AMNIOEXCEL® Plus vs A Marketed Comparator vs SOC in the Management of Diabetic Foot Ulcers

• Sponsor: Integra LifeSciences Corporation (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03547635
• Collaborator: (none)
• Enrollment: 116
• Locations: 7
• Arms: 3
• Actual Duration (Months): 9.8
• Patients Per Site: 16.6
• Patients Per Site Per Month: 1.7

Study Details

Study Description

Brief Summary

This is a multicenter, randomized, parallel-group study comparing the outcomes associated with the use of AMNIOEXCEL Plus Placental Allograft Membrane, a marketed comparator and SOC alone in the management of diabetic foot ulcers (DFUs).

Condition or Disease	Intervention/Treatment	Phase
Diabetic Foot Ulcer	Other: AMNIOEXCEL Plus Amniotic Membrane; Device: A Marketed Comparator; Other: Standard of Care	N/A

Study Design

• Study Type: Interventional
• Actual Enrollment: 116 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: This is a multicenter, randomized, parallel-group study comparing the outcomes associated with the use of AMNIOEXCEL Plus Placental Allograft Membrane, a marketed comparator and SOC alone in the management of diabetic foot ulcers (DFUs).This is a multicenter, randomized, parallel-group study comparing the outcomes associated with the use of AMNIOEXCEL Plus Placental Allograft Membrane, a marketed comparator and SOC alone in the management of diabetic foot ulcers (DFUs).
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Prospective, Multi-Center, Randomized, Parallel-group Study Comparing AMNIOEXCEL Plus Placental Allograft Membrane to a Marketed Comparator and Standard of Care Procedures in the Management of Diabetic Foot Ulcers
• Actual Study Start Date: May 3, 2018
• Actual Primary Completion Date: Feb 26, 2019
• Actual Study Completion Date: Feb 26, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: AMNIOEXCEL Plus Amniotic Membrane	Other: AMNIOEXCEL Plus Amniotic Membrane; AMNIOEXCEL Plus is a human placental-based tissue consisting of dehydrated, tri-layer Placental (Amnion/Chorion/Amnion) Allograft Membrane (T-PAM) layers. T-PAM is a minimally manipulated placental membrane product made from tissues donated by pre-screened mothers during planned C-sections and is intended for use as a wound covering. This product is an allograft tissue intended for homologous use for the repair, reconstruction and replacement of skin at the direction of a physician. AMNIOEXCEL Plus contains Human Cellular and Tissue Based Products (HCT/P) as defined by US FDA 21 CFR Part 1271. All donor recoveries are performed by BioDlogics, LLC, and adhere to the regulations regarding HCT/P recovery and the screening and testing of the tissue donor as verified through supplier audits.
Active Comparator: A Marketed Comparator	Device: A Marketed Comparator; bi-layered skin substitute: the epidermal layer is formed by human keratinocytes and has a well-differentiated stratum corneum; the dermal layer is composed of human fibroblasts in a bovine Type I collagen lattice. It is indicated for use with standard therapeutic compression for the treatment of non-infected partial and full-thickness skin ulcers due to venous insufficiency of greater than 1-month duration and which have not adequately responded to conventional ulcer therapy. This product is also indicated for use with standard DFU care for the treatment of full-thickness neuropathic DFUs of greater than three weeks' duration which have not adequately responded to conventional ulcer therapy and which extend through the dermis but without tendon, muscle, capsule or bone exposure.; Other Names: Apligraf®
Other: Standard of Care	Other: Standard of Care; Coban™ Conforming gauze Optifoam® non-adhesive dressing Cotton Gauze Normal saline (liquid or gel) Non-adhering dressings Steristrips An offloading boot (Pneumatic Short Leg Walker), as appropriate

Outcome Measures

Primary Outcome Measures

1. The Number of Participants Meeting Criteria of Complete Wound Closure, as Assessed by the Investigator at or Before Week 12 of the Treatment Phase, Which is Confirmed Closed Two Weeks Later. [Wound closure assessed up to week 12 and confirmed 2 weeks later; only participants with wound closure at or before Week 12 and who maintained closure in follow-up reported]

   Complete wound closure is defined as complete skin re-epithelialization that is without drainage or dressing requirements.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 21 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Have participated in the informed consent process and signed a study-specific informed consent document.

2. Be able and willing to comply with study procedures, including study visits, study dressing regimens, and compliance with study required offloading device.

3. Be ≥ 21 years of age.

4. Have Type I or Type II diabetes mellitus with Investigator-confirmed glycosylated hemoglobin (HbA1c) of ≤ 12%.

5. Have at least one diabetic foot ulcer Ulcer size (i.e., area) is > 1 cm2 and < 12 cm2.

6. Have adequate vascular perfusion of the affected limb

Exclusion Criteria:

1. The subject was previously randomized and treated under this clinical study protocol.

2. The study ulcer has features that necessitates surgical operating-room debridement and/or penetrates to capsule/tendon/bone.

3. The subject is unable to safely ambulate with the use of a study required offloading boot.

4. The subject has suspected or confirmed gangrene or wound infection of the study ulcer.

5. The subject has suspected or confirmed osteomyelitis.

6. In the opinion of the Investigator, the subject has received or is scheduled to receive during study participation, a medication or treatment which is known to interfere with or affect the rate and quality of wound healing

7. The subject has a history of bone cancer or metastatic disease of the affected limb, radiation therapy to the foot, or has had chemotherapy prior to signing the Informed Consent Form for trial participation.

8. The subject is currently pregnant or is actively trying to conceive.

9. In the opinion of the Investigator, the subject is unable to comply with the treatment regimen

10. In the opinion of the Investigator, the subject has a history of, or is currently diagnosed with, any illness or condition, other than diabetes, that could interfere with wound healing.

11. In the opinion of the Investigator, the subject has a condition that could inhibit wound healing.

12. The subject has ulcers secondary to a disease other than diabetes.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	California 1	Fresno	California	United States	93710
2	California 3	Fresno	California	United States	93710
3	California 2	Los Angeles	California	United States	90063
4	Georgia 1	Gainesville	Georgia	United States	30501
5	Illinois 1	Springfield	Illinois	United States	62704
6	New Jersey 1	Toms River	New Jersey	United States	08753
7	Texas 1	San Antonio	Texas	United States	78229

Sponsors and Collaborators

• Integra LifeSciences Corporation

Investigators

• Study Director: Jessica Knowlton, MS CRA, Integra LifeSciences Corporation

Study Documents (Full-Text)

• Study Protocol - Nov 5, 2018
• Statistical Analysis Plan - Jun 18, 2019

More Information

Publications

• Martinson M, Martinson N. A comparative analysis of skin substitutes used in the management of diabetic foot ulcers. J Wound Care. 2016 Oct 1;25(Sup10):S8-S17. doi: 10.12968/jowc.2016.25.Sup10.S8.
• Snyder RJ, Cardinal M, Dauphinée DM, Stavosky J. A post-hoc analysis of reduction in diabetic foot ulcer size at 4 weeks as a predictor of healing by 12 weeks. Ostomy Wound Manage. 2010 Mar 1;56(3):44-50.
• Snyder RJ, Shimozaki K, Tallis A, Kerzner M, Reyzelman A, Lintzeris D, Bell D, Rutan RL, Rosenblum B. A Prospective, Randomized, Multicenter, Controlled Evaluation of the Use of Dehydrated Amniotic Membrane Allograft Compared to Standard of Care for the Closure of Chronic Diabetic Foot Ulcer. Wounds. 2016 Mar;28(3):70-7.

• Responsible Party: Integra LifeSciences Corporation
• ClinicalTrials.gov Identifier: NCT03547635
• Other Study ID Numbers: T-AEPDFU-001
• First Posted: Jun 6, 2018
• Last Update Posted: Jul 20, 2020
• Last Verified: Jul 1, 2020

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: Yes
• Product Manufactured in and Exported from the U.S.: No
• Additional relevant MeSH terms: Diabetic Foot; Foot Ulcer; Ulcer

Study Results

Participant Flow

Arm/Group Title	AMNIOEXCEL Plus Amniotic Membrane	A Marketed Comparator	Standard of Care
Arm/Group Description	AMNIOEXCEL Plus Amniotic Membrane: AMNIOEXCEL Plus is a human placental-based tissue consisting of dehydrated, tri-layer Placental (Amnion/Chorion/Amnion) Allograft Membrane (T-PAM) layers. T-PAM is a minimally manipulated placental membrane product made from tissues donated by pre-screened mothers during planned C-sections and is intended for use as a wound covering. This product is an allograft tissue intended for homologous use for the repair, reconstruction and replacement of skin at the direction of a physician. AMNIOEXCEL Plus contains Human Cellular and Tissue Based Products (HCT/P) as defined by US FDA 21 CFR Part 1271. All donor recoveries are performed by BioDlogics, LLC, and adhere to the regulations regarding HCT/P recovery and the screening and testing of the tissue donor as verified through supplier audits.	A Marketed Comparator: bi-layered skin substitute: the epidermal layer is formed by human keratinocytes and has a well-differentiated stratum corneum; the dermal layer is composed of human fibroblasts in a bovine Type I collagen lattice. It is indicated for use with standard therapeutic compression for the treatment of non-infected partial and full-thickness skin ulcers due to venous insufficiency of greater than 1-month duration and which have not adequately responded to conventional ulcer therapy. This product is also indicated for use with standard DFU care for the treatment of full-thickness neuropathic DFUs of greater than three weeks' duration which have not adequately responded to conventional ulcer therapy and which extend through the dermis but without tendon, muscle, capsule or bone exposure.	Standard of Care: • Coban™ Conforming gauze Optifoam® non-adhesive dressing Cotton Gauze Normal saline (liquid or gel) Non-adhering dressings Steristrips An offloading boot (Pneumatic Short Leg Walker), as appropriate
Period Title: Overall Study
STARTED	41	38	37
COMPLETED	33	31	29
NOT COMPLETED	8	7	8

Baseline Characteristics

Arm/Group Title	AMNIOEXCEL Plus Amniotic Membrane	A Marketed Comparator	Standard of Care	Total
Arm/Group Description	AMNIOEXCEL Plus Amniotic Membrane: AMNIOEXCEL Plus is a human placental-based tissue consisting of dehydrated, tri-layer Placental (Amnion/Chorion/Amnion) Allograft Membrane (T-PAM) layers. T-PAM is a minimally manipulated placental membrane product made from tissues donated by pre-screened mothers during planned C-sections and is intended for use as a wound covering. This product is an allograft tissue intended for homologous use for the repair, reconstruction and replacement of skin at the direction of a physician. AMNIOEXCEL Plus contains Human Cellular and Tissue Based Products (HCT/P) as defined by US FDA 21 CFR Part 1271. All donor recoveries are performed by BioDlogics, LLC, and adhere to the regulations regarding HCT/P recovery and the screening and testing of the tissue donor as verified through supplier audits.	A Marketed Comparator: bi-layered skin substitute: the epidermal layer is formed by human keratinocytes and has a well-differentiated stratum corneum; the dermal layer is composed of human fibroblasts in a bovine Type I collagen lattice. It is indicated for use with standard therapeutic compression for the treatment of non-infected partial and full-thickness skin ulcers due to venous insufficiency of greater than 1-month duration and which have not adequately responded to conventional ulcer therapy. This product is also indicated for use with standard DFU care for the treatment of full-thickness neuropathic DFUs of greater than three weeks' duration which have not adequately responded to conventional ulcer therapy and which extend through the dermis but without tendon, muscle, capsule or bone exposure.	Standard of Care: • Coban™ Conforming gauze Optifoam® non-adhesive dressing Cotton Gauze Normal saline (liquid or gel) Non-adhering dressings Steristrips An offloading boot (Pneumatic Short Leg Walker), as appropriate	Total of all reporting groups
Overall Participants	41	38	37	116
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	57.2 (11.32)	60.5 (11.10)	59.6 (11.03)	59.1 (11.14)
Sex: Female, Male (Count of Participants)
Female	16 39%	13 34.2%	6 16.2%	35 30.2%
Male	25 61%	25 65.8%	31 83.8%	81 69.8%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	14 34.1%	18 47.4%	20 54.1%	52 44.8%
Not Hispanic or Latino	27 65.9%	20 52.6%	17 45.9%	64 55.2%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%
Black or African American	4 9.8%	1 2.6%	1 2.7%	6 5.2%
White	37 90.2%	37 97.4%	36 97.3%	110 94.8%
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]
United States	41 100%	38 100%	37 100%	116 100%

Outcome Measures

1. Primary Outcome

Title	The Number of Participants Meeting Criteria of Complete Wound Closure, as Assessed by the Investigator at or Before Week 12 of the Treatment Phase, Which is Confirmed Closed Two Weeks Later.
Description	Complete wound closure is defined as complete skin re-epithelialization that is without drainage or dressing requirements.
Time Frame	Wound closure assessed up to week 12 and confirmed 2 weeks later; only participants with wound closure at or before Week 12 and who maintained closure in follow-up reported

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	AMNIOEXCEL Plus Amniotic Membrane	A Marketed Comparator	Standard of Care
Arm/Group Description	AMNIOEXCEL Plus Amniotic Membrane: AMNIOEXCEL Plus is a human placental-based tissue consisting of dehydrated, tri-layer Placental (Amnion/Chorion/Amnion) Allograft Membrane (T-PAM) layers. T-PAM is a minimally manipulated placental membrane product made from tissues donated by pre-screened mothers during planned C-sections and is intended for use as a wound covering. This product is an allograft tissue intended for homologous use for the repair, reconstruction and replacement of skin at the direction of a physician. AMNIOEXCEL Plus contains Human Cellular and Tissue Based Products (HCT/P) as defined by US FDA 21 CFR Part 1271. All donor recoveries are performed by BioDlogics, LLC, and adhere to the regulations regarding HCT/P recovery and the screening and testing of the tissue donor as verified through supplier audits.	A Marketed Comparator: bi-layered skin substitute: the epidermal layer is formed by human keratinocytes and has a well-differentiated stratum corneum; the dermal layer is composed of human fibroblasts in a bovine Type I collagen lattice. It is indicated for use with standard therapeutic compression for the treatment of non-infected partial and full-thickness skin ulcers due to venous insufficiency of greater than 1-month duration and which have not adequately responded to conventional ulcer therapy. This product is also indicated for use with standard DFU care for the treatment of full-thickness neuropathic DFUs of greater than three weeks' duration which have not adequately responded to conventional ulcer therapy and which extend through the dermis but without tendon, muscle, capsule or bone exposure.	Standard of Care: • Coban™ Conforming gauze Optifoam® non-adhesive dressing Cotton Gauze Normal saline (liquid or gel) Non-adhering dressings Steristrips An offloading boot (Pneumatic Short Leg Walker), as appropriate
Measure Participants	41	38	37
Count of Participants [Participants]	12 29.3%	16 42.1%	8 21.6%

Adverse Events

Time Frame	Date of randomization through last treatment visit which could be on or before 12 weeks of treatment.
Adverse Event Reporting Description	Note: A subject in the Marketed Comparator group was randomized, but not treated. This subject was removed from the study by the investigator is not counted in the AE/SAE group.
Arm/Group Title	AMNIOEXCEL Plus Amniotic Membrane		A Marketed Comparator		Standard of Care
Arm/Group Description	AMNIOEXCEL Plus Amniotic Membrane: AMNIOEXCEL Plus is a human placental-based tissue consisting of dehydrated, tri-layer Placental (Amnion/Chorion/Amnion) Allograft Membrane (T-PAM) layers. T-PAM is a minimally manipulated placental membrane product made from tissues donated by pre-screened mothers during planned C-sections and is intended for use as a wound covering. This product is an allograft tissue intended for homologous use for the repair, reconstruction and replacement of skin at the direction of a physician. AMNIOEXCEL Plus contains Human Cellular and Tissue Based Products (HCT/P) as defined by US FDA 21 CFR Part 1271. All donor recoveries are performed by BioDlogics, LLC, and adhere to the regulations regarding HCT/P recovery and the screening and testing of the tissue donor as verified through supplier audits.		A Marketed Comparator: bi-layered skin substitute: the epidermal layer is formed by human keratinocytes and has a well-differentiated stratum corneum; the dermal layer is composed of human fibroblasts in a bovine Type I collagen lattice. It is indicated for use with standard therapeutic compression for the treatment of non-infected partial and full-thickness skin ulcers due to venous insufficiency of greater than 1-month duration and which have not adequately responded to conventional ulcer therapy. This product is also indicated for use with standard DFU care for the treatment of full-thickness neuropathic DFUs of greater than three weeks' duration which have not adequately responded to conventional ulcer therapy and which extend through the dermis but without tendon, muscle, capsule or bone exposure.		Standard of Care: • Coban™ Conforming gauze Optifoam® non-adhesive dressing Cotton Gauze Normal saline (liquid or gel) Non-adhering dressings Steristrips An offloading boot (Pneumatic Short Leg Walker), as appropriate
All Cause Mortality
	AMNIOEXCEL Plus Amniotic Membrane		A Marketed Comparator		Standard of Care
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/41 (0%)		0/37 (0%)		0/37 (0%)
Serious Adverse Events
	AMNIOEXCEL Plus Amniotic Membrane		A Marketed Comparator		Standard of Care
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/41 (4.9%)		1/37 (2.7%)		2/37 (5.4%)
General disorders
Pyrexia	0/41 (0%)	0	1/37 (2.7%)	1	0/37 (0%)	0
Infections and infestations
Diabetic Foot Infection	1/41 (2.4%)	1	0/37 (0%)	0	1/37 (2.7%)	1
Injury, poisoning and procedural complications
Fall	0/41 (0%)	0	0/37 (0%)	0	1/37 (2.7%)	1
Metabolism and nutrition disorders
Diabetic Ketoacidosis	1/41 (2.4%)	1	0/37 (0%)	0	0/37 (0%)	0
Other (Not Including Serious) Adverse Events
	AMNIOEXCEL Plus Amniotic Membrane		A Marketed Comparator		Standard of Care
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/41 (9.8%)		5/37 (13.5%)		9/37 (24.3%)
Infections and infestations
Cellulitis	2/41 (4.9%)	2	2/37 (5.4%)	2	3/37 (8.1%)	3
Diabetic Foot Infection	2/41 (4.9%)	2	3/37 (8.1%)	3	7/37 (18.9%)	7

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

Investigators are barred from publishing or disclosing results until a multicenter publication is published or until a period of 24 months after study completion passes, whichever comes first.