MATRIX-2: Phase 3 Study of Efficacy and Safety of the XaraColl® Bupivacaine Implant After Hernioplasty

• Sponsor: Innocoll (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02525133
• Collaborator: (none)
• Enrollment: 319
• Locations: 24
• Arms: 2
• Duration (Months): 7.6
• Patients Per Site: 13.3
• Patients Per Site Per Month: 1.8

Study Details

Study Description

Brief Summary

This is a Phase 3, multicenter, randomized, double-blind, parallel-group, placebo-controlled efficacy and safety study of postoperative pain in adults who are scheduled for unilateral inguinal hernioplasty via open laparotomy (tension-free technique).

Patients will assess their postoperative pain intensity (PI) using an 11-point numerical rating scale (NRS) from 0 hour through 72 hours postoperatively.

The expected maximum study duration for each patient will be up to 60 days, including a maximum 30-day screening period, the day of surgery and implantation, and a 30-day post implantation period including treatment and follow-up.

Condition or Disease	Intervention/Treatment	Phase
Pain, Postoperative	Drug: XaraColl; Other: Placebo	Phase 3

Detailed Description

This is a Phase 3, multicenter, randomized, double-blind, parallel-group, placebo-controlled study in adults who are scheduled for unilateral inguinal hernioplasty via open laparotomy (tension-free technique). Patients will receive either 3 XaraColl Bupivacaine Implants each containing 100 mg of bupivacaine hydrochloride, for a 300 mg total dose; or 3 placebo-sponges.

Three test article sponges will be implanted according to the patient's blinded treatment assignment. Following surgery, patients will be transferred to a postanesthesia care unit (PACU) and/or other postoperative recovery area for observation where they may receive parenteral morphine as needed (rescue medication for breakthrough pain) and on request for pain control. Once patients can tolerate oral medication, they will commence a standardized oral analgesic regimen with additional PRN medication to manage breakthrough pain only when it occurs.

Patients will assess their postoperative pain intensity (PI) using an 11-point numerical rating scale (NRS) from 0 hour through 72 hours postoperatively.

Patients will be observed postoperatively for a minimum of 3 hours and may be discharged at any time following completion of their 3-hour vital sign and PI assessments. Patients will be contacted at approximately 6, 24 and 48 hours after implantation to ensure protocol compliance and to perform safety assessments (including AEs and concomitant medications). At 72 hours, patients will return to the clinic to perform their final PI assessment, complete a categorical assessment of their overall pain control, and for follow-up safety assessments. They will also be asked to record the incidence of any ongoing or subsequent AEs (and any associated treatment) through Day 7. Additional follow-up assessments for safety will be performed at postoperative Day 7 (telephone call) and Days 15 and 30 (clinic visits).

Study Design

• Study Type: Interventional
• Actual Enrollment: 319 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase 3, Randomized, Double-blind, Placebo-controlled Study to Investigate the Efficacy and Safety of the XaraColl® Bupivacaine Implant (300 mg Bupivacaine Hydrochloride) After Open Laparotomy Hernioplasty
• Study Start Date: Sep 5, 2015
• Actual Primary Completion Date: Apr 22, 2016
• Actual Study Completion Date: Apr 22, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: XaraColl 3 XaraColl Bupivacaine Implants each containing 100 mg of bupivacaine hydrochloride, for a 300 mg total dose	Drug: XaraColl; Surgical implantation of 3 bupivacaine collagen implants; Other Names: Bupivacaine collagen implant
Placebo Comparator: Placebo 3 placebo implants	Other: Placebo; Plain collagen implant (vehicle); Other Names: Collagen implant

Outcome Measures

Primary Outcome Measures

1. SPI24 [0 to 24 hours]

   The primary efficacy variable (time-weighted sum of pain intensity from Time 0 through 24 hours [SPI24]) was compared once at a 2-sided 0.05 level. Therefore, no multiplicity adjustment was necessary for the primary efficacy analysis. Pain Intensity was assessed by the subject using the 11-point NRS, where 0 indicated "no pain" and 10 indicated "worst pain possible". Minimum value would be "0" and Maximum value would be 240. Time-weighted SPI is calculated as the sum of the pain intensities between successive time points (i.e., if SPI24 = ∑[PI x (time t - time t-1)], where "t" represents a given time point,"t-1" represents the previous time point, and time is expressed in hours). This represents the AUC (Area Under the Curve) of the pain intensities when calculated with the trapezoidal rule.

Secondary Outcome Measures

1. TOpA24 [Time 0 through 24 hours]

   Total use of opioid analgesia (TOpA) from Time 0 through 24 hours (TOpA24) This is a basic measurement of counting in total the number of morphine tablets (15 mg) patients had to use within a 24-hour period (typically called "rescue" to help manage pain. Zero (0) is the "lowest" score. The lower the number of tablets the better outcome.

2. TOpA48 [Time 0 through 48 hours]

   Total use of opioid analgesia (TOpA) from Time 0 through 48 hours (TOpA48) This is a basic measurement of counting in total the number of morphine tablets (15 mg) patients had use within a 48-hour period (typically called "rescue" to help manage pain. Zero (0) is the "lowest" score. The lower the number of tablets the better outcome.

3. TOpA72 [Time 0 through 72 hours]

   Total use of opioid analgesia (TOpA) from Time 0 through 72 hours (TOpA72) This is a basic measurement of counting in total the number of morphine tablets (15 mg) patients had use within a 72-hour period (typically called "rescue" to help manage pain. Zero (0) is the "lowest" score. The lower the number of tablets the better outcome.

4. SPI48 [0 to 48 hours]

   Time-weighted sum of pain intensity from Time 0 through 48 hours (SPI48). Lower score has a better outcome. Pain Intensity was assessed by the subject using the 11-point NRS, where 0 indicated "no pain" and 10 indicated "worst pain possible". Minimum value would be "0" and Maximum value would be 480. Time-weighted SPI is calculated as the sum of the pain intensities between successive time points (i.e., if SPI48 = ∑[PI x (time t - time t-1)], where "t" represents a given time point,"t-1" represents the previous time point, and time is expressed in hours). This represents the AUC (Area Under the Curve) of the pain intensities when calculated with the trapezoidal rule.

5. SPI72 [0 to 72 hours]

   Time-weighted sum of pain intensity from Time 0 through 72 hours (SPI72) A lower score is a better outcome. Pain Intensity was assessed by the subject using the 11-point NRS, where 0 indicated "no pain" and 10 indicated "worst pain possible" Minimum value would be "0" and Maximum value would be 720. Time-weighted SPI is calculated as the sum of the pain intensities between successive time points (i.e., if SPI72 = ∑[PI x (time t - time t-1)], where "t" represents a given time point,"t-1" represents the previous time point, and time is expressed in hours). This represents the AUC (Area Under the Curve) of the pain intensities when calculated with the trapezoidal rule.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Has a planned (non-emergent) unilateral inguinal hernioplasty (open laparotomy, tension-free technique) to be performed according to standard surgical technique under general anesthesia. Repair of multiple hernias through a single incision is permitted provided only a single mesh will be used.

• If female, is nonpregnant and nonlactating.

• If female, is either not of childbearing potential (defined as postmenopausal for ≥ 1 year or surgically sterile [bilateral tubal ligation, bilateral oophorectomy or hysterectomy]) or practicing 1 of the protocol specified medically-acceptable methods of birth control and agrees to continue with the regimen throughout the duration of the study:

• Has the ability and willingness to comply with the study procedures and use of the eDiary.

• Is willing to use only permitted medications throughout the study.

• Is willing to use opioid analgesia.

• Must be able to fluently speak and understand either English or Spanish and be able to provide meaningful written informed consent for the study.

Exclusion Criteria:

• Has a known hypersensitivity to amide local anesthetics, morphine, acetaminophen or bovine products.

• Is scheduled for bilateral inguinal hernioplasty or other significant concurrent surgical procedures per investigator discretion.

• Has undergone major surgery within 3 months of the scheduled hernioplasty or plans to undergo another laparotomy procedure within 30 days postoperatively.

• Has used any analgesic other than acetaminophen within 24 hours of surgery. Acetaminophen may be used on the day of surgery but is subject to preoperative restrictions for oral intake.

• Has used aspirin or aspirin-containing products within 7 days of surgery. Aspirin at a dose of ≤ 325 mg is allowed for cardiovascular prophylaxis if the patient has been on a stable dose regimen for ≥ 30 days before Screening.

• Has used systemic steroids, anticonvulsants, antiepileptics, antidepressants for the management of chronic pain, or monoamine oxidase inhibitors on a regular basis within 10 days of surgery.

• Has used any opioid analgesic for an extended daily basis (30 - 60 mg oral morphine equivalent per day for 3 or more days a week) within 4 weeks before surgery. Patients who, in the investigator's opinion, may be developing opioid tolerance are also excluded.

• Has any chronic painful condition (eg, fibromyalgia) or routinely uses pain medication other than acetaminophen (including nonsteroidal anti-inflammatory drugs [NSAIDs]) that, in the opinion of the investigator, may confound the assessment of pain associated with the hernioplasty.

• Has a physical or mental condition that, in the opinion of the investigator, may confound the assessment of postoperative pain after hernioplasty.

• Shows evidence of tolerance or physical dependency on opioid analgesics or sedative-hypnotic medications.

• Has a urine drug screen that tests positive for drugs of abuse or misuse, including cannabinoids.

• Has liver function test results greater than 3x the upper limit of normal or a history of cirrhosis.

• Has any clinically significant unstable cardiac disease (eg, uncontrolled hypertension, clinically significant arrhythmia at baseline, or an implantable cardioverter-defibrillator [ICD])

• Has any clinically significant unstable neurological, immunological, renal, or hematological disease (eg, uncontrolled diabetes or significantly abnormal laboratory findings), or any other condition that, in the opinion of the investigator, could compromise the patient's welfare, ability to communicate with the study staff or otherwise contraindicate study participation.

• Has an open workman's compensation claim.

• Has participated in a clinical trial (investigational or marketed product) within 30 days of surgery.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Anniston	Alabama	United States	36207
2		Birmingham	Alabama	United States	35216
3		Anaheim	California	United States	92801
4		Laguna Hills	California	United States	92653
5		Pasadena	California	United States	91105
6		Placentia	California	United States	92870
7		Aurora	Colorado	United States	80045
8		Miami	Florida	United States	33134
9		Miami	Florida	United States	33155
10		Pembroke Pines	Florida	United States	33028
11		Pensacola	Florida	United States	32503
12		Columbus	Georgia	United States	31904
13		Chicago	Illinois	United States	60645
14		Las Vegas	Nevada	United States	89104
15		Durham	North Carolina	United States	27710
16		Cleveland	Ohio	United States	44106
17		Columbus	Ohio	United States	43210
18		Oklahoma City	Oklahoma	United States	73104
19		Philadelphia	Pennsylvania	United States	19104
20		Houston	Texas	United States	77004
21		Houston	Texas	United States	77024
22		Salt Lake City	Utah	United States	84124
23		Newport News	Virginia	United States	23606
24		Madison	Wisconsin	United States	53792

Sponsors and Collaborators

• Innocoll

Investigators

• Study Director: Gwendolyn Niebler, D.O., Innocoll

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Innocoll
• ClinicalTrials.gov Identifier: NCT02525133
• Other Study ID Numbers: INN-CB-016
• First Posted: Aug 17, 2015
• Last Update Posted: Jan 8, 2021
• Last Verified: Jan 1, 2021

• Keywords provided by Innocoll: post operative pain; hernioplasty; bupivacaine
• Additional relevant MeSH terms: Pain, Postoperative; Bupivacaine

Study Results

Participant Flow

Arm/Group Title	XaraColl	Placebo
Arm/Group Description	3 XaraColl Bupivacaine Implants each containing 100 mg of bupivacaine hydrochloride, for a 300 mg total dose XaraColl: Surgical implantation of 3 bupivacaine collagen implants	3 placebo implants Placebo: Plain collagen implant (vehicle)
Period Title: Overall Study
STARTED	213	106
Randomized But Not Treated	4	0
COMPLETED	203	103
NOT COMPLETED	10	3

Baseline Characteristics

Arm/Group Title	XaraColl	Placebo	Total
Arm/Group Description	3 XaraColl Bupivacaine Implants each containing 100 mg of bupivacaine hydrochloride, for a 300 mg total dose XaraColl: Surgical implantation of 3 bupivacaine collagen implants	3 placebo implants Placebo: Plain collagen implant (vehicle)	Total of all reporting groups
Overall Participants	207	105	312
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	50.7 (13.69)	48.5 (13.84)	50.0 (13.79)
Sex: Female, Male (Count of Participants)
Female	5 2.4%	3 2.9%	8 2.6%
Male	202 97.6%	102 97.1%	304 97.4%

Outcome Measures

1. Primary Outcome

Title	SPI24
Description	The primary efficacy variable (time-weighted sum of pain intensity from Time 0 through 24 hours [SPI24]) was compared once at a 2-sided 0.05 level. Therefore, no multiplicity adjustment was necessary for the primary efficacy analysis. Pain Intensity was assessed by the subject using the 11-point NRS, where 0 indicated "no pain" and 10 indicated "worst pain possible". Minimum value would be "0" and Maximum value would be 240. Time-weighted SPI is calculated as the sum of the pain intensities between successive time points (i.e., if SPI24 = ∑[PI x (time t - time t-1)], where "t" represents a given time point,"t-1" represents the previous time point, and time is expressed in hours). This represents the AUC (Area Under the Curve) of the pain intensities when calculated with the trapezoidal rule.
Time Frame	0 to 24 hours

Outcome Measure Data

Analysis Population Description

modified intent-to-treat - The mITT population consisted of randomized subjects who received any dose of INL-001 or placebo and who had at least 1 NRS PI score prior to hospital discharge, as needed, to compute SPI.

Arm/Group Title	XaraColl	Placebo
Arm/Group Description	3 XaraColl Bupivacaine Implants each containing 100 mg of bupivacaine hydrochloride, for a 300 mg total dose XaraColl: Surgical implantation of 3 bupivacaine collagen implants	3 placebo implants Placebo: Plain collagen implant (vehicle)
Measure Participants	207	105
Mean (Standard Deviation) [units on a scale]	88.3 (47.01)	116.2 (44.04)

2. Secondary Outcome

Title	TOpA24
Description	Total use of opioid analgesia (TOpA) from Time 0 through 24 hours (TOpA24) This is a basic measurement of counting in total the number of morphine tablets (15 mg) patients had to use within a 24-hour period (typically called "rescue" to help manage pain. Zero (0) is the "lowest" score. The lower the number of tablets the better outcome.
Time Frame	Time 0 through 24 hours

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	XaraColl	Placebo
Arm/Group Description	3 XaraColl Bupivacaine Implants each containing 100 mg of bupivacaine hydrochloride, for a 300 mg total dose XaraColl: Surgical implantation of 3 bupivacaine collagen implants	3 placebo implants Placebo: Plain collagen implant (vehicle)
Measure Participants	207	105
Median (95% Confidence Interval) [morphine equivalents]	5.0	14

3. Secondary Outcome

Title	TOpA48
Description	Total use of opioid analgesia (TOpA) from Time 0 through 48 hours (TOpA48) This is a basic measurement of counting in total the number of morphine tablets (15 mg) patients had use within a 48-hour period (typically called "rescue" to help manage pain. Zero (0) is the "lowest" score. The lower the number of tablets the better outcome.
Time Frame	Time 0 through 48 hours

Outcome Measure Data

Analysis Population Description

mITT Population)

Arm/Group Title	XaraColl	Placebo
Arm/Group Description	3 XaraColl Bupivacaine Implants each containing 100 mg of bupivacaine hydrochloride, for a 300 mg total dose XaraColl: Surgical implantation of 3 bupivacaine collagen implants	3 placebo implants Placebo: Plain collagen implant (vehicle)
Measure Participants	207	105
Median (95% Confidence Interval) [morphine equivalent]	5	14

4. Secondary Outcome

Title	TOpA72
Description	Total use of opioid analgesia (TOpA) from Time 0 through 72 hours (TOpA72) This is a basic measurement of counting in total the number of morphine tablets (15 mg) patients had use within a 72-hour period (typically called "rescue" to help manage pain. Zero (0) is the "lowest" score. The lower the number of tablets the better outcome.
Time Frame	Time 0 through 72 hours

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	XaraColl	Placebo
Arm/Group Description	3 XaraColl Bupivacaine Implants each containing 100 mg of bupivacaine hydrochloride, for a 300 mg total dose XaraColl: Surgical implantation of 3 bupivacaine collagen implants	3 placebo implants Placebo: Plain collagen implant (vehicle)
Measure Participants	207	105
Median (95% Confidence Interval) [morphine tablets]	10	20

5. Secondary Outcome

Title	SPI48
Description	Time-weighted sum of pain intensity from Time 0 through 48 hours (SPI48). Lower score has a better outcome. Pain Intensity was assessed by the subject using the 11-point NRS, where 0 indicated "no pain" and 10 indicated "worst pain possible". Minimum value would be "0" and Maximum value would be 480. Time-weighted SPI is calculated as the sum of the pain intensities between successive time points (i.e., if SPI48 = ∑[PI x (time t - time t-1)], where "t" represents a given time point,"t-1" represents the previous time point, and time is expressed in hours). This represents the AUC (Area Under the Curve) of the pain intensities when calculated with the trapezoidal rule.
Time Frame	0 to 48 hours

Outcome Measure Data

Analysis Population Description

(mITT Population)

Arm/Group Title	XaraColl	Placebo
Arm/Group Description	3 XaraColl Bupivacaine Implants each containing 100 mg of bupivacaine hydrochloride, for a 300 mg total dose XaraColl: Surgical implantation of 3 bupivacaine collagen implants	3 placebo implants Placebo: Plain collagen implant (vehicle)
Measure Participants	207	105
Median (95% Confidence Interval) [units on a scale]	188.1	214.9

6. Secondary Outcome

Title	SPI72
Description	Time-weighted sum of pain intensity from Time 0 through 72 hours (SPI72) A lower score is a better outcome. Pain Intensity was assessed by the subject using the 11-point NRS, where 0 indicated "no pain" and 10 indicated "worst pain possible" Minimum value would be "0" and Maximum value would be 720. Time-weighted SPI is calculated as the sum of the pain intensities between successive time points (i.e., if SPI72 = ∑[PI x (time t - time t-1)], where "t" represents a given time point,"t-1" represents the previous time point, and time is expressed in hours). This represents the AUC (Area Under the Curve) of the pain intensities when calculated with the trapezoidal rule.
Time Frame	0 to 72 hours

Outcome Measure Data

Analysis Population Description

mITT Population

Arm/Group Title	XaraColl	Placebo
Arm/Group Description	3 XaraColl Bupivacaine Implants each containing 100 mg of bupivacaine hydrochloride, for a 300 mg total dose XaraColl: Surgical implantation of 3 bupivacaine collagen implants	3 placebo implants Placebo: Plain collagen implant (vehicle)
Measure Participants	207	105
Median (95% Confidence Interval) [units on a scale]	264.5	299.7

Adverse Events

Time Frame	30 days
Adverse Event Reporting Description	Subject 628-018 was randomized to the INL-001 group but received placebo; the subject was included in the INL-001 group for efficacy analyses (ie, ITT and mITT populations) and was included in the placebo group for safety analyses (ie, safety population). The ITT population consisted of all randomized subjects who may or may not have received any dose of INL-001 or placebo
Arm/Group Title	XaraColl		Placebo
Arm/Group Description	3 XaraColl Bupivacaine Implants each containing 100 mg of bupivacaine hydrochloride, for a 300 mg total dose XaraColl: Surgical implantation of 3 bupivacaine collagen implants		3 placebo implants Placebo: Plain collagen implant (vehicle)
All Cause Mortality
	XaraColl		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/208 (0%)		1/107 (0.9%)
Serious Adverse Events
	XaraColl		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/208 (1.4%)		3/107 (2.8%)
Cardiac disorders
Acute myocardial infarction	1/208 (0.5%)	1	1/107 (0.9%)	1
Atrial fibrillation	1/208 (0.5%)	1	0/107 (0%)	0
Gastrointestinal disorders
Abdominal pain	0/208 (0%)	0	1/107 (0.9%)	1
Infections and infestations
Appendicitis	1/208 (0.5%)	1	0/107 (0%)	0
Musculoskeletal and connective tissue disorders
Groin pain	0/208 (0%)	0	1/107 (0.9%)	1
Other (Not Including Serious) Adverse Events
	XaraColl		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	118/208 (56.7%)		76/107 (71%)
Gastrointestinal disorders
Constipation	18/208 (8.7%)	18	19/107 (17.8%)	19
Nausea	16/208 (7.7%)	16	19/107 (17.8%)	19
Injury, poisoning and procedural complications
Incision site complication	13/208 (6.3%)	13	6/107 (5.6%)	6
Incision site pain	19/208 (9.1%)	19	13/107 (12.1%)	13
Incision site swelling	18/208 (8.7%)	18	11/107 (10.3%)	11
Nervous system disorders
Dizziness	34/208 (16.3%)	34	22/107 (20.6%)	22
Dysgeusia	17/208 (8.2%)	17	10/107 (9.3%)	10
Somnolence	33/208 (15.9%)	33	19/107 (17.8%)	19
Psychiatric disorders
Anxiety	6/208 (2.9%)	6	8/107 (7.5%)	8
Restlessness	16/208 (7.7%)	16	10/107 (9.3%)	10

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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