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Trial registered on ANZCTR


Registration number
ACTRN12624001342505
Ethics application status
Approved
Date submitted
22/10/2024
Date registered
5/11/2024
Date last updated
5/11/2024
Date data sharing statement initially provided
5/11/2024
Type of registration
Prospectively registered

Titles & IDs
Public title
A Prospective, Open-Label, Randomized, Controlled Post-Market Clinical Trial Investigating the Safety and Effectiveness of Human Amnion Membrane (AM) in a Cohort of Patients with Loss of Full Thickness Skin Graft Following Reconstruction of a Cutaneous Nasal Defect Secondary to Skin Cancer Resection.
Scientific title
A Prospective, Open-Label, Randomized, Controlled Post-Market Clinical Trial Investigating the Safety and Effectiveness of Human Amnion Membrane (AM) in a Cohort of Patients with Loss of Full Thickness Skin Graft Following Reconstruction of a Cutaneous Nasal Defect Secondary to Skin Cancer Resection.
Secondary ID [1] 313211 0
Nil known
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Failed full thickness skin graft following resection of a cutaneous nasal defect 335512 0
skin cancer 335587 0
Condition category
Condition code
Skin 332068 332068 0 0
Other skin conditions
Other 332069 332069 0 0
Research that is not of generic health relevance and not applicable to specific health categories listed above
Surgery 332157 332157 0 0
Other surgery
Inflammatory and Immune System 332158 332158 0 0
Other inflammatory or immune system disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
An amnion membrane allograft (Revita® Full Thickness Native Placental Membrane) will be used to aid with epithelization and revascularization of failed nasal skin grafts. Firstly, the nasal wound bed will be debrided and excoriated material from the previous failed graft removed. When the amniotic membrane has been appropriately sized and correctly orientated, it will be transplanted into the wound bed and secured with Hypafix tape. A secondary dressing that enables moistened wound healing will be applied above the amnion membrane allograft. This intervention will be performed by an experienced study doctor at the Princess Alexandra Hospital.

After the procedure is complete, patients will be discharged following a review of their vital signs. Study participants will return to clinic at Day 6 (+/- 2) and Day 11 (+/- 2) after intervention, to have their outer dressing changed and the amnion bandage reviewed. At one month and 3 months post-operatively, the study participants will return for further assessments of the wound bed. Imaging investigations of the graft site will be conducted at each follow up visit using a 3D surface scanning device, along with a symptom-directed physical exam and collection of vital sign measures, concomitant medications, and adverse events. A final follow up visit will be conducted at three months after amnion membrane allograft transplant. At the End of Study visit, the wound bed will be assessed for epithelial repair and graft function.
1A. The duration of the debridement procedure including the amnion allograft will be approximately 30 minutes.
Wound review will occur at each follow up. This is a surgical intervention and not medical intervention and the patient will not be responsible for applying the treatment.
A registered nurse will change the dressings.
The dressing will take approximately 15 minutes to remove and change.
2C. A Study Investigator will conduct the 1 month and 3 month review.
The patient will not be responsible for applying the surgical intervention. Safety and effectiveness will be assessed from adverse events, concomitant illnesses, concomitant medications and devices, physical exam findings, clinical pathology results, quality of life questionnaires, wound review observations including surface scanning and clinical photographs.
Intervention code [1] 329786 0
Treatment: Devices
Intervention code [2] 329843 0
Treatment: Surgery
Comparator / control treatment
At the time of screening, study participants will be randomized to receive active treatment with an amnion membrane allograft or standard of care. Those receiving standard of care will make up the active control group. Participants randomized to the control group will have their wound debrided and dressed by a study doctor at the Princess Alexandra Hospital. Wound management for the control group will include covering the open surface with a thin layer of sterile white paraffin gel which will be covered with sterile gauze and fixed in place with Hypafix tape.
Control group
Active

Outcomes
Primary outcome [1] 339679 0
Change in epithelization.
Timepoint [1] 339679 0
Primary outcome measure assessed cumulatively over a 3-month period using clinical photos and 3D surface scans completely at Day 6 (+/- 2 days), Day 11 (+/- 2 days), Day 28 (+/- 5 days) and Day 90 (+/- 10 days)
Secondary outcome [1] 440851 0
Change in cosmetic and functional nasal outcomes (including nasal obstruction) as a composite outcome measure. The SCHNOS survey includes assessment of symmetry, shape, straightness as well as functional outcomes pertaining to capacity to breath at rest and during exercise, nasal obstruction and congestion.
Timepoint [1] 440851 0
Assessed at Day 1, Day 6+/-2, Day 11 +/-2, Day 28 +/-5 and at the end of study (day 90).

Secondary outcome [2] 440852 0
Change in general well-being and activities of daily living as a composite outcome measure
Timepoint [2] 440852 0
Assessed at Day 1, Day 6+/-2, Day 11+/-2, Day 28+/-5 and Day 90.

Eligibility
Key inclusion criteria
1. Patients who are 18 years or older.
2. Fluent in written and spoken English and in a position to provide written informed consent to participate without the need of a SHA.
3. Southeast Queensland (SEQ)-based resident who can attend all scheduled follow up visits after their amnion allograft intervention.
4. Within 3 months of a failed full thickness skin graft (FTSG) characterised by ongoing pain, numbness, erythema, oedema where this clear tissue breakdown and a presence of necrotic eschar.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. A concurrent condition that may limit the decision-making capabilities of the participant during the informed consent process.
2. Head and neck radiation treatment within the last 6 months.
3. A positive diagnosis of Human Immunodeficiency Virus (HIV) or Hepatitis C Virus (HCV with confirmation by polymerase chain reaction diagnostic methods) or Hepatitis B Virus (HBV) infection or IgM positive results to Human Cytomegalovirus (HCMV) or IgM positive results for Epstein Barr Virus (EBV) or Human T Cell Lymphotropic Virus (HTLV-1).
4. Chronic immunosuppression either as a function of current management for pre-existing autoimmune, autoinflammatory, solid organ transplantation or other haematological condition.
5. Acute or chronic graft versus host disease.
6. Uncontrolled Type 1 or type 2 diabetes.
7. Past history of carcinoma (within the last 5 years) not including focal squamous cell carcinoma, melanoma or basal cell carcinoma of the skin that is fully resolved following surgical or medical intervention.
8. Uncontrolled systemic hypertension (>180/110 mmHg) at the screening visit.
9. A genetic condition that is known to impact the connective tissue and affect wound healing characteristics such as Loeys-Dietz, Ehlers-Danlos Syndrome
10. A history of severe allergies which has resulted in previous anaphylactic incidents.
11. A hypersensitivity response to the amnion allograft intervention or similar biological product.
12. Fever and other signs and symptoms of concurrent infection – either focal or systemic
13. Recent travel (within the last 3 months) to areas where exposure to parasites or other infectious agents is highly likely.
14. Serum Alanine Transaminase (ALT) or Aspartate Amino Transferase (AST) ?3-fold the upper limit of normal (ULN) or AST/ALT ratio > 2 ULN or Bilirubin ?2-fold the upper limit of normal at the screening visit.
15. Severe renal impairment where creatinine clearance <30mL/minute at the time of screening based on recent clinical chemistry results.
16. Major elective surgery scheduled during active treatment intervention and follow up.
17. Concurrent enrolment in another interventional (drug or device) clinical trial whilst enrolled in this clinical trial (i.e., between screening and the last follow up visit).
18. Clinically significant medical conditions including but not limited to cardiovascular, neurological, psychiatric, renal, hepatic, haematological or endocrine pathology that in the investigator’s opinion are uncontrolled, severe or end-stage and likely to affect the patient’s ability to comply with the study requirements.
19. Grade III obesity (BMI equal to, or greater than 40) with metabolic syndrome.
20. Social factors that may likely affect the capacity of patient to attend regular study visits as per the schedule of events.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Allocation is not concealed
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation using a computer-generated sequence.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Not Applicable
Type of endpoint/s
Efficacy
Statistical methods / analysis
As this is a novel indication given amnion membrane is not traditionally used as part of the plastic and reconstructive surgical management of failed full thickness skin grafting and, there has been no published literature applying this product or similar in a manner consistent with this trial, it is not feasible to provide an accurate sample size estimate. However, applying industry standards for smaller proof of concept/principle studies, a sample size of 33 participants is considered sufficient to avoid bias and a Type I error. Additionally, the sample size consideration is also based on the minimal clinically important difference expected in epithelization surface area between the active treatment (placental membrane bandage) and standard of care treatment cohorts. Assuming a difference in the effect size of 20% within the 3-month follow up from baseline/screening with a 90% power of detecting change in epithelization and including other conservative constructs such that the test is two-sided with a significance level of 0.05 and the within participant covariance matrix is unstructured and that Bonferroni correction is applied with 15% lost to follow up, a study population of 28 is required to determine the effectiveness of placental membrane bandage in FTSG procedures.
Primary and secondary effectiveness outcomes will be evaluated using data collected from the ITT population. All effectiveness data will be assessed for normality and if necessary, log-transformed, or similar prior to further statistical assessment. A restricted effectiveness analysis set (as per protocol) will be constructed to excluded clinically significant protocol deviations and violations. The per protocol set will also be applied to conduct additional sensitivity analyses.
Assertions of effectiveness will be based upon the study hypothesis (H1) that participants receiving amnion allograft intervention will result in a clinically and statistically significant improvement in wound healing compared with failed FTSG participants receiving standard of care. The amnion allograft intervention is not a replacement to healing by primary intention; it is a biological device designed to expedite healing by secondary intention.
An analysis of covariance (ANCOVA) will be applied to ITT datasets to determine whether at least a single amnion allograft intervention provides superior wound healing in terms of duration (in days) to closure as well as physiological tissue remodelling by way of qualitative review of granulation status. Co-primary endpoints which incorporate quantitative change in wound surface area relative to baseline and qualitative change in wound healing from the Vancouver Scar Scale (VSS; Sullivan et al, 1990) and the Wound Score of Granulation Tissue (Cooper DM, 1990) will be incorporated into the statistical model. To preserve statistical power and the Type I error at 0.05 parallel gatekeeping strategies (Wang et al, 2022) will be applied to account for composite primary outcome measures. This model incorporates treatment effect size and baseline covariates, where a Bonferroni correction will be applied for analysis of repeated measures as a function of time. The mean change at each visit from baseline for composite imaging measures for each amnion allograft intervention will be compared with those from the SoC cohort. Similar statistical modelling will be applied for assessment of the secondary (effectiveness) outcome measures for the purpose of determining the relationship between wound healing outcomes and quality of life / activities of daily living (SF-36) as well as patient reported cosmetic change (SCHNOS).
Cost-effectiveness will also be considered, more from an exploratory perspective, in terms of evaluating and comparing the overall cost of care at the out-patient clinic between cohorts, including any in-patient admissions they may have during the 3-month follow up phase. These considerations are relevant given the amnion allograft is an approved biological product for this broad wound care indication. If determined to be an effective treatment, health economic considerations will need to be provided for this product to be implement as a standard of care intervention, even if for specific sub-populations.
Two interim analyses will be conducted during the trial. The initial interim analysis will occur after the first 12 participants have attended an interventional treatment. A further interim analysis will conducted after 20 participants have completed their end of study visit. Effectiveness and safety outcome measures will be assessed for both interim assessments. These analyses will not impact statistical power as there is not intent to stop the trial early for regulatory purposes.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
11/11/2024
Actual
Date of last participant enrolment
Anticipated
1/08/2025
Actual
Date of last data collection
Anticipated
28/11/2025
Actual
Sample size
Target
33
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
QLD
Recruitment hospital [1] 27257 0
Princess Alexandra Hospital - Woolloongabba
Recruitment postcode(s) [1] 43344 0
4102 - Woolloongabba

Funding & Sponsors
Funding source category [1] 317653 0
Government body
Name [1] 317653 0
Metro South Health Research Support Scheme Grant
Country [1] 317653 0
Australia
Primary sponsor type
Hospital
Name
Princess Alexandra Hospital
Address
Country
Australia
Secondary sponsor category [1] 319988 0
None
Name [1] 319988 0
Address [1] 319988 0
Country [1] 319988 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 316355 0
Metro North Health Human Research Ethics Committee A
Ethics committee address [1] 316355 0
Ethics committee country [1] 316355 0
Australia
Date submitted for ethics approval [1] 316355 0
27/05/2024
Approval date [1] 316355 0
12/07/2024
Ethics approval number [1] 316355 0
108865

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 137626 0
Dr Allison Sutherland
Address 137626 0
Australian Centre for Complex Integrated Surgical Solutions. 199 Ipswich Rd, Wooloongabba, Queensland, 4102
Country 137626 0
Australia
Phone 137626 0
+61423684659
Fax 137626 0
Email 137626 0
allison.sutherland@health.qld.gov.au
Contact person for public queries
Name 137627 0
Jaimee-Lee Wood
Address 137627 0
Australian Centre for Complex Integrated Surgical Solutions. 199 Ipswich Rd, Wooloongabba, Queensland, 4102
Country 137627 0
Australia
Phone 137627 0
+61418665349
Fax 137627 0
Email 137627 0
jaimee-lee.wood@health.qld.gov.au
Contact person for scientific queries
Name 137628 0
Allison Sutherland
Address 137628 0
Australian Centre for Complex Integrated Surgical Solutions. 199 Ipswich Rd, Wooloongabba, Queensland, 4102
Country 137628 0
Australia
Phone 137628 0
+61423684659
Fax 137628 0
Email 137628 0
allison.sutherland@health.qld.gov.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
24290Study protocol  jaimee-lee.wood@health.qld.gov.au
24291Informed consent form  jaimee-lee.wood@health.qld.gov.au



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.