BESST: Bupivacaine Effectiveness and Safety in SABER® Trial

• Sponsor: Durect (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01052012
• Collaborator: Nycomed (Industry), Hospira, now a wholly owned subsidiary of Pfizer (Industry)
• Enrollment: 331
• Locations: 26
• Arms: 3
• Duration (Months): 21
• Patients Per Site: 12.7
• Patients Per Site Per Month: 0.6

Study Details

Study Description

Brief Summary

This is a research study testing SABER-Bupivacaine (an experimental pain-relieving medication). SABER-Bupivacaine is designed to continuously deliver bupivacaine, a common local anesthetic, for a few days in order to treat local post-surgical pain.

The purpose of this study is to investigate safety (side effects) associated with the use of SABER-Bupivacaine and how well it works in reducing pain and opioid-related side effects following various kinds of abdominal surgeries.

Condition or Disease	Intervention/Treatment	Phase
Postoperative Pain; Abdominal Surgery	Drug: SABER-Bupivacaine; Drug: Bupivacaine HCl; Drug: SABER-Placebo	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 331 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Bupivacaine Effectiveness and Safety in SABER Trial (BESST)
• Study Start Date: Dec 1, 2009
• Actual Primary Completion Date: Sep 1, 2011
• Actual Study Completion Date: Sep 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Active: SABER-Bupivacaine SABER-Bupivacaine	Drug: SABER-Bupivacaine; Injectable Extended Release Solution; SABER-Bupivacaine /Once; Other Names: POSIMIR® bupivacaine solution
Active Comparator: Comparator: Bupivacaine HCl Bupivacaine HCl	Drug: Bupivacaine HCl; Injectable Solution; Bupivacaine HCl /Once
Placebo Comparator: Placebo: SABER-Placebo SABER-Placebo	Drug: SABER-Placebo; Injectable Solution; SABER-Placebo/Once

Outcome Measures

Primary Outcome Measures

1. Mean Pain Intensity on Movement [0 to 72 hours post-dose]

   Mean pain intensity on movement AUC (time-normalized AUC) during the period 0 to 72 hours post-dose. Pain intensity was assessed with a standard 0 to 10 numeric rating scale (NRS), where no pain at all was rated as 0 and the worst pain imaginable was rated as 10. The AUC is computed for each patient using the standard trapezoidal rule and normalised by dividing by the time interval over which it is computed. This normalisation converts the AUC to the natural pain scale (NRS 0-10) to allow for better translation of the clinical treatment effect magnitude.

2. Supplemental Opioid Use [0-72 hours post dose]

   Total morphine-equivalent dose during 0-72 hours post dose. Median values were presented because data was not normally distributed.

Secondary Outcome Measures

1. Mean Pain Intensity on Movement [0 to 48 hours post-dose]

   Mean pain intensity on movement AUC (time-normalized AUC) during the period 0 to 48 hours post-dose. Pain intensity was assessed with a standard 0 to 10 numeric rating scale (NRS), where no pain at all was rated as 0 and the worst pain imaginable was rated as 10. The AUC is computed for each patient using the standard trapezoidal rule and normalised by dividing by the time interval over which it is computed. This normalisation converts the AUC to the natural pain scale (NRS 0-10) to allow for better translation of the clinical treatment effect magnitude.

2. Total Morphine-equivalent Dose [0-48 hours post dose]

   Total morphine-equivalent dose during 0-48 hours post dose.

3. Proportion (Percent) of Patients Who Have Evidence of a Wound Infection [0 to 14 days post-dose (Visits 3 and 4)]

   From Surgical Wound Healing and Local Tissue Condition Evaluation

4. Time-to-first Use of Opioid Rescue Medication [0 to 14 days post-dose (Time from extubation until first opioid use)]

5. Number (Incidence) of Participants With Opioid-related Side Effects [0 to 30 days post-dose]

   AEs include: nausea, vomiting, constipation, dizziness, somnolence, urinary retention, respiratory depression

6. Pain Intensity at Rest AUC During 0-72 Hours Post Dose [0-72 hours post dose]

   Mean pain intensity at rest AUC during the period 0 to 72 hours post-dose. Pain intensity was assessed with a standard 0 to 10 numeric rating scale (NRS), where no pain at all was rated as 0 and the worst pain imaginable was rated as 10. The AUC is computed for each patient using the standard trapezoidal rule and normalised by dividing by the time interval over which it is computed. This normalisation converts the AUC to the natural pain scale (NRS 0-10) to allow for better translation of the clinical treatment effect magnitude.

7. Mean Pain Intensity at Rest AUC During 0-48 Hours Post Dose [0-48 hours post dose]

   Mean pain intensity at rest AUC during the period 0 to 48 hours post-dose. Pain intensity was assessed with a standard 0 to 10 numeric rating scale (NRS), where no pain at all was rated as 0 and the worst pain imaginable was rated as 10. The AUC is computed for each patient using the standard trapezoidal rule and normalised by dividing by the time interval over which it is computed. This normalisation converts the AUC to the natural pain scale (NRS 0-10) to allow for better translation of the clinical treatment effect magnitude.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Patients must be able to read and understand the consent form, provide written consent, complete trial-related procedures, and communicate with the trial staff

• Males and females, 18 years of age and older scheduled to undergo elective general abdominal surgery

• Patients must be healthy or have only mild systemic disease

• BMI < 45

• Patients must have ECG wave form within normal limits

• Female and male patients must agree to use medically acceptable method of contraception throughout the entire trial period and for 1 week after the trial participation is completed

Exclusion Criteria:

• Patients who are pregnant or lactating

• Patients undergoing emergency surgery (unless full consent is obtained and all screening procedures are completed prior to surgery)

• Significant concomitant surgical procedure

• History of multiple prior laparotomy procedures

• Cancer with known metastases pre-operatively, which are suspected to impact post-operative recovery or pain

• Planned formation of stoma during surgery or plans to undergo another laparotomy procedure within 30 days post-operatively

• Pre-operative evidence of sepsis or septic shock

• Pre-operative evaluation that suggests a surgery may preclude full closure of the incision(s)

• Patients with current or regular use of systemic steroids, anticonvulsants, antiepileptics, antidepressants, or monoamine oxidase inhibitors, who cannot be withdrawn from these medications

• Patients with current or regular use of drugs known to significantly prolong the QTc interval

• Patients with known hypersensitivity to local anesthetic agents of the amide type (e.g. lidocaine, bupivacaine)

• Patients with known hypersensitivity to morphine

• Patients with conditions contraindicated for use of opioids

• Patients with atrial fibrillation/flutter or other non-sinus rhythm (including paced rhythm); left bundle branch block (LBBB); or the following conditions: right bundle branch block (RBBB) in presence of a cardiac disease, significant cardiomyopathy, and myocardial infarction within last 6 months

• Patients with a serum creatinine level two times more than the local laboratory normal limit

• Patients who have received greater than 600 mg morphine equivalent daily dose for three or more days per week in the month prior to the surgical procedure

• Patients who are currently being treated with methadone, or history of methadone use within the previous 6 months

• Patients with known or suspected abuse of opioids or other illicit drugs

• Patients with known or suspected alcohol abuse

• Participation in another clinical trial at the same time or within 30 days of this trial

• Patients who, in the Investigator's opinion, should not participate in the trial or may not be capable of following the trial schedule for any reason

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	DURECT Study Site	Birmingham	Alabama	United States	35209
2	DURECT Study Site	Florence	Alabama	United States	35630
3	DURECT Study Site	Mobile	Alabama	United States	36608
4	DURECT Study Site	Mobile	Alabama	United States	36617
5	DURECT Study Site	Montgomery	Alabama	United States	36106
6	DURECT Study Site	Sheffield	Alabama	United States	35660
7	DURECT Study Site	Arcadia	California	United States	91007
8	DURECT Study Site	Fontana	California	United States	92335
9	DURECT Study Site	Laguna Hills	California	United States	92653
10	DURECT Study Site	Pasadena	California	United States	91105
11	DURECT Study Site	Tampa	Florida	United States	33606
12	DURECT Study Site	Powder Springs	Georgia	United States	30127
13	DURECT Study Site	Indianapolis	Indiana	United States	46206
14	DURECT Study Site	Boston	Massachusetts	United States	02135
15	DURECT Study Site	Troy	Michigan	United States	48085
16	DURECT Study Site	Duluth	Minnesota	United States	55805
17	DURECT Study Site	New York	New York	United States	10016
18	DURECT Study Site	Durham	North Carolina	United States	27710
19	DURECT Study Site	Columbus	Ohio	United States	43210
20	DURECT Study Site	Hershey	Pennsylvania	United States	17033
21	DURECT Study Site	Houston	Texas	United States	77024
22	DURECT Study Site	Temple	Texas	United States	77375
23	DURECT Study Site	Woodville South	South Australia	Australia	5011
24	DURECT Study Site	Box Hill	Victoria	Australia	3128
25	DURECT Study Site	Ringwood East	Victoria	Australia	3135
26	DURECT Study Site	Christchurch		New Zealand	8022

Sponsors and Collaborators

• Durect
• Nycomed
• Hospira, now a wholly owned subsidiary of Pfizer

Investigators

• Study Director: Dmitri Lissin, MD, Durect

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Durect
• ClinicalTrials.gov Identifier: NCT01052012
• Other Study ID Numbers: C803-025
• First Posted: Jan 20, 2010
• Last Update Posted: Jun 1, 2021
• Last Verified: May 1, 2021

• Keywords provided by Durect: Postoperative pain; Post-operative pain; Opioid; Laparoscopic surgery; Bupivacaine; Local anesthetic
• Additional relevant MeSH terms: Pain, Postoperative; Bupivacaine

Study Results

Participant Flow

Recruitment Details

The trial was conducted at 15 sites in the US, 3 sites in Australia, and 1 site in New Zealand. The study was initiated on 21 December 2009 and completed on 30 September 2011.

Pre-assignment Detail

total of 393 patients were screened and 331 patients were randomized. There were 26 patients who were randomized but not treated. The reasons for not treating these patients included: conditions encountered during surgery necessitated procedures that did not meet protocol requirements, peri-operative epidural analgesia was administered, the test drug was not available, or the patient withdrew consent

Arm/Group Title	Cohort 1-POSIMIR	Cohort 1-Bupivacaine HCl	Cohort 2-POSIMIR	Cohort 2-Bupivacaine HCl	Cohort 3-POSIMIR	Cohort 3-Placebo
Arm/Group Description	Open Laparotomy	Open Laparotomy	Laparoscopic Cholecystectomy	Laparoscopic Cholecystectomy	Laparoscopic Assisted Colectomy	Laparoscopic Assisted Colectomy
Period Title: Overall Study
STARTED	32	23	30	20	140	86
COMPLETED	28	17	30	19	124	76
NOT COMPLETED	4	6	0	1	16	10

Baseline Characteristics

Arm/Group Title	Cohort 1-POSIMIR	Cohort 1-Bupivacaine HCl	Cohort 2-POSIMIR	Cohort 2-Bupivacaine HCl	Cohort 3-POSIMIR	Cohort 3-Placebo	Total
Arm/Group Description	Open Laparotomy	Open Laparotomy	Laparoscopic Cholecystectomy	Laparoscopic Cholecystectomy	Laparoscopic Assisted Colectomy	Laparoscopic Assisted Colectomy	Total of all reporting groups
Overall Participants	30	18	30	20	129	78	305
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]	56.8	53.8	44.2	39.5	60.2	58.2	56.1
Sex: Female, Male (Count of Participants)
Female	18 60%	9 50%	20 66.7%	14 70%	70 54.3%	34 43.6%	165 54.1%
Male	12 40%	9 50%	10 33.3%	6 30%	59 45.7%	44 56.4%	140 45.9%
BMI (kg/m^2) [Mean (Full Range) ]
Mean (Full Range) [kg/m^2]	30.5	27.0	30.8	31.9	29.4	27.5	29.2

Outcome Measures

1. Primary Outcome

Title	Mean Pain Intensity on Movement
Description	Mean pain intensity on movement AUC (time-normalized AUC) during the period 0 to 72 hours post-dose. Pain intensity was assessed with a standard 0 to 10 numeric rating scale (NRS), where no pain at all was rated as 0 and the worst pain imaginable was rated as 10. The AUC is computed for each patient using the standard trapezoidal rule and normalised by dividing by the time interval over which it is computed. This normalisation converts the AUC to the natural pain scale (NRS 0-10) to allow for better translation of the clinical treatment effect magnitude.
Time Frame	0 to 72 hours post-dose

Outcome Measure Data

Analysis Population Description

ITT Population

Arm/Group Title	Cohort 1-POSIMIR	Cohort 1-Bupivacaine HCl	Cohort 2-POSIMIR	Cohort 2-Bupivacaine HCl	Cohort 3-POSIMIR	Cohort 3-Placebo
Arm/Group Description	Open Laparotomy	Open Laparotomy	Laparoscopic Cholecystectomy	Laparoscopic Cholecystectomy	Laparoscopic Assisted Colectomy	Laparoscopic Assisted Colectomy
Measure Participants	26	17	30	20	126	77
Least Squares Mean (95% Confidence Interval) [score on a scale]	4.9	5.0	2.8	3.9	4.8	5.1

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Cohort 1-POSIMIR, Cohort 1-Bupivacaine HCl
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1473
	Comments
	Method	ANCOVA
	Comments	With pooled site and treatment group as factors and incision length as a covariate.
Method of Estimation	Estimation Parameter	LS Mean Difference (Final Values)
	Estimated Value	-0.89
	Confidence Interval	(2-Sided) 95%; -2.11 to 0.33
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.597
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Cohort 2-POSIMIR, Cohort 2-Bupivacaine HCl
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0601
	Comments
	Method	ANCOVA
	Comments	with pooled site and treatment group as factors and incision length as a covariate.
Method of Estimation	Estimation Parameter	LS Mean Difference (Final Values)
	Estimated Value	-1.06
	Confidence Interval	(2-Sided) 95%; -2.16 to 0.05
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.547
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Cohort 3-POSIMIR, Cohort 3-Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1483
	Comments
	Method	ANCOVA
	Comments	with pooled site and treatment group as factors and incision length as a covariate.
Method of Estimation	Estimation Parameter	LS Mean Difference (Final Values)
	Estimated Value	-0.34
	Confidence Interval	(2-Sided) 95%; -0.80 to 0.12
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.233
	Estimation Comments

2. Primary Outcome

Title	Supplemental Opioid Use
Description	Total morphine-equivalent dose during 0-72 hours post dose. Median values were presented because data was not normally distributed.
Time Frame	0-72 hours post dose

Outcome Measure Data

Analysis Population Description

ITT Population

Arm/Group Title	Cohort 1-POSIMIR	Cohort 1-Bupivacaine HCl	Cohort 2-POSIMIR	Cohort 2-Bupivacaine HCl	Cohort 3-POSIMIR	Cohort 3-Placebo
Arm/Group Description	Open Laparotomy	Open Laparotomy	Laparoscopic Cholecystectomy	Laparoscopic Cholecystectomy	Laparoscopic Assisted Colectomy	Laparoscopic Assisted Colectomy
Measure Participants	26	17	30	20	126	77
Median (Inter-Quartile Range) [Milligram equivalents]	87.0	63.0	17.0	22.5	52.0	62.0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Cohort 1-POSIMIR, Cohort 1-Bupivacaine HCl
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.9901
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments
Method of Estimation	Estimation Parameter	Median Difference (Hodge-Lehmann)
	Estimated Value	-1.0
	Confidence Interval	(2-Sided) 95%; -54.5 to 52.0
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Cohort 2-POSIMIR, Cohort 2-Bupivacaine HCl
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2010
	Comments
	Method	Wilcoxon Rank-Sum
	Comments
Method of Estimation	Estimation Parameter	Median Difference (Hodge-Lehmann)
	Estimated Value	-5.0
	Confidence Interval	(2-Sided) 95%; -14.0 to 3.4
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Cohort 3-POSIMIR, Cohort 3-Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5897
	Comments
	Method	Wilcoxon Rank-Sum
	Comments
Method of Estimation	Estimation Parameter	Median Difference (Hodge-Lehmann)
	Estimated Value	-3.0
	Confidence Interval	(2-Sided) 95%; -15.0 to 8.0
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Mean Pain Intensity on Movement
Description	Mean pain intensity on movement AUC (time-normalized AUC) during the period 0 to 48 hours post-dose. Pain intensity was assessed with a standard 0 to 10 numeric rating scale (NRS), where no pain at all was rated as 0 and the worst pain imaginable was rated as 10. The AUC is computed for each patient using the standard trapezoidal rule and normalised by dividing by the time interval over which it is computed. This normalisation converts the AUC to the natural pain scale (NRS 0-10) to allow for better translation of the clinical treatment effect magnitude.
Time Frame	0 to 48 hours post-dose

Outcome Measure Data

Analysis Population Description

ITT Population

Arm/Group Title	Cohort 1-POSIMIR	Cohort 1-Bupivacaine HCl	Cohort 2-POSIMIR	Cohort 2-Bupivacaine HCl	Cohort 3-POSIMIR	Cohort 3-Placebo
Arm/Group Description	Open Laparotomy	Open Laparotomy	Laparoscopic Cholecystectomy	Laparoscopic Cholecystectomy	Laparoscopic Assisted Colectomy	Laparoscopic Assisted Colectomy
Measure Participants	26	17	30	20	126	77
Least Squares Mean (95% Confidence Interval) [score on a scale]	5.2	6.0	3.2	4.4	5.2	5.5

4. Secondary Outcome

Title	Total Morphine-equivalent Dose
Description	Total morphine-equivalent dose during 0-48 hours post dose.
Time Frame	0-48 hours post dose

Outcome Measure Data

Analysis Population Description

ITT Population

Arm/Group Title	Cohort 1-POSIMIR	Cohort 1-Bupivacaine HCl	Cohort 2-POSIMIR	Cohort 2-Bupivacaine HCl	Cohort 3-POSIMIR	Cohort 3-Placebo
Arm/Group Description	Open Laparotomy	Open Laparotomy	Laparoscopic Cholecystectomy	Laparoscopic Cholecystectomy	Laparoscopic Assisted Colectomy	Laparoscopic Assisted Colectomy
Measure Participants	26	17	30	20	126	77
Median (Inter-Quartile Range) [mg IV Morphine equivalents]	69.5	52.0	15.0	19.7	41.5	43.0

5. Secondary Outcome

Title	Proportion (Percent) of Patients Who Have Evidence of a Wound Infection
Description	From Surgical Wound Healing and Local Tissue Condition Evaluation
Time Frame	0 to 14 days post-dose (Visits 3 and 4)

Outcome Measure Data

Analysis Population Description

ITT Population

Arm/Group Title	Cohort 1-POSIMIR	Cohort 1-Bupivacaine HCl	Cohort 2-POSIMIR	Cohort 2-Bupivacaine HCl	Cohort 3-POSIMIR	Cohort 3-Placebo
Arm/Group Description	Open Laparotomy	Open Laparotomy	Laparoscopic Cholecystectomy	Laparoscopic Cholecystectomy	Laparoscopic Assisted Colectomy	Laparoscopic Assisted Colectomy
Measure Participants	26	17	30	20	126	77
yes	2 6.7%	1 5.6%	0 0%	0 0%	6 4.7%	0 0%
no	23 76.7%	14 77.8%	30 100%	19 95%	116 89.9%	73 93.6%
yes	1 3.3%	2 11.1%	0 0%	1 5%	4 3.1%	0 0%
no	23 76.7%	14 77.8%	30 100%	18 90%	119 92.2%	77 98.7%

6. Secondary Outcome

Title	Time-to-first Use of Opioid Rescue Medication
Time Frame	0 to 14 days post-dose (Time from extubation until first opioid use)

Outcome Measure Data

Analysis Population Description

ITT Population

Arm/Group Title	Cohort 1-POSIMIR	Cohort 1-Bupivacaine HCl	Cohort 2-POSIMIR	Cohort 2-Bupivacaine HCl	Cohort 3-POSIMIR	Cohort 3-Placebo
Arm/Group Description	Open Laparotomy	Open Laparotomy	Laparoscopic Cholecystectomy	Laparoscopic Cholecystectomy	Laparoscopic Assisted Colectomy	Laparoscopic Assisted Colectomy
Measure Participants	26	17	30	20	126	77
Median (Full Range) [Hours]	0.6	0.5	0.6	0.5	0.6	0.5

7. Secondary Outcome

Title	Number (Incidence) of Participants With Opioid-related Side Effects
Description	AEs include: nausea, vomiting, constipation, dizziness, somnolence, urinary retention, respiratory depression
Time Frame	0 to 30 days post-dose

Outcome Measure Data

Analysis Population Description

ITT Population

Arm/Group Title	Cohort 1-POSIMIR	Cohort 1-Bupivacaine HCl	Cohort 2-POSIMIR	Cohort 2-Bupivacaine HCl	Cohort 3-POSIMIR	Cohort 3-Placebo
Arm/Group Description	Open Laparotomy	Open Laparotomy	Laparoscopic Cholecystectomy	Laparoscopic Cholecystectomy	Laparoscopic Assisted Colectomy	Laparoscopic Assisted Colectomy
Measure Participants	26	17	30	20	126	77
Count of Participants [Participants]	19 63.3%	10 55.6%	23 76.7%	17 85%	93 72.1%	47 60.3%

8. Secondary Outcome

Title	Pain Intensity at Rest AUC During 0-72 Hours Post Dose
Description	Mean pain intensity at rest AUC during the period 0 to 72 hours post-dose. Pain intensity was assessed with a standard 0 to 10 numeric rating scale (NRS), where no pain at all was rated as 0 and the worst pain imaginable was rated as 10. The AUC is computed for each patient using the standard trapezoidal rule and normalised by dividing by the time interval over which it is computed. This normalisation converts the AUC to the natural pain scale (NRS 0-10) to allow for better translation of the clinical treatment effect magnitude.
Time Frame	0-72 hours post dose

Outcome Measure Data

Analysis Population Description

ITT Population

Arm/Group Title	Cohort 1-POSIMIR	Cohort 1-Bupivacaine HCl	Cohort 2-POSIMIR	Cohort 2-Bupivacaine HCl	Cohort 3-POSIMIR	Cohort 3-Placebo
Arm/Group Description	Open Laparotomy	Open Laparotomy	Laparoscopic Cholecystectomy	Laparoscopic Cholecystectomy	Laparoscopic Assisted Colectomy	Laparoscopic Assisted Colectomy
Measure Participants	26	17	30	20	126	77
Least Squares Mean (95% Confidence Interval) [score on a scale]	3.4	4.2	1.7	2.5	3.1	3.5

9. Secondary Outcome

Title	Mean Pain Intensity at Rest AUC During 0-48 Hours Post Dose
Description	Mean pain intensity at rest AUC during the period 0 to 48 hours post-dose. Pain intensity was assessed with a standard 0 to 10 numeric rating scale (NRS), where no pain at all was rated as 0 and the worst pain imaginable was rated as 10. The AUC is computed for each patient using the standard trapezoidal rule and normalised by dividing by the time interval over which it is computed. This normalisation converts the AUC to the natural pain scale (NRS 0-10) to allow for better translation of the clinical treatment effect magnitude.
Time Frame	0-48 hours post dose

Outcome Measure Data

Analysis Population Description

ITT Population

Arm/Group Title	Cohort 1-POSIMIR	Cohort 1-Bupivacaine HCl	Cohort 2-POSIMIR	Cohort 2-Bupivacaine HCl	Cohort 3-POSIMIR	Cohort 3-Placebo
Arm/Group Description	Open Laparotomy	Open Laparotomy	Laparoscopic Cholecystectomy	Laparoscopic Cholecystectomy	Laparoscopic Assisted Colectomy	Laparoscopic Assisted Colectomy
Measure Participants	26	17	30	20	126	77
Least Squares Mean (95% Confidence Interval) [score on a scale]	3.6	4.5	2.0	2.9	3.4	3.8

Adverse Events

Arm/Group Title	Cohort 1-POSIMIR		Cohort 1-Bupivacaine HCl		Cohort 2-POSIMIR		Cohort 2-Bupivacaine HCl		Cohort 3-POSIMIR		Cohort 3-Placebo
Arm/Group Description	Open Laparotomy		Open Laparotomy		Laparoscopic Cholecystectomy		Laparoscopic Cholecystectomy		Laparoscopic Assisted Colectomy		Laparoscopic Assisted Colectomy
All Cause Mortality
	Cohort 1-POSIMIR		Cohort 1-Bupivacaine HCl		Cohort 2-POSIMIR		Cohort 2-Bupivacaine HCl		Cohort 3-POSIMIR		Cohort 3-Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/30 (0%)		0/18 (0%)		0/30 (0%)		0/20 (0%)		1/129 (0.8%)		0/78 (0%)
Serious Adverse Events
	Cohort 1-POSIMIR		Cohort 1-Bupivacaine HCl		Cohort 2-POSIMIR		Cohort 2-Bupivacaine HCl		Cohort 3-POSIMIR		Cohort 3-Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	9/30 (30%)		4/18 (22.2%)		0/30 (0%)		1/20 (5%)		16/129 (12.4%)		9/78 (11.5%)
Blood and lymphatic system disorders
Anemia	0/30 (0%)		0/18 (0%)		0/30 (0%)		0/20 (0%)		1/129 (0.8%)		0/78 (0%)
Heparin-induced thrombocytopenia	0/30 (0%)		0/18 (0%)		0/30 (0%)		0/20 (0%)		0/129 (0%)		1/78 (1.3%)
Cardiac disorders
Acute myocardial infarction	1/30 (3.3%)		0/18 (0%)		0/30 (0%)		0/20 (0%)		0/129 (0%)		0/78 (0%)
Atrial fibrillation	0/30 (0%)		0/18 (0%)		0/30 (0%)		0/20 (0%)		0/129 (0%)		1/78 (1.3%)
Atrial flutter	0/30 (0%)		0/18 (0%)		0/30 (0%)		0/20 (0%)		0/129 (0%)		1/78 (1.3%)
Supraventricular tachycardia	0/30 (0%)		1/18 (5.6%)		0/30 (0%)		0/20 (0%)		0/129 (0%)		0/78 (0%)
Gastrointestinal disorders
Ileus	0/30 (0%)		1/18 (5.6%)		0/30 (0%)		0/20 (0%)		6/129 (4.7%)		1/78 (1.3%)
Colitis	0/30 (0%)		1/18 (5.6%)		0/30 (0%)		0/20 (0%)		1/129 (0.8%)		0/78 (0%)
Abdominal pain	0/30 (0%)		0/18 (0%)		0/30 (0%)		0/20 (0%)		1/129 (0.8%)		0/78 (0%)
Acute abdomen	1/30 (3.3%)		0/18 (0%)		0/30 (0%)		0/20 (0%)		0/129 (0%)		0/78 (0%)
Diarrhea	0/30 (0%)		0/18 (0%)		0/30 (0%)		0/20 (0%)		1/129 (0.8%)		0/78 (0%)
Intestinal obstruction	0/30 (0%)		0/18 (0%)		0/30 (0%)		0/20 (0%)		0/129 (0%)		1/78 (1.3%)
Nausea	1/30 (3.3%)		0/18 (0%)		0/30 (0%)		0/20 (0%)		0/129 (0%)		0/78 (0%)
Small intestinal obstruction	0/30 (0%)		0/18 (0%)		0/30 (0%)		0/20 (0%)		1/129 (0.8%)		0/78 (0%)
Vomiting	0/30 (0%)		0/18 (0%)		0/30 (0%)		0/20 (0%)		1/129 (0.8%)		0/78 (0%)
Application site discolouration	0/30 (0%)		0/18 (0%)		0/30 (0%)		0/20 (0%)		0/129 (0%)		1/78 (1.3%)
General disorders
Chest pain	2/30 (6.7%)		0/18 (0%)		0/30 (0%)		0/20 (0%)		0/129 (0%)		0/78 (0%)
Infections and infestations
Abdominal abscess	0/30 (0%)		1/18 (5.6%)		0/30 (0%)		0/20 (0%)		1/129 (0.8%)		1/78 (1.3%)
Perirectal abscess	0/30 (0%)		1/18 (5.6%)		0/30 (0%)		0/20 (0%)		0/129 (0%)		1/78 (1.3%)
Clostridium difficile colitis	0/30 (0%)		0/18 (0%)		0/30 (0%)		0/20 (0%)		1/129 (0.8%)		0/78 (0%)
Peridiverticular abscess	1/30 (3.3%)		0/18 (0%)		0/30 (0%)		0/20 (0%)		0/129 (0%)		0/78 (0%)
Pneumonia	0/30 (0%)		0/18 (0%)		0/30 (0%)		1/20 (5%)		0/129 (0%)		0/78 (0%)
Postoperative wound infection	1/30 (3.3%)		0/18 (0%)		0/30 (0%)		0/20 (0%)		0/129 (0%)		0/78 (0%)
Sepsis	0/30 (0%)		1/18 (5.6%)		0/30 (0%)		0/20 (0%)		0/129 (0%)		0/78 (0%)
Injury, poisoning and procedural complications
Wound dehiscence	2/30 (6.7%)		0/18 (0%)		0/30 (0%)		0/20 (0%)		0/129 (0%)		1/78 (1.3%)
Postoperative ileus	0/30 (0%)		0/18 (0%)		0/30 (0%)		0/20 (0%)		1/129 (0.8%)		1/78 (1.3%)
Humerus fracture	0/30 (0%)		0/18 (0%)		0/30 (0%)		0/20 (0%)		1/129 (0.8%)		0/78 (0%)
Nervous system disorders
Presyncope	0/30 (0%)		0/18 (0%)		0/30 (0%)		0/20 (0%)		0/129 (0%)		1/78 (1.3%)
Renal and urinary disorders
Urinary retention	0/30 (0%)		0/18 (0%)		0/30 (0%)		0/20 (0%)		1/129 (0.8%)		0/78 (0%)
Respiratory, thoracic and mediastinal disorders
Apnoea	0/30 (0%)		1/18 (5.6%)		0/30 (0%)		0/20 (0%)		0/129 (0%)		0/78 (0%)
Dyspnoea	1/30 (3.3%)		0/18 (0%)		0/30 (0%)		0/20 (0%)		0/129 (0%)		0/78 (0%)
Pulmonary embolism	1/30 (3.3%)		0/18 (0%)		0/30 (0%)		0/20 (0%)		0/129 (0%)		0/78 (0%)
Respiratory failure	0/30 (0%)		1/18 (5.6%)		0/30 (0%)		0/20 (0%)		0/129 (0%)		0/78 (0%)
Vascular disorders
Deep vein thrombosis	1/30 (3.3%)		0/18 (0%)		0/30 (0%)		0/20 (0%)		0/129 (0%)		1/78 (1.3%)
Other (Not Including Serious) Adverse Events
	Cohort 1-POSIMIR		Cohort 1-Bupivacaine HCl		Cohort 2-POSIMIR		Cohort 2-Bupivacaine HCl		Cohort 3-POSIMIR		Cohort 3-Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	30/30 (100%)		17/18 (94.4%)		28/30 (93.3%)		20/20 (100%)		126/129 (97.7%)		75/78 (96.2%)
Blood and lymphatic system disorders
Anaemia	4/30 (13.3%)	4	1/18 (5.6%)	1	0/30 (0%)	0	0/20 (0%)	0	13/129 (10.1%)	13	7/78 (9%)	7
Leukocytosis	1/30 (3.3%)	1	2/18 (11.1%)	2	0/30 (0%)	0	0/20 (0%)	0	0/129 (0%)	0	0/78 (0%)	0
Haemorrhagic anaemia	1/30 (3.3%)	1	1/18 (5.6%)	1	0/30 (0%)	0	0/20 (0%)	0	0/129 (0%)	0	0/78 (0%)	0
Thrombocytosis	2/30 (6.7%)	2	0/18 (0%)	0	0/30 (0%)	0	0/20 (0%)	0	0/129 (0%)	0	0/78 (0%)	0
Thrombocytopenia	0/30 (0%)	0	1/18 (5.6%)	1	0/30 (0%)	0	0/20 (0%)	0	0/129 (0%)	0	0/78 (0%)	0
Cardiac disorders
Tachycardia	3/30 (10%)	3	4/18 (22.2%)	4	1/30 (3.3%)	1	2/20 (10%)	2	10/129 (7.8%)	11	3/78 (3.8%)	3
Sinus tachycardia	0/30 (0%)	0	2/18 (11.1%)	2	0/30 (0%)	0	0/20 (0%)	0	3/129 (2.3%)	3	1/78 (1.3%)	1
Supraventricular tachycardia	0/30 (0%)	0	2/18 (11.1%)	2	0/30 (0%)	0	0/20 (0%)	0	0/129 (0%)	0	0/78 (0%)	0
Ear and labyrinth disorders
Tinnitus	0/30 (0%)	0	0/18 (0%)	0	0/30 (0%)	0	3/20 (15%)	3	0/129 (0%)	0	1/78 (1.3%)	1
Eye disorders
Vision blurred	0/30 (0%)	0	0/18 (0%)	0	0/30 (0%)	0	1/20 (5%)	2	2/129 (1.6%)	2	0/78 (0%)	0
Gastrointestinal disorders
Nausea	16/30 (53.3%)	18	9/18 (50%)	11	17/30 (56.7%)	23	14/20 (70%)	20	77/129 (59.7%)	80	40/78 (51.3%)	42
Vomiting	9/30 (30%)	12	2/18 (11.1%)	2	9/30 (30%)	13	7/20 (35%)	10	23/129 (17.8%)	26	6/78 (7.7%)	6
Constipation	1/30 (3.3%)	1	1/18 (5.6%)	1	8/30 (26.7%)	8	8/20 (40%)	8	23/129 (17.8%)	23	8/78 (10.3%)	8
Abdominal distension	1/30 (3.3%)	1	2/18 (11.1%)	2	6/30 (20%)	6	3/20 (15%)	3	16/129 (12.4%)	19	12/78 (15.4%)	13
Diarrhoea	4/30 (13.3%)	5	1/18 (5.6%)	1	3/30 (10%)	3	2/20 (10%)	3	16/129 (12.4%)	16	10/78 (12.8%)	10
Flatulence	1/30 (3.3%)	1	2/18 (11.1%)	2	2/30 (6.7%)	2	1/20 (5%)	1	10/129 (7.8%)	10	8/78 (10.3%)	8
Dyspepsia	2/30 (6.7%)	2	2/18 (11.1%)	2	2/30 (6.7%)	4	0/20 (0%)	0	4/129 (3.1%)	4	4/78 (5.1%)	4
Ileus	1/30 (3.3%)	1	1/18 (5.6%)	1	0/30 (0%)	0	0/20 (0%)	0	9/129 (7%)	9	3/78 (3.8%)	3
Abdominal pain	2/30 (6.7%)	2	0/18 (0%)	0	2/30 (6.7%)	2	0/20 (0%)	0	6/129 (4.7%)	6	1/78 (1.3%)	1
Gastrooesophageal reflux disease	2/30 (6.7%)	2	0/18 (0%)	0	1/30 (3.3%)	1	2/20 (10%)	2	4/129 (3.1%)	4	1/78 (1.3%)	1
Haematochezia	0/30 (0%)	0	0/18 (0%)	0	0/30 (0%)	0	1/20 (5%)	1	3/129 (2.3%)	3	1/78 (1.3%)	1
Abdominal pain lower	0/30 (0%)	0	1/18 (5.6%)	1	0/30 (0%)	0	0/20 (0%)	0	2/129 (1.6%)	2	1/78 (1.3%)	1
Abdominal rigidity	1/30 (3.3%)	1	1/18 (5.6%)	1	0/30 (0%)	0	0/20 (0%)	0	1/129 (0.8%)	1	0/78 (0%)	0
Abdominal pain upper	0/30 (0%)	0	0/18 (0%)	0	2/30 (6.7%)	3	0/20 (0%)	0	0/129 (0%)	0	0/78 (0%)	0
Colitis	0/30 (0%)	0	1/18 (5.6%)	1	0/30 (0%)	0	0/20 (0%)	0	1/129 (0.8%)	1	0/78 (0%)	0
Ascites	0/30 (0%)	0	0/18 (0%)	0	0/30 (0%)	0	1/20 (5%)	1	0/129 (0%)	0	0/78 (0%)	0
Gastrointestinal haemorrhage	0/30 (0%)	0	1/18 (5.6%)	1	0/30 (0%)	0	0/20 (0%)	0	0/129 (0%)	0	0/78 (0%)	0
Oesophageal Ulcer	0/30 (0%)	0	1/18 (5.6%)	1	0/30 (0%)	0	0/20 (0%)	0	0/129 (0%)	0	0/78 (0%)	0
General disorders
Application site discolouration	14/30 (46.7%)	17	6/18 (33.3%)	7	15/30 (50%)	18	4/20 (20%)	5	80/129 (62%)	116	46/78 (59%)	66
Pyrexia	7/30 (23.3%)	7	3/18 (16.7%)	3	2/30 (6.7%)	2	1/20 (5%)	1	14/129 (10.9%)	14	11/78 (14.1%)	11
Fatigue	1/30 (3.3%)	1	1/18 (5.6%)	1	5/30 (16.7%)	5	3/20 (15%)	3	4/129 (3.1%)	4	3/78 (3.8%)	3
Chest pain	3/30 (10%)	3	0/18 (0%)	0	3/30 (10%)	6	1/20 (5%)	6	3/129 (2.3%)	3	1/78 (1.3%)	1
Oedema peripheral	1/30 (3.3%)	1	1/18 (5.6%)	1	0/30 (0%)	0	0/20 (0%)	0	1/129 (0.8%)	1	3/78 (3.8%)	3
Chills	1/30 (3.3%)	1	0/18 (0%)	0	0/30 (0%)	0	2/20 (10%)	2	0/129 (0%)	0	1/78 (1.3%)	1
Drug intolerance	0/30 (0%)	0	0/18 (0%)	0	1/30 (3.3%)	1	1/20 (5%)	1	0/129 (0%)	0	0/78 (0%)	0
Infusion site pain	0/30 (0%)	0	1/18 (5.6%)	1	0/30 (0%)	0	0/20 (0%)	0	1/129 (0.8%)	1	0/78 (0%)	0
Induration	0/30 (0%)	0	1/18 (5.6%)	1	0/30 (0%)	0	0/20 (0%)	0	0/129 (0%)	0	0/78 (0%)	0
Infusion site pruritus	0/30 (0%)	0	1/18 (5.6%)	1	0/30 (0%)	0	0/20 (0%)	0	0/129 (0%)	0	0/78 (0%)	0
Non-cardiac chest pain	0/30 (0%)	0	0/18 (0%)	0	0/30 (0%)	0	1/20 (5%)	1	0/129 (0%)	0	0/78 (0%)	0
Infections and infestations
Postoperative wound infection	4/30 (13.3%)	6	2/18 (11.1%)	2	0/30 (0%)	0	1/20 (5%)	1	9/129 (7%)	10	2/78 (2.6%)	2
Urinary tract infection	1/30 (3.3%)	1	0/18 (0%)	0	0/30 (0%)	0	1/20 (5%)	1	7/129 (5.4%)	7	8/78 (10.3%)	8
Pneumonia	3/30 (10%)	3	1/18 (5.6%)	1	0/30 (0%)	0	1/20 (5%)	1	1/129 (0.8%)	1	0/78 (0%)	0
Upper respiratory tract infection	0/30 (0%)	0	0/18 (0%)	0	1/30 (3.3%)	1	3/20 (15%)	3	1/129 (0.8%)	1	0/78 (0%)	0
Abdominal abscess	0/30 (0%)	0	1/18 (5.6%)	1	0/30 (0%)	0	0/20 (0%)	0	1/129 (0.8%)	1	1/78 (1.3%)	1
Lower respiratory tract infection	2/30 (6.7%)	2	0/18 (0%)	0	0/30 (0%)	0	0/20 (0%)	0	0/129 (0%)	0	0/78 (0%)	0
Oral candidiasis	1/30 (3.3%)	1	1/18 (5.6%)	1	0/30 (0%)	0	0/20 (0%)	0	0/129 (0%)	0	0/78 (0%)	0
Perirectal abscess	0/30 (0%)	0	1/18 (5.6%)	1	0/30 (0%)	0	0/20 (0%)	0	0/129 (0%)	0	1/78 (1.3%)	1
Candidiasis	0/30 (0%)	0	1/18 (5.6%)	1	0/30 (0%)	0	0/20 (0%)	0	0/129 (0%)	0	0/78 (0%)	0
Lobar pneumonia	0/30 (0%)	0	1/18 (5.6%)	1	0/30 (0%)	0	0/20 (0%)	0	0/129 (0%)	0	0/78 (0%)	0
Rash pustular	0/30 (0%)	0	1/18 (5.6%)	1	0/30 (0%)	0	0/20 (0%)	0	0/129 (0%)	0	0/78 (0%)	0
Sepsis	0/30 (0%)	0	1/18 (5.6%)	1	0/30 (0%)	0	0/20 (0%)	0	0/129 (0%)	0	0/78 (0%)	0
Skin candida	0/30 (0%)	0	1/18 (5.6%)	1	0/30 (0%)	0	0/20 (0%)	0	0/129 (0%)	0	0/78 (0%)	0
Viral upper respiratory tract infection	0/30 (0%)	0	1/18 (5.6%)	1	0/30 (0%)	0	0/20 (0%)	0	0/129 (0%)	0	0/78 (0%)	0
Injury, poisoning and procedural complications
Incision site haemorrhage	4/30 (13.3%)	4	0/18 (0%)	0	0/30 (0%)	0	0/20 (0%)	0	18/129 (14%)	18	3/78 (3.8%)	3
Wound secretion	2/30 (6.7%)	3	1/18 (5.6%)	1	1/30 (3.3%)	1	1/20 (5%)	1	14/129 (10.9%)	15	6/78 (7.7%)	7
Wound dehiscence	3/30 (10%)	3	0/18 (0%)	0	1/30 (3.3%)	1	0/20 (0%)	0	7/129 (5.4%)	7	4/78 (5.1%)	4
Procedural hypertension	0/30 (0%)	0	0/18 (0%)	0	4/30 (13.3%)	4	3/20 (15%)	4	0/129 (0%)	0	0/78 (0%)	0
Postoperative ileus	1/30 (3.3%)	1	1/18 (5.6%)	1	0/30 (0%)	0	0/20 (0%)	0	2/129 (1.6%)	2	1/78 (1.3%)	1
Procedural hypotension	0/30 (0%)	0	0/18 (0%)	0	0/30 (0%)	0	3/20 (15%)	3	0/129 (0%)	0	0/78 (0%)	0
Procedural nausea	0/30 (0%)	0	0/18 (0%)	0	2/30 (6.7%)	2	0/20 (0%)	0	0/129 (0%)	0	1/78 (1.3%)	1
Incision site hypoaesthesia	0/30 (0%)	0	0/18 (0%)	0	0/30 (0%)	0	1/20 (5%)	1	0/129 (0%)	0	0/78 (0%)	0
Incision site pruritus	0/30 (0%)	0	0/18 (0%)	0	0/30 (0%)	0	1/20 (5%)	1	0/129 (0%)	0	0/78 (0%)	0
Postoperative fever	0/30 (0%)	0	0/18 (0%)	0	0/30 (0%)	0	1/20 (5%)	1	0/129 (0%)	0	0/78 (0%)	0
Investigations
Blood phosphorus decreased	0/30 (0%)	0	1/18 (5.6%)	1	0/30 (0%)	0	0/20 (0%)	0	4/129 (3.1%)	4	2/78 (2.6%)	2
Haemoglobin decreased	2/30 (6.7%)	2	0/18 (0%)	0	0/30 (0%)	0	0/20 (0%)	0	3/129 (2.3%)	3	2/78 (2.6%)	2
Blood glucose increased	0/30 (0%)	0	1/18 (5.6%)	1	0/30 (0%)	0	0/20 (0%)	0	3/129 (2.3%)	3	0/78 (0%)	0
Blood magnesium decreased	1/30 (3.3%)	1	1/18 (5.6%)	1	0/30 (0%)	0	0/20 (0%)	0	1/129 (0.8%)	1	1/78 (1.3%)	1
Oxygen saturation decreased	1/30 (3.3%)	1	1/18 (5.6%)	1	0/30 (0%)	0	0/20 (0%)	0	1/129 (0.8%)	1	1/78 (1.3%)	1
Liver function test abnormal	2/30 (6.7%)	2	0/18 (0%)	0	0/30 (0%)	0	0/20 (0%)	0	1/129 (0.8%)	1	0/78 (0%)	0
Breath sounds abnormal	0/30 (0%)	0	1/18 (5.6%)	1	0/30 (0%)	0	0/20 (0%)	0	0/129 (0%)	0	0/78 (0%)	0
Body temperature increased	1/30 (3.3%)	1	0/18 (0%)	0	1/30 (3.3%)	1	0/20 (0%)	0	7/129 (5.4%)	7	2/78 (2.6%)	2
Blood urine present	0/30 (0%)	0	0/18 (0%)	0	0/30 (0%)	0	0/20 (0%)	0	3/129 (2.3%)	3	4/78 (5.1%)	4
Metabolism and nutrition disorders
Hypokalaemia	8/30 (26.7%)	10	2/18 (11.1%)	2	0/30 (0%)	0	0/20 (0%)	0	14/129 (10.9%)	14	10/78 (12.8%)	11
Decreased appetite	1/30 (3.3%)	1	0/18 (0%)	0	1/30 (3.3%)	1	1/20 (5%)	1	2/129 (1.6%)	2	6/78 (7.7%)	6
Hyperglycaemia	1/30 (3.3%)	1	1/18 (5.6%)	1	0/30 (0%)	0	0/20 (0%)	0	2/129 (1.6%)	2	1/78 (1.3%)	1
Fluid overload	0/30 (0%)	0	1/18 (5.6%)	1	0/30 (0%)	0	0/20 (0%)	0	0/129 (0%)	0	0/78 (0%)	0
Musculoskeletal and connective tissue disorders
Back Pain	2/30 (6.7%)	2	1/18 (5.6%)	1	1/30 (3.3%)	1	5/20 (25%)	8	5/129 (3.9%)	5	9/78 (11.5%)	9
Musculoskeletal pain	1/30 (3.3%)	1	0/18 (0%)	0	8/30 (26.7%)	18	7/20 (35%)	9	6/129 (4.7%)	6	0/78 (0%)	0
Pain in extremity	1/30 (3.3%)	1	1/18 (5.6%)	1	1/30 (3.3%)	1	1/20 (5%)	1	2/129 (1.6%)	2	1/78 (1.3%)	1
Muscle spasms	1/30 (3.3%)	1	0/18 (0%)	0	0/30 (0%)	0	1/20 (5%)	1	0/129 (0%)	0	4/78 (5.1%)	5
Neck pain	0/30 (0%)	0	0/18 (0%)	0	2/30 (6.7%)	2	1/20 (5%)	1	2/129 (1.6%)	2	0/78 (0%)	0
Arthralgia	0/30 (0%)	0	0/18 (0%)	0	0/30 (0%)	0	1/20 (5%)	1	1/129 (0.8%)	1	0/78 (0%)	0
Nervous system disorders
Headache	3/30 (10%)	3	1/18 (5.6%)	1	11/30 (36.7%)	15	1/20 (5%)	1	9/129 (7%)	9	12/78 (15.4%)	12
Dizziness	3/30 (10%)	3	1/18 (5.6%)	1	7/30 (23.3%)	7	4/20 (20%)	5	13/129 (10.1%)	13	6/78 (7.7%)	6
Dysgeusia	2/30 (6.7%)	2	1/18 (5.6%)	1	2/30 (6.7%)	3	0/20 (0%)	0	3/129 (2.3%)	3	2/78 (2.6%)	2
Somnolence	0/30 (0%)	0	1/18 (5.6%)	1	0/30 (0%)	0	2/20 (10%)	2	3/129 (2.3%)	3	3/78 (3.8%)	3
Paraesthesia	0/30 (0%)	0	0/18 (0%)	0	2/30 (6.7%)	3	3/20 (15%)	3	0/129 (0%)	0	2/78 (2.6%)	2
Lethargy	0/30 (0%)	0	0/18 (0%)	0	2/30 (6.7%)	2	0/20 (0%)	0	1/129 (0.8%)	1	0/78 (0%)	0
Hypogeusia	0/30 (0%)	0	0/18 (0%)	0	1/30 (3.3%)	1	1/20 (5%)	1	0/129 (0%)	0	0/78 (0%)	0
Psychiatric disorders
Insomnia	2/30 (6.7%)	2	0/18 (0%)	0	2/30 (6.7%)	2	3/20 (15%)	3	8/129 (6.2%)	8	7/78 (9%)	7
Confusional state	2/30 (6.7%)	2	0/18 (0%)	0	0/30 (0%)	0	0/20 (0%)	0	2/129 (1.6%)	3	1/78 (1.3%)	1
Renal and urinary disorders
Urinary retention	3/30 (10%)	3	1/18 (5.6%)	1	1/30 (3.3%)	1	0/20 (0%)	0	4/129 (3.1%)	4	4/78 (5.1%)	4
Respiratory, thoracic and mediastinal disorders
Dyspnoea	2/30 (6.7%)	2	3/18 (16.7%)	3	2/30 (6.7%)	3	1/20 (5%)	1	1/129 (0.8%)	1	1/78 (1.3%)	1
Cough	1/30 (3.3%)	1	1/18 (5.6%)	1	1/30 (3.3%)	1	1/20 (5%)	1	4/129 (3.1%)	4	1/78 (1.3%)	1
Oropharyngeal pain	3/30 (10%)	3	0/18 (0%)	0	0/30 (0%)	0	0/20 (0%)	0	4/129 (3.1%)	4	0/78 (0%)	0
Productive cough	2/30 (6.7%)	2	2/18 (11.1%)	2	0/30 (0%)	0	0/20 (0%)	0	2/129 (1.6%)	2	0/78 (0%)	0
Atelectasis	2/30 (6.7%)	2	0/18 (0%)	0	0/30 (0%)	0	1/20 (5%)	1	0/129 (0%)	0	2/78 (2.6%)	2
Wheezing	0/30 (0%)	0	1/18 (5.6%)	1	0/30 (0%)	0	0/20 (0%)	0	3/129 (2.3%)	3	1/78 (1.3%)	1
Apnoea	0/30 (0%)	0	1/18 (5.6%)	1	0/30 (0%)	0	0/20 (0%)	0	1/129 (0.8%)	1	0/78 (0%)	0
Hypoxia	0/30 (0%)	0	0/18 (0%)	0	0/30 (0%)	0	1/20 (5%)	2	0/129 (0%)	0	1/78 (1.3%)	1
Tachypnoea	0/30 (0%)	0	0/18 (0%)	0	0/30 (0%)	0	1/20 (5%)	1	1/129 (0.8%)	1	0/78 (0%)	0
Asthma	0/30 (0%)	0	0/18 (0%)	0	0/30 (0%)	0	1/20 (5%)	1	0/129 (0%)	0	0/78 (0%)	0
Nasal congestion	0/30 (0%)	0	0/18 (0%)	0	0/30 (0%)	0	1/20 (5%)	1	0/129 (0%)	0	0/78 (0%)	0
Respiratory Failure	0/30 (0%)	0	1/18 (5.6%)	1	0/30 (0%)	0	0/20 (0%)	0	0/129 (0%)	0	0/78 (0%)	0
Skin and subcutaneous tissue disorders
Pruritus	2/30 (6.7%)	2	2/18 (11.1%)	2	1/30 (3.3%)	1	1/20 (5%)	1	8/129 (6.2%)	8	5/78 (6.4%)	5
Hyperhidrosis	1/30 (3.3%)	1	0/18 (0%)	0	0/30 (0%)	0	1/20 (5%)	1	3/129 (2.3%)	3	3/78 (3.8%)	3
Rash	0/30 (0%)	0	1/18 (5.6%)	1	0/30 (0%)	0	1/20 (5%)	1	4/129 (3.1%)	4	1/78 (1.3%)	1
Pruritus generalised	0/30 (0%)	0	1/18 (5.6%)	1	1/30 (3.3%)	1	0/20 (0%)	0	3/129 (2.3%)	3	1/78 (1.3%)	1
Night sweats	0/30 (0%)	0	0/18 (0%)	0	0/30 (0%)	0	1/20 (5%)	1	2/129 (1.6%)	2	2/78 (2.6%)	2
Dermatitis contact	0/30 (0%)	0	1/18 (5.6%)	1	0/30 (0%)	0	0/20 (0%)	0	0/129 (0%)	0	0/78 (0%)	0
Vascular disorders
Hypertension	2/30 (6.7%)	2	0/18 (0%)	0	0/30 (0%)	0	0/20 (0%)	0	9/129 (7%)	9	1/78 (1.3%)	1
Deep vein thrombosis	2/30 (6.7%)	2	0/18 (0%)	0	0/30 (0%)	0	0/20 (0%)	0	1/129 (0.8%)	1	2/78 (2.6%)	2
Hypotension	1/30 (3.3%)	1	0/18 (0%)	0	0/30 (0%)	0	0/20 (0%)	0	5/129 (3.9%)	5	6/78 (7.7%)	6

Limitations/Caveats

[Not Specified]

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Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.