A Phase 2 interventional study of 5-Fluorouracil and Normal saline in Ectropion and Skin Neoplasms, sponsored by Massachusetts Eye and Ear Infirmary. Completed at 1 site in United States. Open to participants aged 18 Years to 89 Years. Per ClinicalTrials.gov, last updated 2020-03-09.
Sponsored by Massachusetts Eye and Ear Infirmary · Phase 2, Interventional, and Treatment
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.
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.
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This study's enrollment of 1 is below the median of 53 across 416 interventional studies indexed under Skin Neoplasms.
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Exclusion Criteria:
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.
Drug: 5-Fluorouracil
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.
Other: Normal saline
Treatment medication
Also known as: 5-FU
Placebo
Also known as: Saline
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.
Time frame: 12 months
Adverse Events
Treatment side effects will be recorded. Examples include pain, skin thinning, color/texture change, atrophy, telangiectasis, infection, and erythema.
Time frame: 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.
Time frame: 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.\*
Time frame: 12 months
Challenges recruiting patients into the study.
| Milestone | 5-Fluorouracil | Normal Saline |
|---|---|---|
| Started | 1 | 0 |
| Completed | 1 | 0 |
| Not completed | 0 | 0 |
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.
| percent change in graft | 5-Fluorouracil | Normal Saline |
|---|---|---|
| Graft Size Change | 10 | — |
Treatment side effects will be recorded. Examples include pain, skin thinning, color/texture change, atrophy, telangiectasis, infection, and erythema.
| Events | 5-Fluorouracil | Normal Saline |
|---|---|---|
| Adverse Events | 0 | — |
Surgery complications will be recorded, not related to treatment. Examples are wound dehiscence, graft necrosis, infection, bleeding, partial/complete graft failure and/or ectropion.
| Number of events | 5-Fluorouracil | Normal Saline |
|---|---|---|
| Early Post-operative Complications | 0 | — |
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.\*
| score on a scale | 5-Fluorouracil | Normal Saline |
|---|---|---|
| Surgeon and Patient Satisfaction | 1 | — |
Collected over 6 months. Non-serious events are listed at a 0% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| 5-Fluorouracil | 0/1 (0%) | 0/1 (0%) | 0/1 (0%) |
| Normal Saline | — | — | — |
Unable to recruit patients into the study.
| Age, Categorical(Participants) | 5-Fluorouracil | Normal Saline | Total |
|---|---|---|---|
| <=18 years | 0 | — | 0 |
| Between 18 and 65 years | 0 | — | 0 |
| >=65 years | 1 | — | 1 |
| Age, Continuous(years) | 5-Fluorouracil | Normal Saline | Total |
|---|---|---|---|
| Mean | 72 ± 0 | — | 72 ± 0 |
| Sex: Female, Male(Participants) | 5-Fluorouracil | Normal Saline | Total |
|---|---|---|---|
| Female | 0 | — | 0 |
| Male | 1 | — | 1 |
| Race (NIH/OMB)(Participants) | 5-Fluorouracil | Normal Saline | Total |
|---|---|---|---|
| American Indian or Alaska Native | 0 | — | 0 |
| Asian | 0 | — | 0 |
| Native Hawaiian or Other Pacific Islander | 0 | — | 0 |
| Black or African American | 0 | — | 0 |
| White | 1 | — | 1 |
| More than one race | 0 | — | 0 |
| Unknown or Not Reported | 0 | — | 0 |
| Region of Enrollment(participants) | 5-Fluorouracil | Normal Saline | Total |
|---|---|---|---|
| United States | 1 | — | 1 |
| Scar appearance(units on a scale) | 5-Fluorouracil | Normal Saline | Total |
|---|---|---|---|
| Number | 1 | — | 1 |
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Massachusetts Eye and Ear Infirmary