An International Trial to Evaluate the Efficacy and Safety of SABER®-Bupivacaine for Postoperative Pain Control in Patients Undergoing Hysterectomy

• Sponsor: Durect (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00993226
• Collaborator: Nycomed (Industry)
• Enrollment: 115
• Locations: 14
• Arms: 6
• Duration (Months): 14
• Patients Per Site: 8.2
• Patients Per Site Per Month: 0.6

Study Details

Study Description

Brief Summary

The objective is to identify the optimal dose of SABER-Bupivacaine for postoperative pain control in patients undergoing hysterectomy on the basis of pharmacokinetics, efficacy and safety evaluations. The study duration consists of a screening period up to 14 days and a treatment period 14 days with a long term follow up visit at 6 months. The study will provide further data on the efficacy and safety of the product.

Condition or Disease	Intervention/Treatment	Phase
Postoperative Pain	Drug: SABER-Bupivacaine Treatment 1a; Drug: Placebo SABER-Bupivacaine Treatment 1b; Drug: Bupivacaine HCl Treatment 1c; Drug: SABER-Bupivacaine Treatment 2a; Drug: Placebo SABER-Bupivacaine Treatment 2b; Drug: Bupivacaine HCl Treatment 2c	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 115 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: An International, Randomised, Double Blinded, Multi-centre, Active- and Placebo-controlled Dose Response Trial to Evaluate the Efficacy and Safety of SABER-Bupivacaine for Postoperative Pain Control in Patients Undergoing Primary, Elective, Open, Abdominal Hysterectomy
• Study Start Date: May 1, 2009
• Actual Primary Completion Date: Dec 1, 2009
• Actual Study Completion Date: Jul 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Experimental: SABER-Bupivacaine Treatment 1a double-blind	Drug: SABER-Bupivacaine Treatment 1a; 5.0 ml
Placebo Comparator: Placebo SABER-Bupivacaine Treatment 1b double-blind	Drug: Placebo SABER-Bupivacaine Treatment 1b; 5.0 ml; Other Names: POSIMIR® bupivacaine solution
Active Comparator: Bupivacaine HCl Treatment 1c double-blind	Drug: Bupivacaine HCl Treatment 1c; 40 ml
Experimental: SABER-Bupivacaine Treatment 2a double-blind	Drug: SABER-Bupivacaine Treatment 2a; 7.5 ml
Placebo Comparator: Placebo SABER-Bupivacaine Treatment 2b double-blind	Drug: Placebo SABER-Bupivacaine Treatment 2b; 7.5 ml
Active Comparator: Bupivacaine HCl Treatment 2c double-blind	Drug: Bupivacaine HCl Treatment 2c; 40 ml

Outcome Measures

Primary Outcome Measures

1. Pain Intensity (PI) [1 to 72 hours post-surgery]

   Pain intensity (PI) on movement AUC over the period 1 to 72 hours post-surgery. Subjects assessed their pain intensity using an 11-point Pain Intensity Numeric Rating Scale (PI-NRS) with NRS scores ranging from 0 (no pain) to 10 (worst pain possible). 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 [0-3 days after surgery]

   Cumulative IV morphine-equivalent dose of opioid rescue medication

Secondary Outcome Measures

1. Time to First Opioid Rescue Medication Usage [0-14 days after surgery]

2. Opioid Related Side Effects [0-7 days after surgery]

   Opioid-related side effects were recorded 0-7 days after surgery. The Opioid-Related Symptom Distress Scale (OR-SDS) is a composite score computed from a questionnaire containing frequent opioid-related symptoms (Fatigue, Drowsiness, Inability to concentrate, Nausea, Dizziness, Constipation, Itching, Difficulty with urination, Confusion, Retching/vomiting). For each symptom, patients assigned integer scores to assess severity (none=0 to very severe=4), bothersomeness (none=0 to very much=5), and frequency (none=0 to almost constantly=4); patients reported number of Retching/vomiting episodes (none=0, 1-2 episodes=1, 3-4 episodes=2, 5-6 episodes=3, >6 episodes=4). On each day (Day 0-7), the score for each symptom was the mean of the three component scores, and the OR-SDS score was the overall mean of the 10 symptom scores, (values from 0 to 4; larger outcomes are worse). The mean of the daily OR-SDS score from Day 0 to 7 gave the overall OR-SDS Score.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• A planned elective, abdominal hysterectomy

• Patients suitable for general anaesthesia

Exclusion Criteria:

• Known clinically significant hepatic, gastrointestinal, renal, haematological, urologic, neurological, respiratory, endocrine or cardiovascular system abnormalities

• Known serious uncontrolled illness: cancer, psychiatric or metabolic disturbances. History of cured localised malignancies is allowed (i.e. basal or squamous cell skin carcinoma, breast carcinoma or cervical carcinoma)

• Abnormal ECG

• Prolonged QT syndrome

• Current or regular use of analgesic medication for other indication(s)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Nycomed	Paris		France
2	Nycomed	Bayreuth		Germany
3	Nycomed	Dresden		Germany
4	Nycomed	Budapest		Hungary
5	Nycomed	Békéscsaba		Hungary
6	Nycomed	Debrecen		Hungary
7	Nycomed	Györ		Hungary
8	Nycomed	Nyíregyháza		Hungary
9	Nycomed	Szolnok		Hungary
10	Nycomed	Székesfehérvár		Hungary
11	Nycomed	Tatabánya		Hungary
12	Nycomed	Riga		Latvia
13	Nycomed	Stockholm		Sweden
14	Nycomed	London		United Kingdom

Sponsors and Collaborators

• Durect
• Nycomed

Investigators

• Study Chair: Nycomed Clinical Trial Operations, Headquarters

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Durect
• ClinicalTrials.gov Identifier: NCT00993226
• Other Study ID Numbers: BU-001-IM
• First Posted: Oct 12, 2009
• Last Update Posted: Jun 1, 2021
• Last Verified: May 1, 2021

• Keywords provided by Durect: Postoperative pain; Local anaesthesia; Postoperative pain after open abdominal hysterectomy surgery
• Additional relevant MeSH terms: Pain, Postoperative; Bupivacaine

Study Results

Participant Flow

Arm/Group Title	SABER-Bupivacaine	SABER-placebo	Bupivacaine HCl
Arm/Group Description	5 mL, single dose instilled into surgical incision	5 mL, single dose instilled into surgical incision	0.25% 40 mL, single dose infiltrated peri-incisionally
Period Title: Overall Study
STARTED	61	27	27
COMPLETED	60	26	27
NOT COMPLETED	1	1	0

Baseline Characteristics

Arm/Group Title	SABER-Bupivacaine	SABER-placebo	Bupivacaine HCl	Total
Arm/Group Description	5 mL, single dose instilled into surgical incision	5 mL, single dose instilled into surgical incision	0.25% 40 mL, single dose infiltrated peri-incisionally	Total of all reporting groups
Overall Participants	61	27	27	115
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]	46.7	44.3	45.1	45.8
Sex: Female, Male (Count of Participants)
Female	61 100%	27 100%	27 100%	115 100%
Male	0 0%	0 0%	0 0%	0 0%
BMI (kg/m^2) [Mean (Full Range) ]
Mean (Full Range) [kg/m^2]	26.1	26.2	27.0	26.4

Outcome Measures

1. Primary Outcome

Title	Pain Intensity (PI)
Description	Pain intensity (PI) on movement AUC over the period 1 to 72 hours post-surgery. Subjects assessed their pain intensity using an 11-point Pain Intensity Numeric Rating Scale (PI-NRS) with NRS scores ranging from 0 (no pain) to 10 (worst pain possible). 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	1 to 72 hours post-surgery

Outcome Measure Data

Analysis Population Description

ITT population (patients with data available)

Arm/Group Title	SABER-Bupivacaine	SABER-placebo	Bupivacaine HCl
Arm/Group Description	5 mL, single dose instilled into surgical incision	5 mL, single dose instilled into surgical incision	0.25% 40 mL, single dose infiltrated peri-incisionally
Measure Participants	60	27	27
Mean (Standard Deviation) [score on a scale]	4.15 (1.74)	4.46 (1.48)	4.27 (1.69)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	SABER-Bupivacaine, SABER-placebo
	Comments	Exploratory comparison between SABER-Bupivacaine and Bupivacaine HCl not analyzed inferentially
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.467
	Comments
	Method	t-test in ANOVA model
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.21
	Confidence Interval	(2-Sided) 95%; -0.79 to 0.36
	Parameter Dispersion	Type: Standard Deviation; Value: 0.29
	Estimation Comments

2. Primary Outcome

Title	Supplemental Opioid Use
Description	Cumulative IV morphine-equivalent dose of opioid rescue medication
Time Frame	0-3 days after surgery

Outcome Measure Data

Analysis Population Description

ITT population (patients with data available)

Arm/Group Title	SABER-Bupivacaine	SABER-placebo	Bupivacaine HCl
Arm/Group Description	5 mL, single dose instilled into surgical incision	5 mL, single dose instilled into surgical incision	0.25% 40 mL, single dose infiltrated peri-incisionally
Measure Participants	61	27	27
Mean (Standard Deviation) [mg]	22.8 (24.3)	26.3 (25.7)	23.9 (25.9)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	SABER-Bupivacaine, SABER-placebo
	Comments	Exploratory comparison between SABER-Bupivacaine and Bupivacaine HCl not analyzed inferentially
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.331
	Comments
	Method	t-test in ANOVA model
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-2.51
	Confidence Interval	(2-Sided) 95%; -7.59 to 2.58
	Parameter Dispersion	Type: Standard Deviation; Value: 2.57
	Estimation Comments

3. Secondary Outcome

Title	Time to First Opioid Rescue Medication Usage
Time Frame	0-14 days after surgery

Outcome Measure Data

Analysis Population Description

ITT population (patients with data available)

Arm/Group Title	SABER-Bupivacaine	SABER-placebo	Bupivacaine HCl
Arm/Group Description	5 mL, single dose instilled into surgical incision	5 mL, single dose instilled into surgical incision	0.25% 40 mL, single dose infiltrated peri-incisionally
Measure Participants	61	27	27
Median (Standard Deviation) [hours]	7.71 (45.79)	1.53 (1.56)	87.77 (1.11)

4. Secondary Outcome

Title	Opioid Related Side Effects
Description	Opioid-related side effects were recorded 0-7 days after surgery. The Opioid-Related Symptom Distress Scale (OR-SDS) is a composite score computed from a questionnaire containing frequent opioid-related symptoms (Fatigue, Drowsiness, Inability to concentrate, Nausea, Dizziness, Constipation, Itching, Difficulty with urination, Confusion, Retching/vomiting). For each symptom, patients assigned integer scores to assess severity (none=0 to very severe=4), bothersomeness (none=0 to very much=5), and frequency (none=0 to almost constantly=4); patients reported number of Retching/vomiting episodes (none=0, 1-2 episodes=1, 3-4 episodes=2, 5-6 episodes=3, >6 episodes=4). On each day (Day 0-7), the score for each symptom was the mean of the three component scores, and the OR-SDS score was the overall mean of the 10 symptom scores, (values from 0 to 4; larger outcomes are worse). The mean of the daily OR-SDS score from Day 0 to 7 gave the overall OR-SDS Score.
Time Frame	0-7 days after surgery

Outcome Measure Data

Analysis Population Description

ITT population (patients with data available)

Arm/Group Title	SABER-Bupivacaine	SABER-placebo	Bupivacaine HCl
Arm/Group Description	5 mL, single dose instilled into surgical incision	5 mL, single dose instilled into surgical incision	0.25% 40 mL, single dose infiltrated peri-incisionally
Measure Participants	53	25	23
Mean (Standard Deviation) [score on a scale]	0.28 (0.28)	0.34 (0.31)	0.27 (0.24)

Adverse Events

Arm/Group Title	SABER-Bupivacaine		SABER-placebo		Bupivacaine HCl
Arm/Group Description	5 mL, single dose instilled into surgical incision		5 mL, single dose instilled into surgical incision		0.25% 40 mL, single dose infiltrated peri-incisionally
All Cause Mortality
	SABER-Bupivacaine		SABER-placebo		Bupivacaine HCl
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/60 (0%)		0/27 (0%)		0/27 (0%)
Serious Adverse Events
	SABER-Bupivacaine		SABER-placebo		Bupivacaine HCl
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	7/60 (11.7%)		0/27 (0%)		0/27 (0%)
Infections and infestations
Haematoma infection	2/60 (3.3%)		0/27 (0%)		0/27 (0%)
Investigations
ECG abnormal	2/60 (3.3%)		0/27 (0%)		0/27 (0%)
ECG QT prolonged	1/60 (1.7%)		0/27 (0%)		0/27 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Renal neoplasm	1/60 (1.7%)		0/27 (0%)		0/27 (0%)
Respiratory, thoracic and mediastinal disorders
Bronchospasm	1/60 (1.7%)		0/27 (0%)		0/27 (0%)
Laryngeal oedema	1/60 (1.7%)		0/27 (0%)		0/27 (0%)
Other (Not Including Serious) Adverse Events
	SABER-Bupivacaine		SABER-placebo		Bupivacaine HCl
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	48/60 (80%)		17/27 (63%)		19/27 (70.4%)
Blood and lymphatic system disorders
Anaemia	10/60 (16.7%)		4/27 (14.8%)		3/27 (11.1%)
Gastrointestinal disorders
Vomiting	9/60 (15%)		8/27 (29.6%)		4/27 (14.8%)
General disorders
Pyrexia	7/60 (11.7%)		3/27 (11.1%)		7/27 (25.9%)
Injury, poisoning and procedural complications
Post procedural contusion	36/60 (60%)		9/27 (33.3%)		0/27 (0%)
Incision site haematoma	3/60 (5%)		0/27 (0%)		0/27 (0%)
Investigations
CRP increased	7/60 (11.7%)		0/27 (0%)		1/27 (3.7%)
Blood potassium decreased	4/60 (6.7%)		1/27 (3.7%)		0/27 (0%)
Nervous system disorders
Dizziness	9/60 (15%)		3/27 (11.1%)		4/27 (14.8%)
Somnolence	5/60 (8.3%)		0/27 (0%)		2/27 (7.4%)
Vascular disorders
Hypertension	4/60 (6.7%)		1/27 (3.7%)		2/27 (7.4%)

Limitations/Caveats

[Not Specified]

More Information

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.