MATRIX-1: Phase 3 Study of Efficacy and Safety of the XaraColl® Bupivacaine Implant After Hernioplasty

• Sponsor: Innocoll (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02523599
• Collaborator: (none)
• Enrollment: 305
• Locations: 23
• Arms: 2
• Duration (Months): 8
• Patients Per Site: 13.3
• Patients Per Site Per Month: 1.7

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: 305 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: Aug 1, 2015
• Actual Primary Completion Date: Apr 1, 2016
• Actual Study Completion Date: Apr 1, 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)

Outcome Measures

Primary Outcome Measures

1. SPI24 [0 to 24 hours]

   Sum of Pain Intensity (SPI24). The time weighted sum of pain intensity from 0 to 24 hours (ie, the area under the NRS PI curve from 0 to 24 hours). Where 0 indicated "no pain" and 10 indicated "worst pain possible". This type of measurement scale is called "NRS" or Numerical Rating Scale For the purpose of (SPI) computation, PI at Time 0 (Baseline PI) is set to zero for all patients who have test article implantation. SPI will not be calculated for randomized but not treated patients. A lower score is a better outcome. 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 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 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. This is a basic measurement of counting in total the number of morphine tablets 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]

   Sum of pain intensity (SPI).The time weighted sum of pain intensity from 0 to 48 hours (ie, the area under the NRS PI curve from 0 to 48 hours). For the purpose of SPI computation, Pain Intensity at Time 0 (Baseline PI) is set to zero for all patients who have test article implantation. 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 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.

5. SPI72 [0 to 72 hours]

   Sum of pain intensity (SPI). The time weighted sum of pain intensity from 0 to 72 hours (ie, the area under the NRS PI curve from 0 to 72 hours). For the purpose of SPI computation, PI at Time 0 (Baseline PI) is set to zero for all patients who have test article implantation. Where 0 indicates "no pain" and 10 indicated "worst pain possible". A lower score is a better outcome. 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		Mobile	Alabama	United States	36617
2		Sheffield	Alabama	United States	35660
3		Phoenix	Arizona	United States	85023
4		Little Rock	Arkansas	United States	72205
5		Encino	California	United States	91436
6		Bradenton	Florida	United States	34206
7		Clermont	Florida	United States	34711
8		Inverness	Florida	United States	34452
9		Kissimmee	Florida	United States	34741
10		Miami	Florida	United States	33136
11		Miami	Florida	United States	33144
12		Orlando	Florida	United States	32825
13		Saint Petersburg	Florida	United States	33713
14		Tampa	Florida	United States	33606
15		Weston	Florida	United States	33331
16		Indianapolis	Indiana	United States	46202
17		Springfield	Massachusetts	United States	01199
18		Flint	Michigan	United States	48532
19		Las Vegas	Nevada	United States	89102
20		Las Vegas	Nevada	United States	89106
21		El Paso	Texas	United States	79935
22		Houston	Texas	United States	77054
23		Lampasas	Texas	United States	76550

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: NCT02523599
• Other Study ID Numbers: INN-CB-014
• First Posted: Aug 14, 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	204	101
Randomized But Not Treated	1	0
COMPLETED	196	100
NOT COMPLETED	8	1

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	204	101	305
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	53.1 (12.82)	53.3 (14.01)	53.1 (13.20)
Sex: Female, Male (Count of Participants)
Female	8 3.9%	4 4%	12 3.9%
Male	196 96.1%	97 96%	293 96.1%
Region of Enrollment (participants) [Number]
United States	204 100%	101 100%	305 100%

Outcome Measures

1. Primary Outcome

Title	SPI24
Description	Sum of Pain Intensity (SPI24). The time weighted sum of pain intensity from 0 to 24 hours (ie, the area under the NRS PI curve from 0 to 24 hours). Where 0 indicated "no pain" and 10 indicated "worst pain possible". This type of measurement scale is called "NRS" or Numerical Rating Scale For the purpose of (SPI) computation, PI at Time 0 (Baseline PI) is set to zero for all patients who have test article implantation. SPI will not be calculated for randomized but not treated patients. A lower score is a better outcome. 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

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	197	101
Mean (Standard Deviation) [units on a scale]	85.0 (47.18)	106.8 (48.20)

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 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

(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	197	101
Median (95% Confidence Interval) [morphine mg equivalent]	5	10

3. Secondary Outcome

Title	TOpA48
Description	Total use of Opioid Analgesia 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	197	101
Median (95% Confidence Interval) [morphine mg equivalent]	5.0	14.0

4. Secondary Outcome

Title	TOpA72
Description	Total use of Opioid Analgesia (TOpA) from Time 0 through 72 hours. This is a basic measurement of counting in total the number of morphine tablets 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	197	101
Median (95% Confidence Interval) [morphine mg equivalent]	5.0	14.0

5. Secondary Outcome

Title	SPI48
Description	Sum of pain intensity (SPI).The time weighted sum of pain intensity from 0 to 48 hours (ie, the area under the NRS PI curve from 0 to 48 hours). For the purpose of SPI computation, Pain Intensity at Time 0 (Baseline PI) is set to zero for all patients who have test article implantation. 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 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 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	197	101
Median (95% Confidence Interval) [units on a scale]	165.7	190.1

6. Secondary Outcome

Title	SPI72
Description	Sum of pain intensity (SPI). The time weighted sum of pain intensity from 0 to 72 hours (ie, the area under the NRS PI curve from 0 to 72 hours). For the purpose of SPI computation, PI at Time 0 (Baseline PI) is set to zero for all patients who have test article implantation. Where 0 indicates "no pain" and 10 indicated "worst pain possible". A lower score is a better outcome. 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	197	101
Median (95% Confidence Interval) [units on a scale]	245.2	263.3

Adverse Events

Time Frame	30 days
Adverse Event Reporting Description	A total of 204 patients have been randomized to INL-001 active drug arm. However 1 patient was randomized and not treated. This means only 203 patients received the active compound. In the Placebo arm all patient randomized were treated.
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	/ (NaN)		/ (NaN)
Serious Adverse Events
	XaraColl		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/203 (1%)		0/101 (0%)
Gastrointestinal disorders
intestinal ischemia	1/203 (0.5%)	1	0/101 (0%)	0
small intestinal obstruction	1/203 (0.5%)	1	0/101 (0%)	0
large intestine perforation	1/203 (0.5%)	1	0/101 (0%)	0
colitis	1/203 (0.5%)	1	0/101 (0%)	0
Infections and infestations
sepsis	1/203 (0.5%)	1	0/101 (0%)	0
peritonitis bacterial	1/203 (0.5%)	1	0/101 (0%)	0
Metabolism and nutrition disorders
hyponatremia	1/203 (0.5%)	1	0/101 (0%)	0
malnutrition	1/203 (0.5%)	1	0/101 (0%)	0
Renal and urinary disorders
urinary retention	1/203 (0.5%)	1	0/101 (0%)	0
Other (Not Including Serious) Adverse Events
	XaraColl		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	103/203 (50.7%)		55/101 (54.5%)
Gastrointestinal disorders
constipation	17/203 (8.4%)	17	12/101 (11.9%)	12
nausea	23/203 (11.3%)	23	15/101 (14.9%)	15
Injury, poisoning and procedural complications
incision site pain	34/203 (16.7%)	34	19/101 (18.8%)	19
incision site swelling	42/203 (20.7%)	42	19/101 (18.8%)	19
post procedural discharge	15/203 (7.4%)	15	6/101 (5.9%)	6
Nervous system disorders
dizziness	31/203 (15.3%)	31	12/101 (11.9%)	12
dysgeusia	14/203 (6.9%)	14	3/101 (3%)	3
somnolence	36/203 (17.7%)	36	20/101 (19.8%)	20
Psychiatric disorders
restlessness	14/203 (6.9%)	14	9/101 (8.9%)	9

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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