Phase 3 Herniorrhaphy Study for Postoperative Analgesia (EPOCH 2)

• Sponsor: Heron Therapeutics (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03237481
• Collaborator: (none)
• Enrollment: 418
• Locations: 24
• Arms: 3
• Actual Duration (Months): 5.6
• Patients Per Site: 17.4
• Patients Per Site Per Month: 3.1

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 unilateral open inguinal herniorrhaphy.

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

Study Design

• Study Type: Interventional
• Actual Enrollment: 418 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 Open Inguinal Herniorrhaphy
• Actual Study Start Date: Jul 31, 2017
• Actual Primary Completion Date: Dec 22, 2017
• Actual Study Completion Date: Jan 16, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Treatment Group 1: HTX-011 HTX 011 (bupivacaine/meloxicam)	Drug: HTX-011; HTX 011 (bupivacaine/meloxicam), 300 mg/9 mg by instillation; Device: Luer-lock applicator; Applicator for instillation; Device: Vial access device; Device for withdrawal of drug product
Active Comparator: Treatment Group 2: Bupivacaine HCI Bupivacaine HCl	Drug: Bupivacaine HCl; Bupivacaine HCl without epinephrine, 75 mg by injection
Placebo Comparator: Treatment Group 3: Saline Placebo Saline placebo	Drug: Saline placebo; Saline placebo by instillation; Device: Luer-lock applicator; Applicator for instillation

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), sitting up from a resting position.

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), sitting up from a resting position.

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

3. Percetange 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 unilateral open inguinal herniorrhaphy with mesh under general 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:

• Had any prior inguinal hernia repair.

• Has a planned concurrent surgical procedure.

• 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 NSAIDs within 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.

• Has a known history of Hepatitis B, human immunodeficiency virus (HIV), or active Hepatitis C.

• Has uncontrolled anxiety, psychiatric, or neurological disorder that, in the opinion of the Investigator, might interfere with study assessments.

• 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) 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	Eliza Coffee Memorial Hospital	Florence	Alabama	United States	35630
2	Shoals Medical Trials, Inc.	Sheffield	Alabama	United States	35660
3	Arizona Research Center	Phoenix	Arizona	United States	85053
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	Lotus Clinical Research, LLC	Pasadena	California	United States	91105
8	HD Research Corp	Riverside	California	United States	92503
9	American Institute of Research	Whittier	California	United States	90603
10	Yale University School of Medicine	New Haven	Connecticut	United States	06511
11	Cornerstone Research Institute, LLC	Longwood	Florida	United States	32750
12	Park Place Surgery Center	Maitland	Florida	United States	32751
13	University of Miami	Miami	Florida	United States	33136
14	St. Louis Clinical Trials	Saint Louis	Missouri	United States	63141
15	eStudySite	Las Vegas	Nevada	United States	89109
16	Midwest Clinical Research	Dayton	Ohio	United States	45417
17	Hermann Drive Surgical Hospital	Houston	Texas	United States	77004
18	Westside Surgical Hospital	Houston	Texas	United States	77027
19	Plano Surgical Hospital	Plano	Texas	United States	75093
20	Endeavor Clinical Trials, P.A.	San Antonio	Texas	United States	78229
21	EPIC Medical Research, LLC	Murray	Utah	United States	84123
22	Jean Brown Research	Salt Lake City	Utah	United States	84124
23	Jessa Ziekenhuis	Hasselt	Limburg	Belgium	3500
24	Ziekenhuis Oost Limburg	Genk		Belgium	3600

Sponsors and Collaborators

• Heron Therapeutics

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol - Jul 30, 2017
• Statistical Analysis Plan - Oct 24, 2017

More Information

Publications

None provided.

• Responsible Party: Heron Therapeutics
• ClinicalTrials.gov Identifier: NCT03237481
• Other Study ID Numbers: HTX-011-302
• First Posted: Aug 2, 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
• Keywords provided by Heron Therapeutics: inguinal hernia; hernia; hernia surgery; postoperative pain; herniorrhaphy
• Additional relevant MeSH terms: Pain, Postoperative; Bupivacaine

Study Results

Participant Flow

Arm/Group Title	Treatment Group 1: HTX-011	Treatment Group 2: Bupivacaine HCI	Treatment Group 3: Saline Placebo
Arm/Group Description	HTX-011 (bupivacaine/meloxicam), 300 mg/9 mg by instillation.	Bupivacaine HCl without epinephrine, 75 mg by injection.	Saline Placebo by instillation.
Period Title: Overall Study
STARTED	164	172	82
COMPLETED	159	170	81
NOT COMPLETED	5	2	1

Baseline Characteristics

Arm/Group Title	Treatment Group 1: HTX-011	Treatment Group 2: Bupivacaine HCI	Treatment Group 3: Saline Placebo	Total
Arm/Group Description	HTX-011 (bupivacaine/meloxicam), 300 mg/9 mg by instillation.	Bupivacaine HCl without epinephrine, 75 mg by injection.	Saline Placebo by instillation.	Total of all reporting groups
Overall Participants	164	172	82	418
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	149 90.9%	161 93.6%	77 93.9%	387 92.6%
>=65 years	15 9.1%	11 6.4%	5 6.1%	31 7.4%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	48.9 (13.29)	49.4 (11.26)	48.0 (14.59)	48.9 (12.75)
Sex: Female, Male (Count of Participants)
Female	12 7.3%	8 4.7%	3 3.7%	23 5.5%
Male	152 92.7%	164 95.3%	79 96.3%	395 94.5%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	43 26.2%	51 29.7%	30 36.6%	124 29.7%
Not Hispanic or Latino	121 73.8%	121 70.3%	52 63.4%	294 70.3%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	2 1.2%	0 0%	0 0%	2 0.5%
Asian	2 1.2%	2 1.2%	1 1.2%	5 1.2%
Native Hawaiian or Other Pacific Islander	4 2.4%	1 0.6%	0 0%	5 1.2%
Black or African American	17 10.4%	16 9.3%	3 3.7%	36 8.6%
White	139 84.8%	153 89%	78 95.1%	370 88.5%
More than one race	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
Belgium	4 2.4%	0 0%	0 0%	4 1%
United States	160 97.6%	172 100%	82 100%	414 99%

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), sitting up from a resting position.
Time Frame	72 hours

Outcome Measure Data

Analysis Population Description

ITT Population.

Arm/Group Title	Treatment Group 1: HTX-011	Treatment Group 3: Saline Placebo
Arm/Group Description	HTX-011 (bupivacaine/meloxicam), 300 mg/9 mg by instillation.	Saline Placebo by instillation.
Measure Participants	164	82
Mean (Standard Deviation) [pain intensity score*hr]	269.39 (173.719)	350.82 (171.224)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Treatment Group 1: HTX-011, Treatment Group 3: Saline Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	= 0.0004
	Comments
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference (LSMD)
	Estimated Value	-81.43
	Confidence Interval	(2-Sided) 95%; -125.83 to -37.02
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 22.592
	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), sitting up from a resting position.
Time Frame	72 hours

Outcome Measure Data

Analysis Population Description

ITT Population.

Arm/Group Title	Treatment Group 1: HTX-011	Treatment Group 2: Bupivacaine HCI
Arm/Group Description	HTX-011 (bupivacaine/meloxicam), 300 mg/9 mg by instillation.	Bupivacaine HCl without epinephrine, 75 mg by injection.
Measure Participants	164	172
Mean (Standard Deviation) [pain intensity score*hr]	269.39 (173.719)	341.88 (158.303)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Treatment Group 1: HTX-011, Treatment Group 3: 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	-72.49
	Confidence Interval	(2-Sided) 95%; -108.32 to -36.65
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 18.23
	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 3: Saline Placebo
Arm/Group Description	HTX-011 (bupivacaine/meloxicam), 300 mg/9 mg by instillation.	Saline Placebo by instillation.
Measure Participants	164	82
Mean (Standard Deviation) [IV milligram morphine equivalent (MME)]	10.85 (17.062)	17.53 (18.908)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Treatment Group 1: HTX-011, Treatment Group 3: 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	Percetange 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 2: Bupivacaine HCI
Arm/Group Description	HTX-011 (bupivacaine/meloxicam), 300 mg/9 mg by instillation.	Bupivacaine HCl without epinephrine, 75 mg by injection.
Measure Participants	164	172
Count of Participants [Participants]	84 51.2%	69 40.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Treatment Group 1: HTX-011, Treatment Group 3: Saline Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	= 0.0486
	Comments
	Method	Fisher Exact
	Comments
Method of Estimation	Estimation Parameter	Risk Difference (RD)
	Estimated Value	0.111
	Confidence Interval	(2-Sided) 95%; 0.003 to 0.218
	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 2: Bupivacaine HCI
Arm/Group Description	HTX-011 (bupivacaine/meloxicam), 300 mg/9 mg by instillation.	Bupivacaine HCl without epinephrine, 75 mg by injection.
Measure Participants	164	172
Mean (Standard Deviation) [IV milligram morphine equivalent (MME)]	10.85 (17.062)	14.51 (18.185)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Treatment Group 1: HTX-011, Treatment Group 3: Saline Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	= 0.024
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Adverse Events

Time Frame	28 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: Bupivacaine HCI		Treatment Group 3: Saline Placebo
Arm/Group Description	HTX-011 (bupivacaine/meloxicam), 300 mg/9 mg by instillation.		Bupivacaine HCl without epinephrine, 75 mg by injection. 173 = Safety Population because 1 subject was randomized to HTX-011, but received bupivacaine HCl.		Saline Placebo by instillation.
All Cause Mortality
	Treatment Group 1: HTX-011		Treatment Group 2: Bupivacaine HCI		Treatment Group 3: Saline Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/163 (0%)		0/173 (0%)		0/82 (0%)
Serious Adverse Events
	Treatment Group 1: HTX-011		Treatment Group 2: Bupivacaine HCI		Treatment Group 3: Saline Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/163 (1.2%)		1/173 (0.6%)		1/82 (1.2%)
Gastrointestinal disorders
Inguinal hernia, obstructive	0/163 (0%)		0/173 (0%)		1/82 (1.2%)
General disorders
Pyrexia	0/163 (0%)		1/173 (0.6%)		0/82 (0%)
Infections and infestations
Cellulitis of male external genital organ	0/163 (0%)		0/173 (0%)		1/82 (1.2%)
Postoperative wound infection	0/163 (0%)		0/173 (0%)		1/82 (1.2%)
Injury, poisoning and procedural complications
Incision site haematoma	1/163 (0.6%)		0/173 (0%)		0/82 (0%)
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease	1/163 (0.6%)		0/173 (0%)		0/82 (0%)
Other (Not Including Serious) Adverse Events
	Treatment Group 1: HTX-011		Treatment Group 2: Bupivacaine HCI		Treatment Group 3: Saline Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	84/163 (51.5%)		104/173 (60.1%)		49/82 (59.8%)
Cardiac disorders
Bradycardia	15/163 (9.2%)		16/173 (9.2%)		6/82 (7.3%)
Ear and labyrinth disorders
Tinnitus	3/163 (1.8%)		6/173 (3.5%)		5/82 (6.1%)
Gastrointestinal disorders
Nausea	30/163 (18.4%)		37/173 (21.4%)		28/82 (34.1%)
Constipation	28/163 (17.2%)		41/173 (23.7%)		15/82 (18.3%)
Vomiting	7/163 (4.3%)		12/173 (6.9%)		4/82 (4.9%)
Investigations
Gamma-glutamyltransferase increase	2/163 (1.2%)		5/173 (2.9%)		6/82 (7.3%)
Nervous system disorders
Dizziness	24/163 (14.7%)		42/173 (24.3%)		13/82 (15.9%)
Headache	21/163 (12.9%)		24/173 (13.9%)		10/82 (12.2%)
Dysgeusia	15/163 (9.2%)		21/173 (12.1%)		3/82 (3.7%)
Tremor	7/163 (4.3%)		12/173 (6.9%)		8/82 (9.8%)
Skin and subcutaneous tissue disorders
Skin odour abnormal	13/163 (8%)		1/173 (0.6%)		1/82 (1.2%)

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.