Bunionectomy Study for Postoperative Analgesia (EPOCH 1)

• Sponsor: Heron Therapeutics (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03295721
• Collaborator: (none)
• Enrollment: 412
• Locations: 15
• Arms: 3
• Actual Duration (Months): 4.6
• Patients Per Site: 27.5
• Patients Per Site Per Month: 6

Study Details

Study Description

Brief Summary

This is a Phase 3, randomized, double-blind, saline placebo- and active-controlled, multicenter study to evaluate the analgesic efficacy and safety of HTX 011 administered via local administration into the surgical site in subjects undergoing bunionectomy.

Condition or Disease	Intervention/Treatment	Phase
Postoperative Pain	Drug: HTX-011; Drug: Saline Placebo; Drug: Bupivacaine HCl; Device: Luer-lock applicator; Device: Vial access device	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 412 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Prevention
• Official Title: A Phase 3, Randomized, Double Blind, Saline Placebo and Active Controlled, Multicenter Study of HTX 011 Via Local Administration for Postoperative Analgesia and Decreased Opioid Use Following Unilateral Simple Bunionectomy
• Actual Study Start Date: Oct 24, 2017
• Actual Primary Completion Date: Jan 8, 2018
• Actual Study Completion Date: Mar 13, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Treatment Group 1: HTX-011 HTX 011 (bupivacaine/meloxicam)	Drug: HTX-011; HTX 011 (bupivacaine/meloxicam), 60 mg/1.8 mg by instillation; Device: Luer-lock applicator; Applicator for instillation; Device: Vial access device; Device for withdrawal of drug product
Placebo Comparator: Treatment Group 2: Saline Placebo Saline placebo	Drug: Saline Placebo; Saline placebo by instillation; Device: Luer-lock applicator; Applicator for instillation
Active Comparator: Treatment Group 3: Bupivacaine HCI Bupivacaine HCl	Drug: Bupivacaine HCl; Bupivacaine HCl without epinephrine, 50 mg by injection

Outcome Measures

Primary Outcome Measures

1. Mean Area Under the Curve (AUC) of the Numeric Rating Scale of Pain Intensity Scores With Activity (NRS-A; Windowed Worst Observation Carried Forward) for HTX-011 Compared With Saline Placebo. [72 hours]

   Pain intensity scores are assessed using an 11-point Numeric Rating Scale (NRS) (0-10) where 0 represents "no pain" and 10 represents "worst pain imaginable". NRS scores are recorded with activity (NRS-A), seated with the plantar surface of the ball of the surgically attended foot touching the floor (no weight-bearing).

Secondary Outcome Measures

1. Mean AUC of the NRS-A Pain Intensity Scores (Windowed Worst Observation Carried Forward) for HTX 011 Compared With Bupivacaine HCl. [72 hours]

   Pain intensity scores are assessed using an 11-point Numeric Rating Scale (NRS) (0-10) where 0 represents "no pain" and 10 represents "worst pain imaginable". NRS scores are recorded with activity (NRS-A) seated with the plantar surface of the ball of the surgically attended foot touching the floor (no weight-bearing).

2. Mean Total Postoperative Opioid Consumption (in Morphine Equivalents) for HTX 011 Compared With Saline Placebo. [72 hours]

3. Percentage of Subjects Who Are Opioid-free for HTX-011 Compared With Bupivacaine HCl. [72 hours]

4. Mean Total Postoperative Opioid Consumption (in Morphine Equivalents) for HTX 011 Compared With Bupivacaine HCl. [72 hours]

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Is scheduled to undergo a primary unilateral, distal, first metatarsal bunionectomy with osteotomy and internal fixation under regional anesthesia.

• Has an American Society of Anesthesiologists Physical Status of I, II, or III.

• Female subjects are eligible only if not pregnant, not lactating, not planning to become pregnant during the study, sterile; or using acceptable contraceptives.

Exclusion Criteria:

• Has had a contralateral foot bunionectomy in the past 3 months.

• Has a planned concurrent surgical procedure (eg, bilateral bunionectomy or collateral procedures on the surgical foot).

• Has other pre existing concurrent acute or chronic painful physical/restrictive condition expected to require analgesic treatment in the postoperative period for pain.

• Has a contraindication or a known or suspected history of hypersensitivity or clinically significant idiosyncratic reaction to required study medications.

• Has known or suspected daily use of opioids for 7 or more consecutive days within the previous 6 months.

• Has taken any NSAIDs within at least 10 days prior to the scheduled surgery.

• Has taken opioids within 24 hours prior to the scheduled surgery (3 days for long-acting).

• Has been administered bupivacaine within 5 days prior to the scheduled surgery.

• Has initiated treatment with medications within 1 month prior to study drug administration that can impact pain control.

• Has been administered systemic steroids within 5 half-lives or 10 days prior to administration of study drug.

• Has a medical condition such that, in the opinion of the Investigator, participating in the study would pose a health risk to the subject or confound the postoperative assessments.

• As per subject history and/or medical records, has active infection or is currently undergoing treatment for Hepatitis B, Hepatitis C, or human immunodeficiency virus (HIV).

• Has uncontrolled anxiety, psychiatric, or neurological disorder.

• Had a malignancy in the last year, with the exception of nonmetastatic basal cell or squamous cell carcinoma of the skin or localized carcinoma in situ of the cervix.

• Has a known or suspected history of drug abuse, a positive drug screen on the day of surgery, or a recent history of alcohol abuse. Note: Subjects with a positive drug screen who are taking an allowed, prescribed medication that is known to result in a positive drug test (eg, amphetamine and dextroamphetamine for attention deficit/hyperactivity disorder, benzodiazepine for anxiety disorder) may be eligible for participation in the study. Subjects taking medical marijuana are not allowed to participate in the study.

• Received an investigational product or device in a clinical trial within 30 days or within 5 elimination half lives.

• Has undergone 3 or more surgeries within 12 months.

• Has a body mass index (BMI) >39 kg/m2.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Springhill Medical Center	Mobile	Alabama	United States	36608
2	Orthopaedic Specialists of North America, PLLC	Mesa	Arizona	United States	85206
3	Arizona Research Center	Phoenix	Arizona	United States	85059
4	Anaheim Clinical Trials, LLC	Anaheim	California	United States	92801
5	Trovare Clinical Research, Inc.	Bakersfield	California	United States	93301
6	Alliance Research Centers	Laguna Hills	California	United States	92653
7	Chesapeake Research Group, LLC	Pasadena	Maryland	United States	21122
8	Optimal Research , LLC	Austin	Texas	United States	78705
9	Hermann Drive Surgical Hospital	Houston	Texas	United States	77004
10	Westside Surgical Hospital	Houston	Texas	United States	77027
11	Futuro Clinical Trials, LLC	McAllen	Texas	United States	78501
12	Plano Surgical Hospital	Plano	Texas	United States	75093
13	Endeavor Clinical Trials	San Antonio	Texas	United States	78229
14	EPIC Medical Research, LLC	Murray	Utah	United States	84123
15	Jean Brown Research	Salt Lake City	Utah	United States	84124

Sponsors and Collaborators

• Heron Therapeutics

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol - Sep 24, 2017
• Statistical Analysis Plan - Oct 10, 2017

More Information

Publications

None provided.

• Responsible Party: Heron Therapeutics
• ClinicalTrials.gov Identifier: NCT03295721
• Other Study ID Numbers: HTX-011-301
• First Posted: Sep 28, 2017
• Last Update Posted: Oct 27, 2021
• Last Verified: Sep 1, 2021

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: Yes
• Product Manufactured in and Exported from the U.S.: Yes
• Keywords provided by Heron Therapeutics: bunion; bunionectomy; bunion surgery; postoperative pain
• Additional relevant MeSH terms: Pain, Postoperative; Bupivacaine

Study Results

Participant Flow

Arm/Group Title	Treatment Group 1: HTX-011	Treatment Group 2: Saline Placebo	Treatment Group 3: Bupivacaine HCI
Arm/Group Description	HTX 011 (bupivacaine/meloxicam), 60 mg/1.8 mg by instillation.	Saline placebo by instillation.	Bupivacaine HCl without epinephrine, 50 mg by injection.
Period Title: Overall Study
STARTED	157	100	155
COMPLETED	154	99	152
NOT COMPLETED	3	1	3

Baseline Characteristics

Arm/Group Title	Treatment Group 1: HTX-011	Treatment Group 2: Saline Placebo	Treatment Group 3: Bupivacaine HCI	Total
Arm/Group Description	HTX 011 (bupivacaine/meloxicam), 60 mg/1.8 mg by instillation.	Saline placebo by instillation.	Bupivacaine HCl without epinephrine, 50 mg by injection.	Total of all reporting groups
Overall Participants	157	100	155	412
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	133 84.7%	92 92%	139 89.7%	364 88.3%
>=65 years	24 15.3%	8 8%	16 10.3%	48 11.7%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	48.0 (14.47)	47.3 (12.83)	45.5 (14.79)	46.9 (14.22)
Sex: Female, Male (Count of Participants)
Female	138 87.9%	86 86%	132 85.2%	356 86.4%
Male	19 12.1%	14 14%	23 14.8%	56 13.6%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	47 29.9%	32 32%	49 31.6%	128 31.1%
Not Hispanic or Latino	110 70.1%	68 68%	106 68.4%	284 68.9%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	1 0.6%	0 0%	2 1.3%	3 0.7%
Asian	8 5.1%	2 2%	1 0.6%	11 2.7%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	1 0.6%	1 0.2%
Black or African American	24 15.3%	12 12%	22 14.2%	58 14.1%
White	123 78.3%	86 86%	128 82.6%	337 81.8%
More than one race	1 0.6%	0 0%	1 0.6%	2 0.5%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	157 100%	100 100%	155 100%	412 100%

Outcome Measures

1. Primary Outcome

Title	Mean Area Under the Curve (AUC) of the Numeric Rating Scale of Pain Intensity Scores With Activity (NRS-A; Windowed Worst Observation Carried Forward) for HTX-011 Compared With Saline Placebo.
Description	Pain intensity scores are assessed using an 11-point Numeric Rating Scale (NRS) (0-10) where 0 represents "no pain" and 10 represents "worst pain imaginable". NRS scores are recorded with activity (NRS-A), seated with the plantar surface of the ball of the surgically attended foot touching the floor (no weight-bearing).
Time Frame	72 hours

Outcome Measure Data

Analysis Population Description

ITT Population

Arm/Group Title	Treatment Group 1: HTX-011	Treatment Group 2: Saline Placebo
Arm/Group Description	HTX 011 (bupivacaine/meloxicam), 60 mg/1.8 mg by instillation.	Saline placebo by instillation.
Measure Participants	157	100
Mean (Standard Deviation) [pain intensity score*hr]	323.29 (182.641)	445.34 (155.792)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Treatment Group 1: HTX-011, Treatment Group 2: Saline Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	< 0.0001
	Comments
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference (LSMD)
	Estimated Value	-122.05
	Confidence Interval	(2-Sided) 95%; -163.76 to -80.34
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 21.217
	Estimation Comments

2. Secondary Outcome

Title	Mean AUC of the NRS-A Pain Intensity Scores (Windowed Worst Observation Carried Forward) for HTX 011 Compared With Bupivacaine HCl.
Description	Pain intensity scores are assessed using an 11-point Numeric Rating Scale (NRS) (0-10) where 0 represents "no pain" and 10 represents "worst pain imaginable". NRS scores are recorded with activity (NRS-A) seated with the plantar surface of the ball of the surgically attended foot touching the floor (no weight-bearing).
Time Frame	72 hours

Outcome Measure Data

Analysis Population Description

ITT Population

Arm/Group Title	Treatment Group 1: HTX-011	Treatment Group 3: Bupivacaine HCI
Arm/Group Description	HTX 011 (bupivacaine/meloxicam), 60 mg/1.8 mg by instillation.	Bupivacaine HCl without epinephrine, 50 mg by injection.
Measure Participants	157	155
Mean (Standard Deviation) [pain intensity score*hr]	323.29 (182.641)	393.45 (153.756)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Treatment Group 1: HTX-011, Treatment Group 2: Saline Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	= 0.0002
	Comments
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference (LSMD)
	Estimated Value	-70.16
	Confidence Interval	(2-Sided) 95%; -107.07 to -33.25
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 18.777
	Estimation Comments

3. Secondary Outcome

Title	Mean Total Postoperative Opioid Consumption (in Morphine Equivalents) for HTX 011 Compared With Saline Placebo.
Time Frame	72 hours

Outcome Measure Data

Analysis Population Description

ITT Population

Arm/Group Title	Treatment Group 1: HTX-011	Treatment Group 2: Saline Placebo
Arm/Group Description	HTX 011 (bupivacaine/meloxicam), 60 mg/1.8 mg by instillation.	Saline placebo by instillation.
Measure Participants	157	100
Mean (Standard Deviation) [IV milligram morphine equivalent (MME)]	18.80 (19.801)	30.06 (21.016)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Treatment Group 1: HTX-011, Treatment Group 2: Saline Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	< 0.0001
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

4. Secondary Outcome

Title	Percentage of Subjects Who Are Opioid-free for HTX-011 Compared With Bupivacaine HCl.
Time Frame	72 hours

Outcome Measure Data

Analysis Population Description

ITT Population

Arm/Group Title	Treatment Group 1: HTX-011	Treatment Group 3: Bupivacaine HCI
Arm/Group Description	HTX 011 (bupivacaine/meloxicam), 60 mg/1.8 mg by instillation.	Bupivacaine HCl without epinephrine, 50 mg by injection.
Measure Participants	157	155
Count of Participants [Participants]	45 28.7%	17 17%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Treatment Group 1: HTX-011, Treatment Group 2: Saline Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0001
	Comments
	Method	Fisher Exact
	Comments
Method of Estimation	Estimation Parameter	Risk Difference (RD)
	Estimated Value	.177
	Confidence Interval	(2-Sided) 95%; .085 to .265
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Mean Total Postoperative Opioid Consumption (in Morphine Equivalents) for HTX 011 Compared With Bupivacaine HCl.
Time Frame	72 hours

Outcome Measure Data

Analysis Population Description

ITT Population

Arm/Group Title	Treatment Group 1: HTX-011	Treatment Group 3: Bupivacaine HCl
Arm/Group Description	HTX 011 (bupivacaine/meloxicam), 60 mg/1.8 mg by instillation.	Bupivacaine HCl without epinephrine, 50 mg by injection.
Measure Participants	157	155
Mean (Standard Deviation) [IV milligram morphine equivalent (MME)]	18.80 (19.801)	25.09 (21.553)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Treatment Group 1: HTX-011, Treatment Group 2: Saline Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	= 0.0022
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Adverse Events

Time Frame	42 days.
Adverse Event Reporting Description	For each Preferred Term (PT), subjects are included only once, even if they experienced multiple events in that PT.
Arm/Group Title	Treatment Group 1: HTX-011		Treatment Group 2: Saline Placebo		Treatment Group 3: Bupivacaine HCl
Arm/Group Description	HTX 011 (bupivacaine/meloxicam), 60 mg/1.8 mg by instillation.		Saline placebo by instillation. 1 subject was randomized to bupivacaine HCl, but received saline placebo. (Ie, ITT = 100 and Safety population = 101).		Bupivacaine HCl without epinephrine, 50 mg by injection.
All Cause Mortality
	Treatment Group 1: HTX-011		Treatment Group 2: Saline Placebo		Treatment Group 3: Bupivacaine HCl
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/157 (0%)		0/101 (0%)		1/154 (0.6%)
Serious Adverse Events
	Treatment Group 1: HTX-011		Treatment Group 2: Saline Placebo		Treatment Group 3: Bupivacaine HCl
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/157 (1.9%)		1/101 (1%)		3/154 (1.9%)
Cardiac disorders
Atrial fibrillation	0/157 (0%)		0/101 (0%)		1/154 (0.6%)
Gastrointestinal disorders
Intestinal perforation	1/157 (0.6%)		0/101 (0%)		0/154 (0%)
General disorders
Death	0/157 (0%)		0/101 (0%)		1/154 (0.6%)
Hepatobiliary disorders
Bile duct stone	1/157 (0.6%)		0/101 (0%)		0/154 (0%)
Injury, poisoning and procedural complications
Thoracic vertebral fracture	1/157 (0.6%)		0/101 (0%)		0/154 (0%)
Respiratory, thoracic and mediastinal disorders
Pulmonary embolism	0/157 (0%)		0/101 (0%)		1/154 (0.6%)
Vascular disorders
Venous thrombosis	1/157 (0.6%)		0/101 (0%)		0/154 (0%)
Deep vein thrombosis postoperative	0/157 (0%)		1/101 (1%)		1/154 (0.6%)
Other (Not Including Serious) Adverse Events
	Treatment Group 1: HTX-011		Treatment Group 2: Saline Placebo		Treatment Group 3: Bupivacaine HCl
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	111/157 (70.7%)		70/101 (69.3%)		112/154 (72.7%)
Cardiac disorders
Bradycardia	12/157 (7.6%)		6/101 (5.9%)		12/154 (7.8%)
Sinus arrhythmia	6/157 (3.8%)		6/101 (5.9%)		10/154 (6.5%)
Ear and labyrinth disorders
Tinnitus	2/157 (1.3%)		2/101 (2%)		8/154 (5.2%)
Gastrointestinal disorders
Nausea	59/157 (37.6%)		44/101 (43.6%)		70/154 (45.5%)
Vomiting	23/157 (14.6%)		19/101 (18.8%)		33/154 (21.4%)
Constipation	9/157 (5.7%)		7/101 (6.9%)		18/154 (11.7%)
General disorders
Impaired healing	10/157 (6.4%)		1/101 (1%)		6/154 (3.9%)
Injury, poisoning and procedural complications
Incision site oedema	27/157 (17.2%)		13/101 (12.9%)		22/154 (14.3%)
Incision site erythema	20/157 (12.7%)		8/101 (7.9%)		18/154 (11.7%)
Post procedural contusion	19/157 (12.1%)		13/101 (12.9%)		18/154 (11.7%)
Musculoskeletal and connective tissue disorders
Muscle twitching	9/157 (5.7%)		5/101 (5%)		8/154 (5.2%)
Nervous system disorders
Dizziness	34/157 (21.7%)		18/101 (17.8%)		36/154 (23.4%)
Headache	22/157 (14%)		10/101 (9.9%)		20/154 (13%)
Dysgeusia	4/157 (2.5%)		6/101 (5.9%)		6/154 (3.9%)
Skin and subcutaneous tissue disorders
Pruritus	8/157 (5.1%)		6/101 (5.9%)		1/154 (0.6%)
Pruritus generalised	4/157 (2.5%)		4/101 (4%)		8/154 (5.2%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

There is NOT 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.