper. Also manages the day-to-day running of this clinical trial. Darin J. Correll: Provided advice on parts of the protocol relating to surgical postoperative management. He is the clinical lead for the project at BWH. Xiaodong Bao: Provided advice on parts of the protocol relating to anesthetic and surgical postoperative pain management. He is the clinical lead for the project at MGH. Natacha Zamor: Provided advice on parts of the protocol relating to anesthetic and surgical postoperative management. She is the clinical lead for the project at BIDMC. Jose L. Zeballos: Provided advice on parts of the protocol relating to anesthetic intraoperative management. He is involved in executing the protocol at BWH. Yi Zhang MD: Provided advice on parts of the protocol relating to surgical postoperative pain management. He is involved in executing the protocol at MGH. Mark J. Young: Provided advice on parts of the protocol relating to surgical postoperative pain management. He is involved in executing the protocol at BIDMC. Johanna Ledley: Provided input regarding parts of the protocol regarding subject enrollment, data collection, and coordination with pharmacy and laboratory service at BWH. Jessica Sorace: Provided input regarding parts of the protocol regarding subject enrollment, data collection, and coordination with pharmacy and laboratory service at BWH. Kristen Eng: Provided input regarding parts of the protocol regarding subject enrollment, data collection, and coordination with pharmacy and laboratory service at MGH. Carlyle P. Hamsher: Provided input regarding parts of the protocol related to postoperative data collection and pK sampling at BWH.

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Rajivan Maniam: Provided input regarding parts of the protocol related to postoperative data collection and pK sampling at BWH. Jonathan W. Chin: Provided input regarding parts of the protocol related to postoperative data collection and pK sampling at BWH. Becky Tsui: Provided input regarding parts of the protocol related to postoperative data collection and pK sampling at MGH. Sunyoung Cho: Conceived of and planned the trial, provided basic science input, and approved the final version. Doo H. Lee: Conceived of and planned the trial, drafted the protocol and approved the final version. All authors contributed to development of the research protocol, manuscript writing, and editing of this protocol paper. All of the authors read and approved the final version of the protocol and of the manuscript submission. ACKNOWLEDGEMENTS: The authors thank all participating sites, clinicians and investigators for their support with the clinical study. Additionally, we thank the staff at KCRN, a contract research organization, and especially Ms. Rachel Kim and Mr. Hugh Lee, for their oversight of this research. FUNDING: Funding to conduct this study is being provided by Vivozon, Inc., a privately held company based in South Korea, supported by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant number: HI15C2006). REFERENCES: 1. White PF, Kehlet H. Improving Postoperative Pain Management: What Are the Unresolved Issues? Anesthesiology 2010; 112: 220-5.

2. Kissin, I. The development of new analgesics over the past 50 years: a lack of real breakthrough drugs. Anesthesia Analgesia 2010; 110(3): 780-9.

3. Apfelbaum JL, Chen C, Mehta SS, Gan TJ. Postoperative pain experience: Result from a national survey suggest postoperative pain continues to be undermanaged. Anesthesia Analgesia 2003; 97: 534–40.

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5. Horl WH. Nonsteroidal anti-inflammatory drugs and the kidney. Pharmaceuticals 2010; 3: 2291-2321.

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8. Wongyingsinn M, Baldini G, Stein B, Charlebois P, Liberman S, Carli F. Spinal analgesia for laparoscopic colonic resection using an enhanced recovery after surgery programme: better analgesia, but no benefits on postoperative recovery: a randomized controlled trial. British Journal of Anaesthesia 2012; 108(5): 850-6.

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12. Werdehausen R, Mittnacht S, Bee LA, Minett MS, Armbruster A, Bauer I, Wood JN, Hermanns H, Eulenburg V. The lidocaine metabolite N-ethylglycine has antinociceptive effects in experimental inflammatory and neuropathic pain. Pain 2015: 156(9): 1647-1659.

13. Yoshikawa S, Oguchi T, Funahashi Y, de Groat WC, Yoshimura N. Glycine Transporter Type 2 (GlyT2) Inhibitor Ameliorates Bladder Overactivity and Nociceptive Behavior in Rats. European Urology 2012; 62(4): 704-712.

14. Zeilhofer HU. The glycinergic control of spinal pain processing. Cellular and Molecular Life Sciences CMLS, 2005; 62(18): 2027-35.

15. Beig MI, Baumert M, Walker FR, Day TA, Nalivaiko E. Blockade of 5-HT2A receptors suppresses hyperthermic but not cardiovascular responses to psychosocial stress in rats. Neuroscience 2009; 159(3): 1185-1191.

16. Calejesan AA, Ch’ang MHC, Zhuo M. Spinal serotonergic receptors mediate facilitation of a nociceptive reflex by subcutaneous formalin injection into the hindpaw in rats. Brain Research 1998; 798(1-2): 46-54.

17. Mannion RJ, Costigan M, Decosterd I, Amaya F, Ma QP, Holstege JC, Ji RR, Acheson A, Lindsay RM, Wilkinson GA, Woolf CJ. Neurotrophins: Peripherally and centrally acting modulators of tactile stimulus-induced inflammatory pain hypersensitivity. Proceedings of the National Academy of Sciences, 1999; 96(16): 9385-90.

18. Okamoto K, Imbe H, Morikawa Y, Itoh M, Sekimoto M, Nemoto K, Senba E. 5-HT2A receptor subtype in the peripheral branch of sensory fibers is involved in the potentiation of inflammatory pain in rats. Pain 2002; 99(1-2): 133-143.

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21. Joshi GP, Bonnet F, Kehlet H, PROSPECT collaboration. Evidence-based postoperative pain management after laparoscopic colorectal surgery. Colorectal Dis 2013; 15(2): 146-55.

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22. Katz JN, Chang LC, Sangha O, Fossel AH, Bates DW. Can comorbidity be assessed by questionnaire rather than medical record review? Med Care 1996; 34: 73-84

23. Callahan CM, Unverzagt FW, Hui SL, Perkins AJ, Hendrie HC. Six-Item Screener to Identify Cognitive Impairment Among Potential Subjects for Research. Med Care 2002; 40(9): 771-81.

24. Brown R L, Leonard T, Saunders L A, Papasouliotis O. A two-item conjoint screen for alcohol and other drug problems. J Am Board Fam Pract 2001; 14: 95-106.

25. Zigmond AS, Snaith RP. The hospital anxiety and depression scale. Acta Psychiatr Scand 1983; 67: 361-70.

26. Sullivan, MJ, Thorn B, Haythornthwaite JA, Keefe F, Martin M, Bradley LA, Lefebre JC. Theoretical perspectives on the relation between catastrophizing and pain. Clin J Pain 2001; 17: 52-64.

27. Sessler CN, Gosnell MS, Grap MJ, Brophy GM, O'Neal PV, Keane KA, Tesoro EP, Elswick RK. The Richmond Agitation-Sedation Scale: validity and reliability in adult intensive care unit patients. Am J Respir Crit Care Med 2002; 166: 1338-44.

28. Wengritzky R, Mettho T, Myles PS. Burke J, Kakos A. Development and validation of a postoperative nausea and vomiting intensity scale. Br J Anaesth 2010; 104(2): 158-66.

29. Barden J, Edwards JE, Mason L, McQuay HJ, Moore RA. Outcomes in acute pain trials: Systematic review of what was reported? Pain 2004; 109: 351-6.

30. Singla N, Hunsinger M, Chang PD, McDermott MP, Chowdhry AK, Desjardins PJ, Turk DC, Dowrkin RH. Assay sensitivity of pain intensity versus pain relief in acute pain chlinical trials: ACTTION Systematic Review and Meta-Analysis. Journal of Pain 2015; 16(8): 683-91.

31. Patel S, Lutz JM, Panchagnula U, Bansal S. Anesthesia and perioperative management of colorectal surgical patients – a clinical review (Part 1). J Anaesthesiolo Clin Pharmacol 2012; 28(2): 162-71.

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Note: Regarding the submission to BMJ Open of the Protocol Manuscript entitled:

A Randomized, Double-Blind, Parallel Group, Placebo-Controlled Study to Evaluate the

Analgesic Efficacy and Safety of VVZ-149 Injections for Post-Operative Pain Following

Laparoscopic Colorectal Surgery

Please be advised that the recommended items noted below have been addressed in the

IRB-approved protocol and described in the protocol manuscript.

Srdjan S. Nedeljkovic, M.D.

January 3, 2016

SPIRIT 2013 Checklist: Recommended items to address in a clinical trial protocol and

related documents*

Section/item ItemNo

Description

Administrative information

Title 1 Descriptive title identifying the study design, population, interventions,

and, if applicable, trial acronym

Trial registration 2a Trial identifier and registry name. If not yet registered, name of

intended registry

2b All items from the World Health Organization Trial Registration Data

Set

Protocol version 3 Date and version identifier

Funding 4 Sources and types of financial, material, and other support

Roles and

responsibilities

5a Names, affiliations, and roles of protocol contributors

5b Name and contact information for the trial sponsor

5c Role of study sponsor and funders, if any, in study design; collection,

management, analysis, and interpretation of data; writing of the report;

and the decision to submit the report for publication, including whether

they will have ultimate authority over any of these activities

5d Composition, roles, and responsibilities of the coordinating centre,

steering committee, endpoint adjudication committee, data

management team, and other individuals or groups overseeing the

trial, if applicable (see Item 21a for data monitoring committee)

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Introduction

Background and

rationale

6a Description of research question and justification for undertaking the

trial, including summary of relevant studies (published and

unpublished) examining benefits and harms for each intervention

6b Explanation for choice of comparators

Objectives 7 Specific objectives or hypotheses

Trial design 8 Description of trial design including type of trial (eg, parallel group,

crossover, factorial, single group), allocation ratio, and framework (eg,

superiority, equivalence, noninferiority, exploratory)

Methods: Participants, interventions, and outcomes

Study setting 9 Description of study settings (eg, community clinic, academic hospital)

and list of countries where data will be collected. Reference to where

list of study sites can be obtained

Eligibility criteria 10 Inclusion and exclusion criteria for participants. If applicable, eligibility

criteria for study centres and individuals who will perform the

interventions (eg, surgeons, psychotherapists)

Interventions 11a Interventions for each group with sufficient detail to allow replication,

including how and when they will be administered

11b Criteria for discontinuing or modifying allocated interventions for a

given trial participant (eg, drug dose change in response to harms,

participant request, or improving/worsening disease)

11c Strategies to improve adherence to intervention protocols, and any

procedures for monitoring adherence (eg, drug tablet return,

laboratory tests)

11d Relevant concomitant care and interventions that are permitted or

prohibited during the trial

Outcomes 12 Primary, secondary, and other outcomes, including the specific

measurement variable (eg, systolic blood pressure), analysis metric

(eg, change from baseline, final value, time to event), method of

aggregation (eg, median, proportion), and time point for each

outcome. Explanation of the clinical relevance of chosen efficacy and

harm outcomes is strongly recommended

Participant

timeline

13 Time schedule of enrolment, interventions (including any run-ins and

washouts), assessments, and visits for participants. A schematic

diagram is highly recommended (see Figure)

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Sample size 14 Estimated number of participants needed to achieve study objectives

and how it was determined, including clinical and statistical

assumptions supporting any sample size calculations

Recruitment 15 Strategies for achieving adequate participant enrolment to reach

target sample size

Methods: Assignment of interventions (for controlled trials)

Allocation:

Sequence

generation

16a Method of generating the allocation sequence (eg, computer-

generated random numbers), and list of any factors for stratification.

To reduce predictability of a random sequence, details of any planned

restriction (eg, blocking) should be provided in a separate document

that is unavailable to those who enrol participants or assign

interventions

Allocation

concealment

mechanism

16b Mechanism of implementing the allocation sequence (eg, central

telephone; sequentially numbered, opaque, sealed envelopes),

describing any steps to conceal the sequence until interventions are

assigned

Implementation 16c Who will generate the allocation sequence, who will enrol participants,

and who will assign participants to interventions

Blinding

(masking)

17a Who will be blinded after assignment to interventions (eg, trial

participants, care providers, outcome assessors, data analysts), and

how

17b If blinded, circumstances under which unblinding is permissible, and

procedure for revealing a participant’s allocated intervention during

the trial

Methods: Data collection, management, and analysis

Data collection

methods

18a Plans for assessment and collection of outcome, baseline, and other

trial data, including any related processes to promote data quality (eg,

duplicate measurements, training of assessors) and a description of

study instruments (eg, questionnaires, laboratory tests) along with

their reliability and validity, if known. Reference to where data

collection forms can be found, if not in the protocol

18b Plans to promote participant retention and complete follow-up,

including list of any outcome data to be collected for participants who

discontinue or deviate from intervention protocols

Data

management

19 Plans for data entry, coding, security, and storage, including any

related processes to promote data quality (eg, double data entry;

range checks for data values). Reference to where details of data

management procedures can be found, if not in the protocol

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Statistical

methods

20a Statistical methods for analysing primary and secondary outcomes.

Reference to where other details of the statistical analysis plan can be

found, if not in the protocol

20b Methods for any additional analyses (eg, subgroup and adjusted

analyses)

20c Definition of analysis population relating to protocol non-adherence

(eg, as randomised analysis), and any statistical methods to handle

missing data (eg, multiple imputation)

Methods: Monitoring

Data monitoring 21a Composition of data monitoring committee (DMC); summary of its role

and reporting structure; statement of whether it is independent from

the sponsor and competing interests; and reference to where further

details about its charter can be found, if not in the protocol.

Alternatively, an explanation of why a DMC is not needed

21b Description of any interim analyses and stopping guidelines, including

who will have access to these interim results and make the final

decision to terminate the trial

Harms 22 Plans for collecting, assessing, reporting, and managing solicited and

spontaneously reported adverse events and other unintended effects

of trial interventions or trial conduct

Auditing 23 Frequency and procedures for auditing trial conduct, if any, and

whether the process will be independent from investigators and the

sponsor

Ethics and dissemination

Research ethics

approval

24 Plans for seeking research ethics committee/institutional review board

(REC/IRB) approval

Protocol

amendments

25 Plans for communicating important protocol modifications (eg,

changes to eligibility criteria, outcomes, analyses) to relevant parties

(eg, investigators, REC/IRBs, trial participants, trial registries, journals,

regulators)

Consent or assent 26a Who will obtain informed consent or assent from potential trial

participants or authorised surrogates, and how (see Item 32)

26b Additional consent provisions for collection and use of participant data

and biological specimens in ancillary studies, if applicable

Confidentiality 27 How personal information about potential and enrolled participants will

be collected, shared, and maintained in order to protect confidentiality

before, during, and after the trial

Declaration of

interests

28 Financial and other competing interests for principal investigators for

the overall trial and each study site

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Access to data 29 Statement of who will have access to the final trial dataset, and

disclosure of contractual agreements that limit such access for

investigators

Ancillary and

post-trial care

30 Provisions, if any, for ancillary and post-trial care, and for

compensation to those who suffer harm from trial participation

Dissemination

policy

31a Plans for investigators and sponsor to communicate trial results to

participants, healthcare professionals, the public, and other relevant

groups (eg, via publication, reporting in results databases, or other

data sharing arrangements), including any publication restrictions

31b Authorship eligibility guidelines and any intended use of professional

writers

31c Plans, if any, for granting public access to the full protocol, participant-

level dataset, and statistical code

Appendices

Informed consent

materials

32 Model consent form and other related documentation given to

participants and authorised surrogates

Biological

specimens

33 Plans for collection, laboratory evaluation, and storage of biological

specimens for genetic or molecular analysis in the current trial and for

future use in ancillary studies, if applicable

*It is strongly recommended that this checklist be read in conjunction with the SPIRIT 2013

Explanation & Elaboration for important clarification on the items. Amendments to the

protocol should be tracked and dated. The SPIRIT checklist is copyrighted by the SPIRIT

Group under the Creative Commons “Attribution-NonCommercial-NoDerivs 3.0 Unported”

license.

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Study Protocol – A Randomized, Double-Blind, Parallel Group, Placebo-Controlled Study to Evaluate the Analgesic

Efficacy and Safety of VVZ-149 Injections for Post-Operative Pain Following Laparoscopic Colorectal Surgery

Journal: BMJ Open

Manuscript ID bmjopen-2016-011035.R1

Article Type: Protocol

Date Submitted by the Author: 02-Jun-2016

Complete List of Authors: Nedeljkovic, Srdjan; Brigham and Women\'s Hospital, Department of Anesthesiology, Perioperative and Pain Medicine Correll, Darin; Brigham and Women\'s Hospital, Department of Anesthesiology, Perioperative and Pain Medicine Bao, Xiaodong; Massachusetts General Hospital, Department of Anesthesia, Critical Care and Pain Medicine Zamor, Natacha ; Beth Israel Deaconess Medical Center, Department of Anesthesia, Critical Care and Pain Medicine Zeballos, Jose; Brigham and Women\'s Hospital, Department of Anesthesiology, Perioperative and Pain Medicine

Zhang, Yi; Massachusetts General Hospital, Department of Anesthesia, Critical Care and Pain Medicine Young, Mark; Beth Israel Deaconess Medical Center, Department of Anesthesia, Critical Care and Pain Medicine Ledley, Johanna; Brigham and Women\'s Hospital, Department of Anesthesiology, Perioperative and Pain Medicine Sorace, Jessica; Brigham and Women\'s Hospital, Department of Anesthesiology, Perioperative and Pain Medicine Eng, Kristen; Massachusetts General Hospital, Department of Anesthesia, Critical Care and Pain Medicine Hamsher, Carlyle; Brigham and Women\'s Hospital, Department of Anesthesiology, Perioperative and Pain Medicine

Maniam, Rajivan; Brigham and Women\'s Hospital, Department of Anesthesiology, Perioperative and Pain Medicine Chin, Jonathan; Brigham and Women\'s Hospital, Department of Anesthesiology, Perioperative and Pain Medicine Tsui, Becky; Massachusetts General Hospital, Department of Anesthesia, Critical Care and Pain Medicine Cho, Sunyoung; Vivozon, Inc, Research Director Lee, Doo; Vivozon, Inc., Chief Executive Officer

<b>Primary Subject Heading</b>:

Pharmacology and therapeutics

Secondary Subject Heading: Anaesthesia

Keywords: Pain management < ANAESTHETICS, PAIN MANAGEMENT, CLINICAL PHARMACOLOGY, Clinical trials < THERAPEUTICS


BMJ Open on M

arch 9, 2020 by guest. Protected by copyright.

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Note: The following files were submitted by the author for peer review, but cannot be converted to PDF. You must view these files (e.g. movies) online.

Vivozon(ProtocolManuscript)(06_01_16)(BMJ).doc

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Study Protocol – A Randomized, Double-Blind, Parallel Group, Placebo-Controlled Study to Evaluate the Analgesic Efficacy and Safety of VVZ-149 Injections for Post-Operative Pain Following Laparoscopic Colorectal Surgery Srdjan S. Nedeljkovic MD1, Darin J. Correll MD1, Xiaodong Bao MD PhD2, Natacha Zamor MD3, Jose L. Zeballos MD1, Yi Zhang MD PhD2, Mark J. Young MD3, Johanna Ledley BA MS1, Jessica Sorace BS1, Kristen Eng BS2, Carlyle P. Hamsher MD1, Rajivan Maniam MD1, Jonathan W. Chin MD1, Becky Tsui MD2, Sunyoung Cho PhD4, Doo H. Lee PhD4. Corresponding author: Dr. Srdjan S. Nedeljkovic <[email protected]> 1. Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women’s Hospital,

Boston, MA, USA

2. Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Boston, MA, USA

3. Department of Anesthesia, Critical Care and Pain Medicine, Beth Israel Deaconess Medical Center,

Boston, MA, USA

4. Vivozon, Inc. Seoul, South Korea

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ABSTRACT Introduction: In spite of advances in understanding and technology, postoperative pain remains poorly treated for a significant number of patients. In colorectal surgery, the need for developing novel analgesics is especially important. Patients after bowel surgery are assessed for rapid return of bowel function and opioids worsen ileus, nausea, and constipation. We describe a prospective, double-blind, parallel group, placebo-controlled randomized controlled trial testing the hypothesis that a novel analgesic drug, VVZ-149, is safe and effective in improving pain compared to providing opioid analgesia alone among adults undergoing laparoscopic colorectal surgery. Methods and analysis: Based on sample size calculations for primary outcome, we plan to enroll 120 subjects. Adult patients without significant medical comorbidities or ongoing opioid use and who are undergoing laparoscopic colorectal surgery will be enrolled. Participants are randomly assigned to receive either VVZ-149 with IV hydromorphone PCA or the control intervention (IV PCA alone) in the postoperative period. The primary outcome is the SPID-8 (Sum of Pain Intensity Difference over 8 hours post-dose). Subjects receive VVZ-149 for 8 hours postoperatively to the primary study endpoint, after which they continue to be assessed for up to 24 hrs. We measure opioid consumption, record pain intensity and pain relief, and evaluate the number of rescue doses and requests for opioid. To assess safety, we record sedation, nausea and vomiting, respiratory depression, laboratory tests and EKG readings after study drug administration. We evaluate for possible confounders of analgesic response, such as anxiety, depression, and catastrophizing behaviors. The study will also collect blood sample data and evaluate for pharmacokinetic and pharmacodynamic relationships. Ethics and dissemination: Ethical approval of the study protocol has been obtained from Institutional Review Boards at the participating institutions. Trial results will be disseminated through scientific conference presentations and by publication in scientific journals. Trial Registration: Clinicaltrials.gov NCT02489526 STRENGTHS AND LIMITATIONS

• This is a prospective, randomized, double blind design that will evaluate for a clinically meaningful response to a novel analgesic agent. The new drug could broadly expand treatment options for postoperative pain for patients.

• The trial assesses for many of the common potential confounders of analgesic response, including perioperative anxiety, depression, and catastrophizing behaviors that may influence reporting of pain levels and affect use of opioids in the postoperative period.

• The protocol includes an assessment of perception of treatment both on the part of subjects and investigators, which will help evaluate the effectiveness of blinding to treatment allocation.

• A potential limitation is that a diverse and heterogenous group of patients may be enrolled, potentially confounding the results.

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INTRODUCTION Although there have been numerous studies published regarding the use of existing drugs classes for analgesia, manuscripts related to opioid-type drugs dominate (1). In spite of significant research efforts, novel non-opioid or non-NSAID drugs have been found to have questionable efficacy in the treatment of postoperative pain, and are not in routine clinical use. As noted by Kissin in 2010, there has been no new analgesic drug based on a novel pain mechanism introduced to the market in more than a generation (2). Therefore, there is an unmet need for such research to come to fruition, especially since postoperative pain continues to be inadequately managed in some patients even with full availability of existing therapies. The currently available analgesic therapies for acute postoperative pain based on providing opioid analgesics often lead to unsatisfactory pain relief or excessive side effects (3). Providing additional opioids can result in intolerable side effects such as nausea, pruritis, constipation, respiratory depression, and may induce tolerance, rendering the analgesic treatment less effective. In addition, opioid management can lead to the development of hyperalgesia (increased pain sensitivity) in some patients in the postoperative period (4). Furthermore, the use of NSAIDs can be linked to the development of gastrointestinal complications and renal injury, especially in patients who have altered fluid shifts in the perioperative period (5)(6). Although patients may benefit from perioperative use of drugs like gabapentin, non-opioid, non-NSAID drugs are poorly effective as stand-alone agents for acute postoperative pain management (7). Finally, regional anesthetic techniques, although useful for many patients, also have limitations, side effects, and can still be poorly effective (8). In colorectal surgery, the need for novel analgesics is especially important. Patients after bowel surgery are assessed for rapid return of bowel function and opioids can worsen or prolong ileus, nausea, and constipation – which are highly undesirable outcomes in this patient population. Excessive pain and use of opioids not only delays return of normal gastrointestinal function, but patients may require prolonged stays in the hospital – increasing the risk of iatrogenic infections. Prolonged immobility due to pain can increase the risk of thromboembolic events and result in muscle wasting and debilitation, which may have an overall adverse effect on patients’ outcomes, satisfaction, and quality of life. Therefore, the need to develop alternate and novel analgesics is desirable for improving management of postoperative pain, being specifically desirable and needed in managing patients postoperatively who have undergone bowel surgery. VVZ-149 is a small molecular compound in the benzamide family that has been developed as an injectable product to improve postoperative pain control. A novel analgesic drug, VVZ-149 is a dual antagonist of GlyT2 (glycine transporter type 2) and 5HT2A (serotonin receptor 2A). GlyT2 blockage increases inhibitory synaptic transmission by glycine in the spinal cord, resulting in a reduction of pain transmissions to the brain (9)(10)(11)(12)(13)(14). 5HT2A blockage decreases descending serotonergic facilitatory modulation on pain transmission by the brain and reduces nociceptor activation in peripheral nerves, both of which are primary sources of post-surgical pain (15)(16)(17)(18)(19). There is good rationale for developing drugs that act on multiple targets, as this may improve therapeutic benefit while reducing side effects of therapy (20). VVZ-149 has 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. A clinical Phase 1 study performed in healthy subjects has shown no clinically significant adverse events (21). Laparoscopic colorectal surgery is typically associated with a burst of moderate to severe pain (NRS ≥4, scale 0-10) in the immediate postoperative period (22). Because of the significant analgesic requirements for patients who undergo this type of surgery, using this postoperative pain model is an appropriate

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condition under which to study VVZ-149. In addition, due to potentially undesirable effects that opioids often have upon bowel function and recovery, studying the efficacy and side effect profile of VVZ-149 is ideally suited to the colorectal surgery patient population. In summary, VVZ-149 is potentially a favorable non-opioid and non-NSAID analgesic candidate with comparable efficacy to morphine that may be able to provide superior analgesia and reduce side effects for patients who are recovering from laparoscopic colorectal surgery. OBJECTIVES The overall objective of this multi-center, double-blind RCT is to evaluate the safety and efficacy of VVZ-149 for treating postoperative pain in patients who undergo laparoscopic colorectal surgery. When compared to providing patients with intravenous opioids alone (hydromorphone PCA), we hypothesize that patients randomized to receive VVZ-149 with hydromorphone PCA will show significantly greater improvement in pain with an acceptable side effect profile compared to patients randomized to receive IV hydromorphone PCA only. We are also examining whether VVZ-149 is effective in reducing opioid consumption, as well as its side effect and safety profile (e.g. nausea and vomiting, sedation, EKG changes, other laboratory parameters, and respiratory depression). We are examining potential confounders, such as pre-existing anxiety, depression, and catastrophizing behaviors, and reporting on overall patient satisfaction with this novel therapy. Finally, we are also evaluating the robustness of our blinding by assessing expectation of treatment in study participants and perception of treatment in both study personnel and patients. METHODS AND STUDY DESIGN The VVZ-149 study is a randomized, double-blind, parallel group, placebo-controlled study to evaluate the efficacy and safety of the analgesic drug candidate VVZ-149 for subjects with pain following laparoscopic colorectal surgery. Patients, study investigators, and the research team collecting data are blind to patient treatment allocation. Subjects of age 18 to 70 undergoing laparoscopic colorectal surgery are screened within 30 days prior to the day of the surgery. After completion of the surgery, subjects are transferred to the post-operative anesthesia care unit (PACU), where the study drug is initiated as soon as possible once the subject is admitted. During surgery, eligible subjects are randomized in a 2:1 ratio to one of two study groups, VVZ-149 Injections or placebo. Then, subjects who have a pain score of at least 4 on the 11-point NRS are administered the study drug. Subjects who are deemed ineligible have no further data collected and receive routine postoperative care. A randomized subject receives a dosing regimen of VVZ-149 injections or placebo via IV infusion for 8 hours. In addition to receiving the study drug or placebo, all subjects receive IV patient-controlled analgesia (PCA) with hydromorphone on demand to facilitate achieving adequate pain relief. Subjects are evaluated per the study protocol through 24 hours after dosing. A follow-up assessment is performed 14-30 days following the treatment. Please refer to FIGURE 1 (Consort Flow Diagram). Setting and Recruitment Patients are being recruited from three academic medical centers: Brigham and Women’s Hospital, Beth Israel Deaconess Medical Center, and Massachusetts General Hospital. All three hospitals are located in Boston, Massachusetts and are teaching affiliates of Harvard Medical School. The study was approved by the local IRBs in July 2015 and enrollment is expected to conclude by December 2016.

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Patients undergoing planned laparoscopic colorectal surgery are informed about the study at their local surgeon’s office or at the facility’s preoperative test center, where they are asked if they would like to participate in the VVZ-149 trial. Prior to recruitment, members of the research team evaluate whether the patient is potentially an appropriate candidate for enrollment into the study based on diagnosis, age, and the nature of the planned procedure. The physician or study representative introduces the study during the patient’s planned visit to their surgeon or the preoperative test center, or by telephone call for those patients who do not require pre-hospital evaluation within the facility. Each potential patient is given detailed information about the procedures involved with the study protocol as well as the IRB-approved consent form to review prior to agreeing to participate in the study. All patients are required to provide written informed consent when enrolling in the study. Eligibility Criteria Inclusion and exclusion criteria for patients to participate in the study are listed in Table 1. Inclusion criteria were developed to allow enrollment of adult patients age 70 or lower who are without high anesthetic risk classification (ASA 1-III) and who are scheduled to undergo laparoscopic colorectal surgery. Patients must have the ability to understand study procedures and communicate in English. To be enrolled in the study, a patient must have minimal pain intensity of ≥4 (on a 0-10 scale) at the time of their initial pain measurement after surgery in the PACU. Patients may be excluded from participation in the study due to certain surgical factors, subject characteristics, anesthetic factors, or pharmacological considerations. Many of the exclusion factors were chosen to reduce or eliminate possible confounders that could affect study outcomes, like the use of neuraxial, regional, or local anesthesia or the use of certain analgesic drugs such as NSAIDs, anticonvulsants, ketamine, acetaminophen, or herbal agents. Other exclusion factors were chosen to maintain safety of study participants, such as exclusion of patients who have prolonged QTc on their EKG, those with unstable or acute medical conditions, or those who have clinically important renal or hepatic impairment. To avoid the confounder of ongoing pain and opioid use, subjects with a chronic pain diagnosis or those taking opioids on regular basis preoperatively were excluded. To ensure that treatment results are not affected by recent prior surgery or use of analgesics, we are excluding patients who have a cancer related condition causing preoperative pain, those who are having a repeat operation within 30 days, and those who are having emergency surgery. Baseline Assessments, Treatment Phase, and Post-treatment Follow-up Patients scheduled to undergo laparscopic colorectal surgery are invited to participate in the study by the treating physician, research physicians, and/or research staff. Potentially eligible and interested patients are then screened for eligibility by research staff at each of the sites. If a patient is eligible, the potential subject is asked to complete the informed consent process. A physician investigator reviews each potential patient’s eligibility and pre-operative test results (laboratory tests, EKG, and response to questionnaires) to confirm the eligibility of the subject for enrollment into the study protocol. On screening, questionnaires are administered to assess demographic and clinical factors, including medical and surgical history (Charlson-Katz questionnaire) (23), medication history, vital signs, cognitive impairment (Six-item Cognitive Screening questionnaire) (24), alcohol/drug use (TICS questionnaire) (25), EKG, and blood samples are obtained to assess baseline hematologic, coagulation, renal, hepatic, thyroid, and metabolic parameters. Patients are asked to complete self-report questionnaires to assess for anxiety, depression, and pain catastrophizing behaviors (26)(27. Subjects who meet eligibility criteria based on assessments done at screening check-in 2-4 hours prior to the scheduled surgery. At that time, any changes in medications are recorded and the eligibility of the

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subject is confirmed. Patients complete an “Expectations of Treatment” questionnaire (28). Randomization of eligible subjects occurs during the time of surgery. After completion of surgery, subjects are transferred to the PACU. There, it is confirmed that the subject continues to meet inclusion/exclusion criteria. An EKG is done to ensure that there has been no significant increase in QTc interval that would otherwise render the patient ineligible. Pain intensity (NRS), level of sedation (RASS), presence of postoperative nausea and vomiting (PONV), and level of respiratory depression are assessed. In patients who use postoperative IV PCA with opioids, a level of respiratory depression of less than 8 breaths per minute and an oxygen saturation level of <90% is considered clinically significant (29). Upon regaining a level of alertness (RASS score -1 or greater) and no more than one hour after emergence from anesthesia, subjects are asked to report a pre-dose pain intensity score. Subjects who indicate a pain score of at least 4 on the 11-point NRS are dosed with the study medication within 30 minutes of measuring the pre-dose pain intensity score. The experimental group receives a 1.8 mg/kg VVZ-149 intravenous infusion for 0.5 hour. This loading dose is followed by a maintenance dose of an intravenous VVZ-149 infusion of 1.3 mg/kg/hr for 7.5 hours.

A PCA pump containing hydromorphone (1 mg/ml) is connected to an intravenous infusion line and programmed to deliver 0.2-0.3 mg boluses of hydromorphone on demand by the subject, with a lockout time interval of 6 minutes. If adequate pain relief is not achieved with the IV PCA titration (pain score NRS ≥6), a mandatory “rescue” dose of 0.5 mg IV hydromorphone is administered as needed at a time interval of every 5 minutes to achieve a pain score of NRS ≤5, but total number of rescue doses cannot be more than 3 times per hour. Subjects who no longer require IV PCA can be transitioned to oral hydromorphone (4 mg q 3-4 hours as needed) after 12 or more hours post-dosing. Once the treatment infusion has been initiated, subjects are observed for 24 hours. Patients are placed on centrally monitored continuous pulse oximetry for up to 12 hours post-dosing regardless of whether they are receiving VVZ-149 and while they are receiving IV PCA. In addition, respiratory depression assessments are done at pre-dose and each post-baseline time point and prior to administering any rescue doses of hydromorphone. Subjects complete the treatment phase of the study on post-operative Day 1 after a 24-hour post-dose assessment has been completed. In subjects who receive rescue dosing, the pain intensity (NRS) rating that is measured immediately before the dose is documented to replace the closest measurement scheduled to be recorded as part of the study protocol. If the number of rescue doses exceeds 3 times per hour, the subject is withdrawn from the study and allowed additional boluses of opioid and other analgesic treatments that are deemed clinically appropriate. During the drug infusion phase (0 to 8 hours) and treatment assessment phase (8 to 24 hours), patients are periodically assessed for pain intensity at rest and with movement, pain relief, RASS (Richmond Agitation and Sedation Scale) (30), the incidence and clinical importance of PONV (Post operative Nausea and Vomiting scale) (31), opioid consumption, respiratory depression, adverse events, and concomitant use of medications. Vital signs are recorded and EKG’s are obtained at several time points. Blood samples for pharmacokinetic analysis are also obtained (predose, and then at 0.5 hr, 1, 4, 8, 9, 12, and 24 hrs after dosing). At 8 hr and 24 hr post-dose, patient satisfaction with treatment is evaluated using the “Global Measure of Subject Satisfaction Scale.” At 24 hours post-dosing, a blood sample to evaluate hematologic, coagulation, renal, hepatic, thyroid, and metabolic parameters is collected.

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To assess the robustness of blinding, a “Perception of Treatment” questionnaire is administered to both study subjects and to the study personnel who most closely observed the subject during the treatment phase of the protocol (32). Subject expectation of treatment and overall satisfaction with the study drug is evaluated to see if these parameters are associated with treatment outcomes. Randomization and Blinding In this double-blind study, the investigator, research assistants involved in obtaining data, the treating clinicians, and the study subjects are blinded to the treatment assignment of the study subjects while the site pharmacist and study project manager remain unblinded. After confirming the initial eligibility of subjects, the randomization is requested by the site project team during the time of surgery. The site pharmacist is 1) notified of the randomization code generated via the electronic data capture (EDC) system, 2) confirms which group the subject is assigned through the list of randomization code and group provided to only the site pharmacist, 3) mixes VVZ-149 Injections or placebo in a 500mL saline IV bag after calculating the dosing volume according to the subject’s weight, and 4) dispenses the IV bag to the nurse for the dosing. The list of randomization codes and group assignment lists are securely retained by the site pharmacist. The randomization information of each subject can be disclosed to the investigator in an emergency situation only. If unblinding occurs, the study medication for the subject is discontinued and a written explanation of the event is prepared immediately. Subjects who are unblended will receive opioid analgesics as needed, per the standard of practice for postoperative pain management at the institution, and at the discretion of their clinician.. Upon discontinuation of the study medication and completion of the study period at 24 hours after dosing, subjects will managed per the standard practice of the clinician following laparoscopic colorectal surgery. Treatment Administered and Selection of Doses in the Study The treatment consists of a loading dose of 1.8 mg/kg VVZ-149 Injections administered by intravenous infusion for 0.5 hour, followed by a maintenance dose of 1.3 mg/kg/h VVZ-149 Injections for 7.5 hours. The placebo group receives the corresponding volume of placebo for the proscribed time of the study. The estimated therapeutic range of targeted pooled plasma concentration has been determined to be 600-1900 ng/mL, which corresponds to 2-6 mg/kg in a 4-h infusion as the Cmax of the dose in a Phase 1 study (PT-VVZ149-01) (21). Using NONMEM (Non-linear Mixed Effects Modeling) with individual PK data from the Phase 1 study, the expected plasma concentration and individual variability of an initial loading dose followed by a maintenance dose were simulated. The results suggest that a loading dose of 1.5 mg/kg of 0.5 hour followed by a maintenance dose of 1.1 mg/kg/h for 7.5 hours will achieve a similar level of pooled plasma concentration at a steady state with Cmax of 5 mg/kg in a 4-h IV infusion, a level within the range where VVZ-149 Injections is expected to demonstrate its maximum efficacy. However, actual plasma concentration in a Phase 1 study with elderly subjects (PT-VVZ149-02) appeared to be about 20% less than the expected level by the simulation (21). Thus, the doses used for this protocol have been adjusted to 1.8 mg/kg of 0.5 hour for a loading dose followed by a maintenance dose of 1.3 mg/kg/h for 7.5 hours to increase the plasma exposure level by about 20% of the level of maximally efficacious analgesic effect without adverse side effects. Anesthesia Protocol

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All subjects have general anesthesia without any regional or neuraxial anesthesia, and subjects do not receive ketamine or lidocaine > 1 mg/kg. Only IV hydromorphone, fentanyl, or morphine are administered as opioids during anesthesia. The dose and type of IV opioid given intraoperatively is recorded as one of the variables that can affect treatment outcome. No more than the following doses are given intraoperatively: IV morphine 10 mg, IV fentanyl 500 µg total during entire anesthetic, and IV hydromorphone 2 mg. Within 1 hour of expected surgical completion, only IV fentanyl up to 200 µg is administered. Opioid doses are determined at the clinical discretion of the anesthesiologist based on subjects’ surgical response and hemodynamic parameters while under anesthesia. The amount of opioid administered intraoperatively will be converted to a total morphine equivalent dose and will be considered in the analysis of outcomes. No NSAID, gabapentin, pregabalin, or acetaminophen is provided intraoperatively or during the postoperative study period. No more than 20 ml of 1% lidocaine anesthetic wound infiltration may be given. At the discretion of the anesthesiologist, subjects may receive standard doses of intra-operative prophylactic or post-operative therapeutic anti-emetics (dexamethasone ≤10 mg, haloperidol ≤1 mg, ondansetron ≤4 mg) and the use of these drugs is recorded. After the completion of surgery, subjects will be transferred to the PACU within 30 minutes of emergence from anesthesia. In the PACU, the study protocol and the IV PCA pump will be ready to initiate as soon as possible once the anesthesiologist delivers the subject to the PACU. If there is a need to administer IV opioid from the time of emergence of the subject from general anesthesia to the time they are transferred to the PACU and therefore before the study protocol is initiated, fentanyl up to 3 µg/kg may be administered incrementally as needed and the dose recorded.

Use of Opioid PCA An opioid PCA pump containing hydromorphone (0.5-1.0 mg/mL) is connected to an intravenous infusion line and programmed to deliver 0.2-0.3 mg boluses of hydromorphone on demand by the subject, with a lockout time interval of 6 minutes. If adequate pain relief is not achieved with the IV hydromorphone PCA (if pain score NRS is ≥6), a “rescue” bolus of 0.5 mg/bolus IV hydromorphone may be administered as needed at a time interval of every 5 minutes to achieve a pain score of NRS ≤5, but the total number of rescue doses may not be given over 3 times per hour. In subjects who receive rescue dosing, the pain intensity (NRS) rating that is measured immediately before the dose and the measurement is documented to replace the closest measurement scheduled to be recorded as part of the study protocol. If the number of rescue doses exceeds 3 times per hour, the subject is withdrawn from the study and allowed additional boluses and analgesic treatments that are deemed clinically appropriate. Subjects who are withdrawn continue to be monitored as part of the study protocol and safety and efficacy data continues to be collected and recorded for future analysis. Subjects who no longer require IV PCA may be transitioned to oral hydromorphone (2-4 mg q 3-4 hours prn) to replace IV PCA 12 hours or longer post-dosing. The amount and frequency of oral hydromorphone used by the subject 12-24 hours post-dosing is recorded, as well as any IV rescue dosing necessary during this time.

OUTCOMES The primary outcome is the Sum of Pain Intensity Difference over 8 hours post dosing of the study drug (SPID-8) (33). This is assessed using an 11-point Numerical Pain Rating Scale pain scores (NRS, 0-10) measured up to 8 hours post-dose. Pain intensity difference is calculated by subtracting each subject’s baseline score of pain with movement minus post-dosing pain scores so that positive differences indicated decreased pain. Pain intensity difference (PID) scores are evaluated using pre-dose scores, and then at 0.25 hr, 0.50 hr, 1 hr, 2 hr, 4 hr, 6 hr, and 8 hrs post dosing.

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A number of secondary outcome measures are being analyzed. Opioid consumption up to 24 hours post-dosing of study drug at 0-2, 2-4, 6-8, 8-12, 12-6, and 16-24 hours post-dosing of study drug is assessed while also evaluating the total number of PCA demands for opioid, the total number of rescue doses given, and the time to the first rescue dose. Pain Intensity at rest and with movement is assessed as recorded on the 11-point numerical rating scale (NRS). Categorical Pain Relief scores are assessed using a 6-point scale (0: worse, 1: none, 2: a little relief, 3: some relief, 4: a lot of relief, 5: complete relief) up to 24 hours post-dose). Using this data, Total Pain Relief (TOTPAR) over the 8-hour and 24-hour time points is calculated (34). Global Measurement of Subjects Satisfaction with the study medication is assessed using a 5-point scale (extremely dissatisfied, 1: dissatisfied, 2: neutral, 3: satisfied, 4: extremely satisfied) at 8 and 24 hours post-dose. Finally, side effects of the study medication are evaluated by analyzing results of the Richmond Agitation Sedation Scale (RASS), Post-operative Nausea and Vomiting scale (PONV), and by reviewing the Respiratory Depression Assessments for up to 24 hours post-dose. As part of this efficacy and safety study, blood samples are collected from patients at various time points pre- and post-dosing to perform pharmacokinetic evaluation of the study product. A pharmacokinetic to pharmacodynamic correlation assessment will eventually be performed. Subjects are assessed at one additional time point after discharge from the hospital, 14-30 days after surgery. At that time, vital signs are measured, an EKG is performed, and any adverse events or changes in medications are noted. A blood sample to evaluate hematologic, coagulation, renal, hepatic, thyroid, and metabolic parameters is collected.

SAMPLE SIZE CALCULATION The sample size for this study was determined based on the conjectures for the primary endpoint of SPID. Specifically, a minimum clinically important difference between group means of 5, with a maximum standard deviation of 7 were conjectured. A statistical power of 90% with an overall alpha-level of 5% (4.5% for the final analysis and 0.5% for the interim analysis) was assumed in the calculations. In addition, a maximum attrition rate of 15% is incorporated. With all the above specifications, 120 subjects with a 2:1 ratio will be enrolled into the study (n=80) and control (n=40) groups. STATISTICAL METHODS Unless otherwise specified, standard descriptive statistics will be computed for all endpoints and other observed values. The standard descriptive statistics for continuous variables include: number of observations analyzed, mean, standard deviation, median, minimum, and maximum. The standard descriptive statistics for categorical variables include: frequency distribution with the number and percent of subjects included in each category. Calculation of percentage will use the denominator of the total number of subjects in the particular group of analysis population used in the data display unless otherwise specified. All observed data will be summarized and analyzed. No imputations are planned for missing data. Analysis of Primary Endpoint SPID-8 will be summarized descriptively for each of the two groups. Groups will be compared using a t-test if the endpoint is approximately normally distributed, or using a Wilcoxon rank sum test if the endpoint is markedly non-normally distributed.

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Analysis of Secondary Endpoints Opioid consumption, NRS, PID, RASS, respiratory depression assessment, Pain Relief, TOPAR, global assessment of satisfaction, and intensity of PONV (number of instances and duration) will be summarized and analyzed using the same methodology as described for the primary endpoint, SPID. The time to first rescue hydromorphone dose will be summarized with Kaplan-Meier estimates and groups will be compared with a log-rank test. Analysis of Potential Confounders Potential confounders of analgesic response include baseline levels of anxiety and depression, expectations of treatment, and catastrophizing behavior. For each potential confounder, we will construct an analysis of covariance model (ANCOVA). To examine if the effect of treatment differs depending on any patient characteristics that precede treatment, we will assess statistical significance with a likelihood ratio test. We will evaluate baseline characteristics to assess if there are non-specific predictors of outcome that may have an impact on results in both the active and placebo treatment groups. For an evaluation of the robustness of blinding (another potential confounder), we will use Fisher’s exact test to compare treatment guesses between arms.

Safety Analyses

Adverse events will be compared between groups using chi-square tests or Fisher’s exact tests, as appropriate. The remaining safety endpoints will either be analyzed using the same methodology as described for the primary endpoint, if continuous, or using chi-square tests or Fisher’s exact tests, as appropriate, if categorical. Pharmacokinetic Analyses The actual sampling time for each subject will be used in the PK analysis. Drug concentrations under lower limit of quantification (LLOQ), not applicable or not sampled will be recorded as < LLOQ, NA, or ND, respectively. PK parameters will be calculated from the data from individual plasma concentration times of VVZ-149 Injections using non-compartmental methods. PK calculations will be performed using WinNonlin®. The PK parameters of VVZ-149 Injections will be calculated as per TABLE 2. PK parameters will be summarized using descriptive statistics (e.g. mean, SD, median, minimum, maximum and coefficient of variation). Plasma drug-concentration time curves will be expressed as linear or log/linear graphs for each subject, and the mean of the plasma drug-concentration time curve for each dose level will be used in the same manner. Linearity and dose proportionality will be evaluated using linear regressions of AUClast, AUCinf, AUCτ,ss, Cmax and Cmax,ss to the dose and of log-transformed AUClast, AUCinf, AUCτ,ss, Cmax and Cmax,ss to the log-transformed dose. A graphical presentation of the linearity and dose proportionality will also be provided. Interim Analyses When 60 subjects complete the study, there will be a single blinded interim analysis planned. The main purpose of this blinded interim analysis will be futility (Go / No Go). The details of this interim analysis will be presented in the statistical analysis plan which will be finalized before the interim analysis.

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ETHICS AND DISSEMINATION Institutional Review Board Approval The trial has been approved by the IRB at the participating institutions. Two of the three participating clinical sites (BWH and MGH) are under the auspices of a single Institutional Review Board (IRB), the Partners Human Research Committee, and the third site (BIDMC) is under review by its own IRB, the Committee on Clinical Investigations. The study is being conducted in accordance with Declaration of Helsinki standards and FDA regulations regarding Good Clinical Practice. Informed Consent All participants will have been provided with information about the possible risks and benefits of participating in this clinical trial. After being given time and opportunity to ask questions, subjects will be provided an informed consent form approved by the local IRB. A signed copy of the consent form will be maintained with the study records. Subject Confidentiality and Dissemination of Results Trial participants will be given a unique subject identification number to maintain confidentiality, and no Protected Health Information will be disseminated. Study results will be published in a scientific journal upon study completion. DISCUSSION Although significant strides have been made in treating postoperative pain, there continue to be patients in whom the level of pain creates dissatisfaction and impedes recovery. In colorectal surgery, the use of standard analgesics such as opioids is problematic due to the desire for a rapid return of bowel function and the tendency of these drugs to worsen or prolong ileus (35). NSAIDs can lead to bleeding problems, renal dysfunction, or thrombotic events, which may have adverse effects on patient recovery (5)(6). For those reasons, many surgeons have begun to adapt ERAS protocols (Enhanced Recovery After Surgery). These protocols involve early mobilization of patients after surgery, maintaining a euvolemic state by avoiding overhydration, and optimizing pain management through multimodal techniques while minimizing opioid use. Data on outcomes of ERAS protocols in patients undergoing colorectal surgery have been favorable (36).

Various in vivo pharmacological studies with laboratory animals have consistently demonstrated dose-dependent analgesic or anti-allodynic effects of VVZ-149 in rat models of post-operative pain, formalin-induced nociceptive/inflammatory pain and neuropathic pain. The analgesic effect of VVZ-149 has been shown to be due to a non-opioid mechanism and was not blocked by pre-treatment with naloxone, an opioid-receptor antagonist, in the formalin model. VVZ-149 did not inhibit cyclooxygenase activity in an in vitro assay. These results suggest that the analgesic effect of VVZ-149 is neither based on opioid nor non-steroidal anti-inflammatory-based mechanisms. VVZ-149 is thus a non-opioid and non-NSAID analgesic candidate with morphine-comparable efficacy that may be able to provide analgesic benefits to patients. Consistent with the implementation of ERAS protocols, we anticipate that the use of this novel non-opioid analgesic VVZ-149 will provide an alternate and novel method of reducing post-operative pain in patients undergoing laparoscopic colorectal surgery. We have developed a study protocol that evaluates the efficacy and safety of using VVZ-149 in this surgical population and our research will determine if the use of this drug leads to the improved management of postoperative pain. In addition to evaluating the

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primary endpoint of pain intensity difference over time, we are assessing secondary outcomes such as opioid use, pain relief, sedation, nausea, and overall levels of patient satisfaction with treatment. We have implemented recruitment strategies and engaged in collaborative relationships at three academic hospitals and we believe that we have a successful strategy that will improve our ability to recruit patients who fulfill inclusion and exclusion criteria into our trial. It is our hope that this study will provide high quality data to show whether VVZ-149 is safe and efficacious for use as an analgesic for postoperative pain in this study population.

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TABLE 1: Inclusion and Exclusion Criteria for Phase II VVZ-149 Study

Inclusion Criteria • Men and women age between 18-70, inclusive.

• Pain intensity (NRS) ≥4 at initial post-operative measurement in PACU

• Subjects undergoing planned laparoscopic colorectal surgery

• Ability to provide written informed consent

• Ability to understand study procedures and communicate clearly with the investigator and staff

• American Society of Anesthesiologists (ASA) risk class of I to III

Exclusion Criteria Surgical factors

• Emergency or unplanned surgery

• Repeat operation (e.g., previous surgery within 30 days for same condition)

• Cancer-related condition causing preoperative pain in site of surgery

Exclusion Criteria Subject criteria

• Women with childbearing potential (Women age 18-55 must undergo pregnancy test)

• Women who are pregnant or breastfeeding

• Chronic pain diagnosis (e.g., ongoing pain at baseline with NRS ≥ 4/10).

• 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

• Unstable or acute medical condition (e.g., unstable angina, congestive heart failure, renal failure, hepatic failure, AIDS)

Exclusion Criteria Pharmacologic considerations

• Renal or hepatic impairment

• History of alcohol, opiate or other drug abuse or dependence within 12 months prior to Screening (TICS alcohol/drug screen will be performed at Screening)

• Ongoing or recent (within 30 days prior to surgery) use of steroids, opioids, or antipsychotics

• Alcohol consumption within 24 hours of surgery

• Use of nonsteroidal anti-inflammatory drugs (NSAIDs) or acetaminophen within 24 hours of surgery

• 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

Exclusion Criteria Anesthetic considerations

• Use of neuraxial or regional anesthesia related to the surgery

• Use of local anesthetic wound infiltration > 20 ml of 1% lidocaine

• Use of ketamine, gabapentin, pregabalin, or lidocaine (>1 mg/kg) intra or peri-operatively, or within 24 hours of surgery

• Subjects with known allergies to hydromorphone

• Subjects who received another investigational drug within 30 days of scheduled surgery

• Subjects who have long PR (>200 msec) or prolonged QTc (> 450 msec for males and > 470 msec for females) at screening or clinically significant prolonged QTc (> 500 msec or change in baseline of > 60 msec) on an ECG done immediately prior to dosing

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TABLE 2: Pharmacokinetic parameters collected in the VVZ-149 protocol

Cmax Maximum plasma concentration over the time span specified

Cmax,ss Maximum plasma concentration at steady-state

Ctrough,ss Plasma concentration at a dosing interval after the treatment at steady-state (trough concentration at steady-state)

Cav,ss Average plasma concentration during a dosing interval at steady-state, calculated as AUCτ,ss/τt

Clast Area under the plasma concentration versus time curve, from time 0 to the last measurable concentration, calculated by the linear/log trapezoidal method

AUCinf The area under the plasma concentration versus time curve from time 0 to infinity. AUCinf is calculated as the sum of AUClast plus the ratio of the last measurable plasma concentration to the elimination rate constant; AUCinf = AUClast+Clast/λZ

AUCτ,sst Area under the plasma concentration versus time curve during a dosing interval (τ) at steady-state, calculated by the linear/log trapezoidal method.

CL (VVZ-149 Injection) The total body clearance after IV administration, calculated as Dose/AUCinf

CL/F (VVZ-368) Apparent total body clearance after IV administration, calculated as Dose/AUCinf

MRT Mean residence time from the time of dosing to the time of the last measurable concentration. MRT = AUMClast/AUClast

PTF Peak-trough fluctuation, calculated as [(Cmax,ss - Ctrough,ss)/Cav,ss] x 100 (%)

Tmax Time of the maximum measured plasma concentration

Tmax,ss Time of the maximum measured plasma concentration at steady-state

t1/2 Terminal half-life, calculated as ln(2)/λz

R Accumulation ratio, AUCτ,ss/AUC0-τt

Vd (VVZ-149 Injection) The total volume of distribution after IV administration, calculated as Dose/(AUCss × λ)

Metabolic Ratio

Metabolic Ratio, AUClast of VVZ-368 / AUClast of VVZ-149 Injection

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ABBREVIATIONS: PACU: Postoperative Anesthesia Care Unit; PCA: Patient-controlled Analgesia; HADS: Hospital Anxiety and Depression Scale; PONV: Post Operative Nausea and Vomiting Scale; RASS: Richmond Agitation and Sedation Scale; NSAIDs: Non-Steroidal Anti-Inflammatory Drugs; IV: Intravenous; AEs: Adverse Events; PID: Pain Intensity Differences; SPID: Sum of Pain Intensity Differences; TOTPAR: Total Pain Relief; ERAS: Enhanced Recovery After Surgery; NRS: Numeric Rating Scale; EKG: Electrocardiogram; RCT: Randomized Controlled Trial; IRB: Institutional Review Board; Pharmacokinetic analysis abbreviations noted in Table 2. COMPETING INTERESTS: The following authors confirm that research grant funding has been assigned by the study sponsor, Vivozon Inc., to Brigham and Women’s Hospital, Massachusetts General Hospital, and Beth Israel Deaconess Medical Center, which are the employing institutions of authors SSN, DJC, XB, JLZ, YZ, MJY, JL, JS, KE, CPH, RM, JWC, and BT. In addition, the authors noted below report the following potential competing interests: SSN: consulting fees (Vivozon Inc); DJC: none declared; XB: none declared; JLZ: none declared; YZ: none declared; MJY: none declared; JL: none declared; JS: none declared; KE: none declared; CPH: none declared; RM: none declared; JWC: none declared; BT: none declared. SC and DHL are employees of Vivozon Company, the sponsor of this study, and have received funding from the South Korean Ministry of Health & Welfare for R&D support for pharmaceutical development of the product that is described in this manuscript. AUTHOR CONTRIBUTIONS: Srdjan S. Nedeljkovic: Provided advice on designing and drafting the protocol, edited and approved the final version. Prepared the protocol for manuscript submission and is the lead author for this paper. Also manages the day-to-day running of this clinical trial. Darin J. Correll: Provided advice on parts of the protocol relating to surgical postoperative management. He is the clinical lead for the project at BWH. Xiaodong Bao: Provided advice on parts of the protocol relating to anesthetic and surgical postoperative pain management. He is the clinical lead for the project at MGH.

Natacha Zamor: Provided advice on parts of the protocol relating to anesthetic and surgical postoperative management. She is the clinical lead for the project at BIDMC. Jose L. Zeballos: Provided advice on parts of the protocol relating to anesthetic intraoperative management. He is involved in executing the protocol at BWH.

Yi Zhang MD: Provided advice on parts of the protocol relating to surgical postoperative pain management. He is involved in executing the protocol at MGH.

Mark J. Young: Provided advice on parts of the protocol relating to surgical postoperative pain management. He is involved in executing the protocol at BIDMC. Johanna Ledley: Provided input regarding parts of the protocol regarding subject enrollment, data collection, and coordination with pharmacy and laboratory service at BWH.

Jessica Sorace: Provided input regarding parts of the protocol regarding subject enrollment, data collection, and coordination with pharmacy and laboratory service at BWH.

Kristen Eng: Provided input regarding parts of the protocol regarding subject enrollment, data collection, and coordination with pharmacy and laboratory service at MGH.

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Carlyle P. Hamsher: Provided input regarding parts of the protocol related to postoperative data collection and pK sampling at BWH.

Rajivan Maniam: Provided input regarding parts of the protocol related to postoperative data collection and pK sampling at BWH.

Jonathan W. Chin: Provided input regarding parts of the protocol related to postoperative data collection and pK sampling at BWH.

Becky Tsui: Provided input regarding parts of the protocol related to postoperative data collection and pK sampling at MGH.

Sunyoung Cho: Conceived of and planned the trial, provided basic science input, and approved the final version.

Doo H. Lee: Conceived of and planned the trial, drafted the protocol and approved the final version. All authors contributed to development of the research protocol, manuscript writing, and editing of this protocol paper. All of the authors read and approved the final version of the protocol and of the manuscript submission. ACKNOWLEDGEMENTS: The authors thank all participating sites, clinicians and investigators for their support with the clinical study. Additionally, we thank the staff at KCRN, a contract research organization, and especially Ms. Rachel Kim and Mr. Hugh Lee, for their oversight of this research. FUNDING: Funding to conduct this study is being provided by Vivozon, Inc., a privately held company based in South Korea, supported by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant number: HI15C2006). REFERENCES: 1. White PF, Kehlet H. Improving Postoperative Pain Management: What Are the Unresolved Issues? Anesthesiology 2010; 112: 220-5.

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34. Singla N, Hunsinger M, Chang PD, McDermott MP, Chowdhry AK, Desjardins PJ, Turk DC, Dowrkin RH. Assay sensitivity of pain intensity versus pain relief in acute pain chlinical trials: ACTTION Systematic Review and Meta-Analysis. Journal of Pain 2015; 16(8): 683-91.

35. Patel S, Lutz JM, Panchagnula U, Bansal S. Anesthesia and perioperative management of colorectal surgical patients – a clinical review (Part 1). J Anaesthesiolo Clin Pharmacol 2012; 28(2): 162-71.

36. Rawlinson A, Kang P, Evans J, Khanna A. A systematic review of enhanced recovery protocols in colorectal surgery. Ann R Coll Surg Engl 2011; 93(8): 583-8.

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CONSORT diagram for VVZ-149 study flow

97x106mm (600 x 600 DPI)

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1

Note: Regarding the submission to BMJ Open of the Protocol Manuscript entitled:

A Randomized, Double-Blind, Parallel Group, Placebo-Controlled Study to Evaluate the

Analgesic Efficacy and Safety of VVZ-149 Injections for Post-Operative Pain Following

Laparoscopic Colorectal Surgery

Please be advised that the recommended items noted below have been addressed in the

IRB-approved protocol and described in the protocol manuscript.

Srdjan S. Nedeljkovic, M.D.

January 3, 2016

SPIRIT 2013 Checklist: Recommended items to address in a clinical trial protocol and

related documents*

Section/item ItemNo

Description

Administrative information

Title 1 Descriptive title identifying the study design, population, interventions,

and, if applicable, trial acronym

Trial registration 2a Trial identifier and registry name. If not yet registered, name of

intended registry

2b All items from the World Health Organization Trial Registration Data

Set

Protocol version 3 Date and version identifier

Funding 4 Sources and types of financial, material, and other support

Roles and

responsibilities

5a Names, affiliations, and roles of protocol contributors

5b Name and contact information for the trial sponsor

5c Role of study sponsor and funders, if any, in study design; collection,

management, analysis, and interpretation of data; writing of the report;

and the decision to submit the report for publication, including whether

they will have ultimate authority over any of these activities

5d Composition, roles, and responsibilities of the coordinating centre,

steering committee, endpoint adjudication committee, data

management team, and other individuals or groups overseeing the

trial, if applicable (see Item 21a for data monitoring committee)

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2

Introduction

Background and

rationale

6a Description of research question and justification for undertaking the

trial, including summary of relevant studies (published and

unpublished) examining benefits and harms for each intervention

6b Explanation for choice of comparators

Objectives 7 Specific objectives or hypotheses

Trial design 8 Description of trial design including type of trial (eg, parallel group,

crossover, factorial, single group), allocation ratio, and framework (eg,

superiority, equivalence, noninferiority, exploratory)

Methods: Participants, interventions, and outcomes

Study setting 9 Description of study settings (eg, community clinic, academic hospital)

and list of countries where data will be collected. Reference to where

list of study sites can be obtained

Eligibility criteria 10 Inclusion and exclusion criteria for participants. If applicable, eligibility

criteria for study centres and individuals who will perform the

interventions (eg, surgeons, psychotherapists)

Interventions 11a Interventions for each group with sufficient detail to allow replication,

including how and when they will be administered

11b Criteria for discontinuing or modifying allocated interventions for a

given trial participant (eg, drug dose change in response to harms,

participant request, or improving/worsening disease)

11c Strategies to improve adherence to intervention protocols, and any

procedures for monitoring adherence (eg, drug tablet return,

laboratory tests)

11d Relevant concomitant care and interventions that are permitted or

prohibited during the trial

Outcomes 12 Primary, secondary, and other outcomes, including the specific

measurement variable (eg, systolic blood pressure), analysis metric

(eg, change from baseline, final value, time to event), method of

aggregation (eg, median, proportion), and time point for each

outcome. Explanation of the clinical relevance of chosen efficacy and

harm outcomes is strongly recommended

Participant

timeline

13 Time schedule of enrolment, interventions (including any run-ins and

washouts), assessments, and visits for participants. A schematic

diagram is highly recommended (see Figure)

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Sample size 14 Estimated number of participants needed to achieve study objectives

and how it was determined, including clinical and statistical

assumptions supporting any sample size calculations

Recruitment 15 Strategies for achieving adequate participant enrolment to reach

target sample size

Methods: Assignment of interventions (for controlled trials)

Allocation:

Sequence

generation

16a Method of generating the allocation sequence (eg, computer-

generated random numbers), and list of any factors for stratification.

To reduce predictability of a random sequence, details of any planned

restriction (eg, blocking) should be provided in a separate document

that is unavailable to those who enrol participants or assign

interventions

Allocation

concealment

mechanism

16b Mechanism of implementing the allocation sequence (eg, central

telephone; sequentially numbered, opaque, sealed envelopes),

describing any steps to conceal the sequence until interventions are

assigned

Implementation 16c Who will generate the allocation sequence, who will enrol participants,

and who will assign participants to interventions

Blinding

(masking)

17a Who will be blinded after assignment to interventions (eg, trial

participants, care providers, outcome assessors, data analysts), and

how

17b If blinded, circumstances under which unblinding is permissible, and

procedure for revealing a participant’s allocated intervention during

the trial

Methods: Data collection, management, and analysis

Data collection

methods

18a Plans for assessment and collection of outcome, baseline, and other

trial data, including any related processes to promote data quality (eg,

duplicate measurements, training of assessors) and a description of

study instruments (eg, questionnaires, laboratory tests) along with

their reliability and validity, if known. Reference to where data

collection forms can be found, if not in the protocol

18b Plans to promote participant retention and complete follow-up,

including list of any outcome data to be collected for participants who

discontinue or deviate from intervention protocols

Data

management

19 Plans for data entry, coding, security, and storage, including any

related processes to promote data quality (eg, double data entry;

range checks for data values). Reference to where details of data

management procedures can be found, if not in the protocol

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4

Statistical

methods

20a Statistical methods for analysing primary and secondary outcomes.

Reference to where other details of the statistical analysis plan can be

found, if not in the protocol

20b Methods for any additional analyses (eg, subgroup and adjusted

analyses)

20c Definition of analysis population relating to protocol non-adherence

(eg, as randomised analysis), and any statistical methods to handle

missing data (eg, multiple imputation)

Methods: Monitoring

Data monitoring 21a Composition of data monitoring committee (DMC); summary of its role

and reporting structure; statement of whether it is independent from

the sponsor and competing interests; and reference to where further

details about its charter can be found, if not in the protocol.

Alternatively, an explanation of why a DMC is not needed

21b Description of any interim analyses and stopping guidelines, including

who will have access to these interim results and make the final

decision to terminate the trial

Harms 22 Plans for collecting, assessing, reporting, and managing solicited and

spontaneously reported adverse events and other unintended effects

of trial interventions or trial conduct

Auditing 23 Frequency and procedures for auditing trial conduct, if any, and

whether the process will be independent from investigators and the

sponsor

Ethics and dissemination

Research ethics

approval

24 Plans for seeking research ethics committee/institutional review board

(REC/IRB) approval

Protocol

amendments

25 Plans for communicating important protocol modifications (eg,

changes to eligibility criteria, outcomes, analyses) to relevant parties

(eg, investigators, REC/IRBs, trial participants, trial registries, journals,

regulators)

Consent or assent 26a Who will obtain informed consent or assent from potential trial

participants or authorised surrogates, and how (see Item 32)

26b Additional consent provisions for collection and use of participant data

and biological specimens in ancillary studies, if applicable

Confidentiality 27 How personal information about potential and enrolled participants will

be collected, shared, and maintained in order to protect confidentiality

before, during, and after the trial

Declaration of

interests

28 Financial and other competing interests for principal investigators for

the overall trial and each study site

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Access to data 29 Statement of who will have access to the final trial dataset, and

disclosure of contractual agreements that limit such access for

investigators

Ancillary and

post-trial care

30 Provisions, if any, for ancillary and post-trial care, and for

compensation to those who suffer harm from trial participation

Dissemination

policy

31a Plans for investigators and sponsor to communicate trial results to

participants, healthcare professionals, the public, and other relevant

groups (eg, via publication, reporting in results databases, or other

data sharing arrangements), including any publication restrictions

31b Authorship eligibility guidelines and any intended use of professional

writers

31c Plans, if any, for granting public access to the full protocol, participant-

level dataset, and statistical code

Appendices

Informed consent

materials

32 Model consent form and other related documentation given to

participants and authorised surrogates

Biological

specimens

33 Plans for collection, laboratory evaluation, and storage of biological

specimens for genetic or molecular analysis in the current trial and for

future use in ancillary studies, if applicable

*It is strongly recommended that this checklist be read in conjunction with the SPIRIT 2013

Explanation & Elaboration for important clarification on the items. Amendments to the

protocol should be tracked and dated. The SPIRIT checklist is copyrighted by the SPIRIT

Group under the Creative Commons “Attribution-NonCommercial-NoDerivs 3.0 Unported”

license.

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