A RCT Evaluating Efficacy of Type-I Collagen Skin Substitute vs. Human Amnion Membrane in Treatment of Venous Leg Ulcers

A Randomized, Controlled Clinical Trial Evaluating the Efficacy of Type-I Collagen-based Skin Substitute vs. Dehydrated Human Amnion/Chorion Membrane in the Treatment of Venous Leg Ulcers

Venous leg ulcers are chronic wounds caused by venous insufficiency, leading to significant morbidity. The purpose of this randomized, controlled study is to evaluate the safety and efficacy of the application of Type-I Collagen-based Skin Substitute (HPTC) vs. Dehydrated Human Amnion/Chorion Membrane (dHCAM) in the treatment of VLUs and to compare their efficacy.

Study Overview

• Status: Completed
• Conditions: Venous Leg Ulcers
• Intervention / Treatment: Device: SOC and Type-I Collagen-based Skin Substitute; Device: SOC and Human Amnion/Chorion Membrane

Detailed Description

Venous leg ulcers (VLUs) are chronic wounds caused by venous insufficiency, leading to significant morbidity. Current treatment options often include compression therapy, wound debridement, and advanced dressings. Despite advances in wound care, effective treatment remains challenging. The purpose of this randomized, controlled study is to evaluate the safety and efficacy of the application of Type-I Collagen-based Skin Substitute (HPTC) vs. Dehydrated Human Amnion/Chorion Membrane (dHCAM) in the treatment of VLUs and to compare the efficacy of these two advanced wound care modalities in accelerating VLU healing.

• Study Type: Interventional
• Enrollment (Actual): 60
• Phase: Not Applicable

Contacts and Locations

Study Locations

• India
  • Karnataka
    • Mandya, Karnataka, India, 571448
      • Adichunchanagiri Institute of Medical Sciences

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Subjects must be at least 18 years of age or older.
2. Subjects must have a diagnosis of a venous leg ulcer (confirmed by clinical and duplex ultrasound evaluation).
3. At enrolment subjects must have a target VLU with a minimum surface area of 2.0 cm2 and a maximum surface area of 25.0 cm2 measured post debridement using a ruler to measure wound area.
4. The target ulcer must have been present for a minimum of 4 weeks and a maximum of 52 weeks of standard of care prior to the initial screening visit.
5. The target ulcer must be located on the foot, ankle and lower leg region.
6. The target ulcer must be full thickness on the foot or ankle that does not probe to bone.
7. Adequate circulation to the affected foot as documented by any of the following methods performed within 3 months of the first screening visit:

i. TCOM ≥30 mmHg ii. ABI between 0.7 and 1.3 iii. PVR: Biphasic iv. TBI ˃0.6 v. As an alternative arterial, Doppler ultrasound can be performed evaluating for biphasic dorsalis pedis and posterior tibial vessels at the level of the ankle of the target extremity.

h. If the subject has two or more ulcers, they must be separated by at least 2 cm. The largest ulcer satisfying the inclusion and exclusion criteria will be designated as the target ulcer.

i. The subject must consent to using the prescribed off-loading method for the duration of the study.

j. The subject must agree to attend the twice-weekly/weekly study visits required by the protocol.

k. The subject must be willing and able to participate in the informed consent process.

l. Patients must have read and signed the IRB approved ICF before screening procedures are undertaken.

Exclusion Criteria:

1. A subject known to have a life expectancy of <6 months
2. If the target ulcer is infected or if there is cellulitis in the surrounding skin.
3. Presence of osteomyelitis or exposed bone, probes to bone or joint capsule on investigator's exam or radiographic evidence.
4. A subject that has an infection in the target ulcer that requires systemic antibiotic therapy.
5. A subject receiving immunosuppressants (including systemic corticosteroids at doses greater than 10 mg of Prednisone per day or equivalent) or cytotoxic chemotherapy.
6. Topical application of steroids to the ulcer surface within one month of initial screening.
7. A subject with a previous partial amputation on the affected foot is excluded if the resulting deformity impedes proper offloading of the target ulcer.
8. A subject with autoimmune or connective tissue disorders.
9. A subject with malignant wounds or non-venous ulcers.
10. A subject with a serum creatinine ≥ 3.0mg/dL within 6 months of the initial screening visit.
11. Women who are pregnant or considering becoming pregnant within the next 6 months and those who are breast feeding.
12. A subject with end stage renal disease requiring dialysis.
13. A subject who participated in a clinical trial involving treatment with an investigational product within the previous 30 days.
14. A subject who, in the opinion of the Investigator, has a medical or psychological condition that may interfere with study assessments.
15. A subject treated with hyperbaric oxygen therapy or a Cellular and/or Tissue Product (CTP) in the 30 days prior to the initial screening visit.
16. History of autoimmune disease, malignancy, or uncontrolled diabetes (HbA1c >10%).
17. Allergy to components of High Purity Type-I Collagen-based Skin Substitute or Dehydrated Human Amnion/Chorion Membrane.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: SOC and Type-I Collagen-based Skin Substitute; The SOC in this study is wound care covering with High Purity Type-I Collagen-based Skin Substitute applied weekly or as needed followed by a padded 3-layer dressing	Device: SOC and Type-I Collagen-based Skin Substitute; The SOC in this study is wound care covering with High Purity Type-I Collagen-based Skin Substitute applied weekly or as needed followed by a padded 3-layer dressing comprised of first layer - non-adherent and porous, second layer - absorbent 4x4 gauze pads & third layer - soft roll and compressive wrap
Other: SOC and Human Amnion/Chorion Membrane; The SOC in this study is wound care covering with Dehydrated Human Amnion/Chorion Membrane followed by a padded 3-layer dressing	Device: SOC and Human Amnion/Chorion Membrane; The SOC in this study is wound care covering with Dehydrated Human Amnion/Chorion Membrane followed by a padded 3-layer dressing comprised of first layer - non-adherent and porous, second layer - absorbent 4x4 gauze pads & third layer - soft roll and compressive wrap

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage Wound Area Change	Percentage wound area change from week 1 through week 7 measured manually with digital photography	7 Weeks
Histopathological Parameters - Vascular Infiltration	Histopathological Assessment - Before application and on the 5th day post-application of either HPTC or dHCAM, a 2mm punch biopsy was obtained from the wound edge extending into the wound bed under local anaesthesia. Serial sections of 4μm thickness were prepared and stained with Hematoxylin and Eosin (H&E) for general morphology. Vascular Infiltration: Assessed by counting new blood vessels per High Power Field (hpf) (0-3 scale) 0: Minimal vascular ingrowth (<5 vessels/hpf); Mild infiltration (5-10 vessels/hpf); Moderate infiltration (11-20 vessels/hpf); Abundant infiltration (>20 vessels/hpf) (0-worse; 3-better)	5 days
Histopathological Parameters - Neo-epithelialization	Before application and on the 5th day post-application of either HPTC or dHCAM, a 2mm punch biopsy was obtained from the wound edge extending into the wound bed under local anaesthesia. Serial sections of 4μm thickness were prepared and stained with: Hematoxylin and Eosin (H&E) for general morphology. Neo-epithelialization: Measured as epithelial migration distance from wound edge (0-3 scale) 0: No epithelial migration; Minimal migration (<25% wound coverage); Moderate migration (25-75% coverage); Extensive migration (>75% coverage) (0-worse; 3-better)	5 days
Histopathological Parameters - Fibroblast Activity	Before application and on the 5th day post-application of either HPTC or dHCAM, a 2mm punch biopsy was obtained from the wound edge extending into the wound bed under local anaesthesia. Serial sections of 4μm thickness were prepared and stained with: α-SMA immunohistochemistry for fibroblast activity. Fibroblast Activity: Quantified by counting α-SMA positive fibroblasts per HPF and assessment of fibroblast morphology (0-3 scale) 0: Sparse, inactive fibroblasts; Moderate cellularity, minimal matrix production; High cellularity, active-matrix synthesis; Very high activity with extensive matrix deposition (0-worse; 3-better)	5 Days
Histopathological Parameters - Capillary Density	Histopathological Assessment - Before application and on the 5th day post-application of either HPTC or dHCAM, a 2mm punch biopsy was obtained from the wound edge extending into the wound bed under local anaesthesia. Serial sections of 4μm thickness were prepared and stained with: CD31 immunohistochemistry for capillary density evaluation Capillary Density: Evaluated using CD31 staining, counted as vessels per mm² of tissue	5 days
Histopathological Parameters - Inflammatory Response	Histopathological Assessment - Before application and on the 5th day post-application of either HPTC or dHCAM, a 2mm punch biopsy was obtained from the wound edge extending into the wound bed under local anaesthesia. Serial sections of 4μm thickness were prepared and stained with: Hematoxylin and Eosin (H&E) for general morphology Inflammatory Response: Graded semi-quantitatively (0-3 scale) 0: Minimal inflammatory infiltrate; Mild chronic inflammation; Moderate mixed inflammation; Severe acute inflammation (0-worse; 3-better)	5 days
Histopathological Parameters - Collagen Deposition	Histopathological Assessment - Before application and on the 5th day post-application of either HPTC or dHCAM, a 2mm punch biopsy was obtained from the wound edge extending into the wound bed under local anaesthesia. Serial sections of 4μm thickness were prepared and stained with: Masson's Trichrome for collagen assessment Collagen Deposition: Assessed using Masson's Trichrome staining (0-3 scale) 0: Minimal collagen matrix; Loose, immature collagen; Moderate organized collagen; Dense, mature collagen architecture (0-worse; 3-better)	5 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to Achieve Complete Wound Closure	The time to achieve complete wound closure of the target ulcer by the end of 7 weeks	7 weeks
Percentage of Subjects to Obtain Complete Closure	The percentage of subjects that obtain complete closure over the 7 week treatment period	7 Weeks
Number of Patients Requiring Repeated Application	Number of patients requiring repeated applications of the Advanced Skin Substitute & Human Amnion/Chorion Membrane used to obtain wound closure	6 Weeks
Intervention Related Adverse Events	Number of participants with intervention related adverse events related to the intervention (e.g., infection, allergic reactions)	6 Weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Pain	Change in pain measured by a Visual Analog Scale with score range from 0 to 10, wherein 0="no pain" to 10="severe pain"	7 weeks including 1-week follow-up
Improvement in Quality of Life	Change in quality of life assessed using the Wound-QoL questionnaire measured as 'not at all', 'a little', 'moderately', 'quite a lot' and 'very much' for 17 questions and total number of patients who reported improvement in Quality of Life was measured	7 weeks including 1-week follow-up
Healed Wound Appearance Assessment Using Manchester Scar Scale	The resultant new skin is assessed and documented at each visit using the Manchester Scar Scale (MSS) assessing: Colour: Perfect - 1, Slight mismatch - 2, Obvious mismatch - 3, Gross mismatch - 4; Finish: Matte - 1, Shiny - 2; Contour: Flush with surrounding skin - 1, Slightly proud / indented - 2, Hypertrophic - 3, Keloid - 4; Distortion: None -1, Mild - 2, Moderate - 3, Severe - 4 Lower score denotes a better outcome using the MSS (range: 4-14). In the study, scores were categorized as such: Excellent: Scores 4 and 5; Good: Scores from 6 to 8; Fair: Scores from 9 to 11; Poor: Scores from 12 to 14	7 weeks including 1-week follow-up

Collaborators and Investigators

• Sponsor: Dr Naveen Narayan MS, MCh (Plastic Surgery)
• Investigators: Study Chair: Prema Dhanraj, MS, MCh, Rajarajeshwari Medical College and Hospital

Publications and helpful links

General Publications

• Serena TE, Carter MJ, Le LT, Sabo MJ, DiMarco DT; EpiFix VLU Study Group. A multicenter, randomized, controlled clinical trial evaluating the use of dehydrated human amnion/chorion membrane allografts and multilayer compression therapy vs. multilayer compression therapy alone in the treatment of venous leg ulcers. Wound Repair Regen. 2014 Nov-Dec;22(6):688-93. doi: 10.1111/wrr.12227. Epub 2015 Jan 8.
• Bianchi C, Cazzell S, Vayser D, Reyzelman AM, Dosluoglu H, Tovmassian G; EpiFix VLU Study Group. A multicentre randomised controlled trial evaluating the efficacy of dehydrated human amnion/chorion membrane (EpiFix(R) ) allograft for the treatment of venous leg ulcers. Int Wound J. 2018 Feb;15(1):114-122. doi: 10.1111/iwj.12843. Epub 2017 Oct 11.
• Narayan N, Gowda S, Shivannaiah C. A Randomized Controlled Clinical Trial Comparing the Use of High Purity Type-I Collagen-Based Skin Substitute vs. Dehydrated Human Amnion/Chorion Membrane in the Treatment of Diabetic Foot Ulcers. Cureus. 2024 Dec 5;16(12):e75182. doi: 10.7759/cureus.75182. eCollection 2024 Dec.

Study record dates

Study Major Dates

• Study Start (Actual): February 1, 2025
• Primary Completion (Actual): June 30, 2025
• Study Completion (Actual): July 10, 2025

Study Registration Dates

• First Submitted: January 27, 2025
• First Submitted That Met QC Criteria: February 16, 2025
• First Posted (Actual): February 18, 2025

Study Record Updates

• Last Update Posted (Actual): September 22, 2025
• Last Update Submitted That Met QC Criteria: September 19, 2025
• Last Verified: September 1, 2025

More Information

Terms related to this study

• Keywords: leg ulcer; venous leg ulcer; skin substitute; chronic leg ulcer; high purity type-I collagen; dehydrated human amnion / chorion membrane
• Additional Relevant MeSH Terms: Vascular Diseases; Cardiovascular Diseases; Skin Diseases; Skin Ulcer; Varicose Veins; Skin and Connective Tissue Diseases; Varicose Ulcer; Leg Ulcer
• Other Study ID Numbers: AIMS/IEC/004/2025

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• 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.: Yes