EctropionPhase 2NCT02705352
5-fluorouracil Versus Placebo in Periocular Full Thickness Skin Grafts
A Phase 2 study testing 5-Fluorouracil and Normal saline in people with Ectropion and Skin Neoplasms, run by Massachusetts Eye and Ear Infirmary at 1 site in United States.
Trial summary
Full thickness skin grafts are an essential tool in surgery around the eyelids for reconstruction or rehabilitation following injury or surgery. Common conditions where skin grafts are needed include cicatricial ectropion, restoration of eyelid function after tumor removal, burns to the eyelids, or trauma. Read more about this study
- Who is it for?
- Ages 18 to 89 years
- Conditions the study is for
- Ectropion, Skin Neoplasms
- What is being tested?
- 5-Fluorouracil and Normal saline
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 1 participants
- Where
- 1 siteUnited States
- Study dates
- 25 Aug 2016to 25 Jan 2019
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 89 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Outpatients
- Ages 18 to 89 years of age
- Has a condition (e.g. trauma, skin/tissue defect, scar) requiring a skin graft for repair
- Sufficient education to understand study procedures and to give consent
Who cannot join
- Women lactating, pregnant or planning to get pregnant in the near future
- Immunosuppression/immunocompromise or serious/active infections
- Dihydropyrimidine dehydrogenase enzyme deficiency
- Severe hepatic or renal impairment or failure
- Unable to give consent or understand the study
Trial locations and contacts
1 site in 1 country.
United States1 site
Massachusetts Eye and Ear Infirmary
Boston, Massachusetts, 02114
About this study
Official title: A Prospective, Randomized, Double-blinded Comparison of the Use of 5-fluorouracil Versus Placebo in Periocular Full Thickness Skin Grafts.
Full thickness skin grafts are an essential tool in surgery around the eyelids for reconstruction or rehabilitation following injury or surgery. Common conditions where skin grafts are needed include cicatricial ectropion, restoration of eyelid function after tumor removal, burns to the eyelids, or trauma. Early complications, occurring in the first 2 weeks after surgery, are rare: wound dehiscence, necrosis, infection, bleeding, partial or complete graft failure. However, late postoperative complications generally categorized as "scarring" (including graft hypertrophy and contraction, keloid formation, and hypo/hyper pigmentation) can limit the success and acceptability of the procedure by patients. Scars form following any insult to the deep dermis as a result of wound healing. Factors such as age, skin type, racial pigmentation, genetics, and sex may influence fibroblast proliferation as part of the healing response, resulting in a suboptimal result. Graft contraction is perhaps the most worrisome result, since it can result in failure of the initial surgery and may require additional surgery to correct. Many treatments have been used to manage these complications: corticosteroid injection, cryotherapy, pressure therapy, radiotherapy, laser therapy, silicone based products, and antimetabolite therapy. One such antimetabolite, 5-fluorouracil (5-FU), has been used over the last 15 years as an adjunct or primary treatment to modulate wound healing and scar formation. Other studies have demonstrated safety for cutaneous and subcutaneous injection in the periocular region. However, no controlled studies exist. This prospective, randomized, and double-blinded clinical study will evaluate the use and benefit of 5-FU versus saline in patients undergoing skin grafting for periocular reconstruction. The decision for the need for skin grafting will be at the discretion of the attending surgeon and will be made separate from enrollment in the study. Surgery will be performed as indicated. The study medication or placebo (normal saline) will be administered 2-3 weeks after surgery and then every 2-3 weeks afterwards for up to a total of 4 injections. After the injections, regular scheduled follow-up will be at 3, 6, and 12 months post-op. Outcomes at each study visit (up to 12 months post-operatively) include graft size, color, contour, and complications between study treatment group and placebo group.
Read the detailed description
In oculofacial surgery, full thickness skin grafts are a fundamental tool used to restore function to the eyelid. This can be required after removal of skin cancer, correction of eyelid malposition such as cicatricial eyelid ectropion (the eyelid edge is pulled away from the eye), retraction (the eyelid is pulled lower than normal, exposing more of the eye to the air), scar formation (such as a medial pulling or web), or trauma with loss of tissue. These conditions affect patients of all ages, ranging from newborns to nonagenarians. Skin grafting in the periorbital area is relatively safe, although complications may arise. The most common and challenging complication scarring and graft shrinkage. This can lead to requiring additional surgery to add additional skin or to improve the appearance of the graft. In addition to the morbidity of another surgery, some patients have limited or no additional skin available (e.g. young patients, burn patients). The eyelid skin is the thinnest of the body, so only thin skin can be used as donor material. However, the amount of skin available for this purpose is very little.
There are limited options for preventing graft shrinkage and scarring in this situation. The oldest and most commonly used technique is injection of steroid medication. Steroids decrease proliferation of a fibroblast cells, which create collagen and glycosaminoglycan, two proteins created by the body that contract and cause graft shrinkage. Data in literature shows that one form of steroid, triamcinolone, is effective for this purpose. However, there is a risk of embolization of this solid steroid material that care rarely cause blindness. In addition, in the periocular area, steroids can elevate eye (intraocular) pressure (that can cause glaucoma in some cases) and accelerate the formation of cataracts.
Another medication used for this purpose is 5-fluorouracil (5-FU). This is an antimetabolite (a drug that inhibits another chemical that is part of normal processes) that works by irreversibly inhibiting the enzyme thymidylate synthetase resulting in impaired DNA synthesis. This reduces fibroblast proliferation and inhibits collagen type 1 production which is a key protein in scar formation. This medication is commonly used in ophthalmology after glaucoma filtration surgery. In this usage, it is injected under the conjunctiva to prevent scarring around the surgical site.
There have been two retrospective studies that have investigated the safety and efficacy of 5-FU injected in periorbital skin grafts with or without Kenalog. The first (Massry 2011) used post-operative injections of a 50:50 mixture of 5-FU and triamcinolone for correction of medial canthal webs. In 2 patients, they found it to be safe and effective. The author noted he has used it previously for other scar management cases and was "very pleased with the results and [had] negligible side-effect[s]." The same author performed another study using 5-FU for skin grafts. This study evaluated 19 patients who had skin grafts for various purposes and were injected following surgery (similar to our protocol). This study demonstrated safety of the injection, with no cases of complication. The author concluded that the 5-FU is effective with "minimal scarring, high patient and surgeon satisfaction, and few complications." However, there was no comparison group to truly evaluate the effect. With only two retrospective studies by the same author, there is no strong evidence that it is effective, although safety has been demonstrated.
The investigators therefore propose a randomized controlled prospective study to evaluate the outcomes of periocular skin grafts with or without the use of 5-FU injected in the post-operative period. Patients will be recruited from the investigators' practices who need full thickness skin grafts for reconstruction after cancer removal, pre-existing scarring, eyelid malposition, or trauma. Patients will be introduced to the study, and will come back for detailed explanation and consent. The injection medication will be prepared by the Mass Eye and Ear Research Pharmacy and labeled for this double-blinded study. Injections will be given 2-3 weeks after surgery and up to 4 times (also every 2-3 weeks). Measurements and photographs of the skin graft will be taken at each visit (following injections, at 3, 6, and 12 months) to monitor for complications. Patients will be followed for at least 12 months.
If effective, this medication could change the post-operative management of skin grafts, reduce complications and reoperations.
- Conditions
- Ectropion, Skin Neoplasms
- Being tested
- 5-Fluorouracil, Normal saline
- Keywords
- Skin graft, 5-Fluorouracil, Periocular reconstruction
- Medical subject headings
- Ectropion, Skin Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
5-FluorouracilDrug
Also called 5-FU
Treatment medication
Normal salineOther
Also called Saline
Placebo
| Study group | Role | What they receive |
|---|---|---|
| 5-Fluorouracil | Experimental | Antimetabolite will be injected 2 weeks after periocular reconstruction with full thickness skin graft. Injection will be repeated every 2 weeks for a total of up to 4 injections. Receives: Drug: 5-Fluorouracil |
| Normal saline | Placebo comparator | Normal saline will be injected 2 weeks after periocular reconstruction with full thickness skin graft. Injection will be repeated every 2 weeks for a total of up to 4 injections. Receives: Other: Normal saline |
What is being measured
The primary outcome is the main question the study is designed to answer.
Graft Size Change
Full thickness skin grafts will be measured prior to treatment (at time of surgery) and 12 months after surgery. Although the graft will be measured at each visit, the outcome is the percent change from baseline at 12 months.
Measured: 12 months
Secondary outcomes (3)
Adverse Events
Treatment side effects will be recorded. Examples include pain, skin thinning, color/texture change, atrophy, telangiectasis, infection, and erythema.
Measured: 12 months
Early Post-operative Complications
Surgery complications will be recorded, not related to treatment. Examples are wound dehiscence, graft necrosis, infection, bleeding, partial/complete graft failure and/or ectropion.
Measured: 2 weeks after surgery
Surgeon and Patient Satisfaction
Patient and Observer Scar Assessment Scale (POSAS). This has 2 parts: Patient and Observer Scale. Both contain 6 items scored numerically on a 10 step scale (1 most normal, 10 worst scar imaginable). Together they sum to 'Total Score' of the Patient and Observer Scale. Category boxes are available to score nominal parameters (e.g. type of colour). Moreover, the patient and observer also score their 'Overall Opinion'. Total and subscales are averaged.
*There was 1 participant, and the score average was 1.*
Measured: 12 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted10 Mar 2016 (estimated)
- Study start25 Aug 2016
- Primary completion25 Jan 2019
- Study completion25 Jan 2019
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for EctropionStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind
- Who is masked
- Participant, Investigator
- Enrolment
- 1 participants (actual)
Sponsor and investigators
- Lead sponsor
- Massachusetts Eye and Ear Infirmary
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Michael Yoon, Massachusetts Eye and Ear Infirmary
- Investigators
- Michael K Yoon, MD, Principal investigator, Massachusetts Eye and Ear Infirmary
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02705352
- Sponsor's protocol ID
- 786680-1
- Status last verified
- Feb 2020
- First submitted
- 22 Feb 2016
- Last updated
- 9 Mar 2020
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 9 Mar 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Prospective, Randomized, Double-blinded Comparison of the Use of 5-fluorouracil Versus Placebo in Periocular Full Thickness Skin Grafts.
- ClinicalTrials.gov ID
- NCT02705352
- Acronym / sponsor ID
- 786680-1
- Conditions
- Ectropion, Skin Neoplasms
- Keywords
- Skin graft, 5-Fluorouracil, Periocular reconstruction
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 1 participants (actual)
- Lead sponsor
- Massachusetts Eye and Ear InfirmaryUniversity, hospital or other
- Study start
- 25 Aug 2016 (actual)
- Primary completion
- 25 Jan 2019 (actual)
- Study completion
- 25 Jan 2019 (actual)
- First posted
- 10 Mar 2016 (estimated)
- Results
- Posted 25 Feb 2020
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Full thickness skin grafts are an essential tool in surgery around the eyelids for reconstruction or rehabilitation following injury or surgery. Common conditions where skin grafts are needed include cicatricial ectropion, restoration of eyelid function after tumor removal, burns to the eyelids, or trauma. Early complications, occurring in the first 2 weeks after surgery, are rare: wound dehiscence, necrosis, infection, bleeding, partial or complete graft failure. However, late postoperative complications generally categorized as "scarring" (including graft hypertrophy and contraction, keloid formation, and hypo/hyper pigmentation) can limit the success and acceptability of the procedure by patients. Scars form following any insult to the deep dermis as a result of wound healing. Factors such as age, skin type, racial pigmentation, genetics, and sex may influence fibroblast proliferation as part of the healing response, resulting in a suboptimal result. Graft contraction is perhaps the most worrisome result, since it can result in failure of the initial surgery and may require additional surgery to correct. Many treatments have been used to manage these complications: corticosteroid injection, cryotherapy, pressure therapy, radiotherapy, laser therapy, silicone based products, and antimetabolite therapy. One such antimetabolite, 5-fluorouracil (5-FU), has been used over the last 15 years as an adjunct or primary treatment to modulate wound healing and scar formation. Other studies have demonstrated safety for cutaneous and subcutaneous injection in the periocular region. However, no controlled studies exist. This prospective, randomized, and double-blinded clinical study will evaluate the use and benefit of 5-FU versus saline in patients undergoing skin grafting for periocular reconstruction. The decision for the need for skin grafting will be at the discretion of the attending surgeon and will be made separate from enrollment in the study. Surgery will be performed as indicated. The study medication or placebo (normal saline) will be administered 2-3 weeks after surgery and then every 2-3 weeks afterwards for up to a total of 4 injections. After the injections, regular scheduled follow-up will be at 3, 6, and 12 months post-op. Outcomes at each study visit (up to 12 months post-operatively) include graft size, color, contour, and complications between study treatment group and placebo group.
Detailed description
In oculofacial surgery, full thickness skin grafts are a fundamental tool used to restore function to the eyelid. This can be required after removal of skin cancer, correction of eyelid malposition such as cicatricial eyelid ectropion (the eyelid edge is pulled away from the eye), retraction (the eyelid is pulled lower than normal, exposing more of the eye to the air), scar formation (such as a medial pulling or web), or trauma with loss of tissue. These conditions affect patients of all ages, ranging from newborns to nonagenarians. Skin grafting in the periorbital area is relatively safe, although complications may arise. The most common and challenging complication scarring and graft shrinkage. This can lead to requiring additional surgery to add additional skin or to improve the appearance of the graft. In addition to the morbidity of another surgery, some patients have limited or no additional skin available (e.g. young patients, burn patients). The eyelid skin is the thinnest of the body, so only thin skin can be used as donor material. However, the amount of skin available for this purpose is very little.
There are limited options for preventing graft shrinkage and scarring in this situation. The oldest and most commonly used technique is injection of steroid medication. Steroids decrease proliferation of a fibroblast cells, which create collagen and glycosaminoglycan, two proteins created by the body that contract and cause graft shrinkage. Data in literature shows that one form of steroid, triamcinolone, is effective for this purpose. However, there is a risk of embolization of this solid steroid material that care rarely cause blindness. In addition, in the periocular area, steroids can elevate eye (intraocular) pressure (that can cause glaucoma in some cases) and accelerate the formation of cataracts.
Another medication used for this purpose is 5-fluorouracil (5-FU). This is an antimetabolite (a drug that inhibits another chemical that is part of normal processes) that works by irreversibly inhibiting the enzyme thymidylate synthetase resulting in impaired DNA synthesis. This reduces fibroblast proliferation and inhibits collagen type 1 production which is a key protein in scar formation. This medication is commonly used in ophthalmology after glaucoma filtration surgery. In this usage, it is injected under the conjunctiva to prevent scarring around the surgical site.
There have been two retrospective studies that have investigated the safety and efficacy of 5-FU injected in periorbital skin grafts with or without Kenalog. The first (Massry 2011) used post-operative injections of a 50:50 mixture of 5-FU and triamcinolone for correction of medial canthal webs. In 2 patients, they found it to be safe and effective. The author noted he has used it previously for other scar management cases and was "very pleased with the results and [had] negligible side-effect[s]." The same author performed another study using 5-FU for skin grafts. This study evaluated 19 patients who had skin grafts for various purposes and were injected following surgery (similar to our protocol). This study demonstrated safety of the injection, with no cases of complication. The author concluded that the 5-FU is effective with "minimal scarring, high patient and surgeon satisfaction, and few complications." However, there was no comparison group to truly evaluate the effect. With only two retrospective studies by the same author, there is no strong evidence that it is effective, although safety has been demonstrated.
The investigators therefore propose a randomized controlled prospective study to evaluate the outcomes of periocular skin grafts with or without the use of 5-FU injected in the post-operative period. Patients will be recruited from the investigators' practices who need full thickness skin grafts for reconstruction after cancer removal, pre-existing scarring, eyelid malposition, or trauma. Patients will be introduced to the study, and will come back for detailed explanation and consent. The injection medication will be prepared by the Mass Eye and Ear Research Pharmacy and labeled for this double-blinded study. Injections will be given 2-3 weeks after surgery and up to 4 times (also every 2-3 weeks). Measurements and photographs of the skin graft will be taken at each visit (following injections, at 3, 6, and 12 months) to monitor for complications. Patients will be followed for at least 12 months.
If effective, this medication could change the post-operative management of skin grafts, reduce complications and reoperations.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind (participant, investigator)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| 5-Fluorouracil | Experimental | Drug: 5-FluorouracilAntimetabolite will be injected 2 weeks after periocular reconstruction with full thickness skin graft. Injection will be repeated every 2 weeks for a total of up to 4 injections. |
| Normal saline | Placebo comparator | Other: Normal salineNormal saline will be injected 2 weeks after periocular reconstruction with full thickness skin graft. Injection will be repeated every 2 weeks for a total of up to 4 injections. |
Who may qualify
- Ages
- 18 to 89 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (4 listed)
- Outpatients
- Ages 18 to 89 years of age
- Has a condition (e.g. trauma, skin/tissue defect, scar) requiring a skin graft for repair
- Sufficient education to understand study procedures and to give consent
Key exclusion criteria (5 listed)
- Women lactating, pregnant or planning to get pregnant in the near future
- Immunosuppression/immunocompromise or serious/active infections
- Dihydropyrimidine dehydrogenase enzyme deficiency
- Severe hepatic or renal impairment or failure
- Unable to give consent or understand the study
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| 5-FluorouracilAlso: 5-FUTreatment medication | Drug | 5-Fluorouracil |
| Normal salineAlso: SalinePlacebo | Other | Normal saline |
Primary outcome
Graft Size Change
Time frame: 12 months
Full thickness skin grafts will be measured prior to treatment (at time of surgery) and 12 months after surgery. Although the graft will be measured at each visit, the outcome is the percent change from baseline at 12 months.
3 secondary outcomes
Adverse Events
Time frame: 12 months
Early Post-operative Complications
Time frame: 2 weeks after surgery
Surgeon and Patient Satisfaction
Time frame: 12 months
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 9 Mar 2020.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Michael K Yoon, MD principal investigator
Massachusetts Eye and Ear Infirmary
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing 5-Fluorouracil and Normal saline in people with Ectropion and Skin Neoplasms, run by Massachusetts Eye and Ear Infirmary at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 4 inclusion and 5 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 9 Mar 2020. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 25 Feb 2020). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Graft Size Change (time frame: 12 months). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 9 Mar 2020.