Diabetes
Conditions
Keywords
Thymosin beta 4, Corneal wound healing, Vitrectomy, Diabetes
Brief summary
As a consequence of damage to multiple organ systems throughout the course of their disease, diabetic patients suffer a number of chronic complications giving rise to increased morbidity, mortality, and health care costs specific to this population. Within the ophthalmic domain, diabetic retinopathy (DR) frequently induces serious visual impairment. Although DR can be addressed surgically, surgery remains a less than ideal intervention within this population with a well-characterized compromised ability to heal. The introduction of a therapeutic agent that could accelerate wound closure and decrease healing time, thereby reducing the risk and incidence of infection and corneal scarring in these susceptible patients, would represent a significant clinical and pharmacoeconomic advance in the treatment of this condition.
Detailed description
In individuals with certain clinical conditions, such as diabetes, corneal epithelial defects persist and do not necessarily respond to conventional treatment regimens because of delayed epithelial wound healing. While wound closure should occur following an injury to the corneal epithelium, a timely re-establishment of the epithelial barrier is of utmost importance. The wound repair process is intricately linked to a complex inflammatory response that must be properly regulated to ensure healing and optimal visual outcome. Infiltration of inflammatory cells into injured corneal tissue is a hallmark of wound repair, and the association of polymorphonuclear (PMN) leukocyte infiltration with sterile corneal ulceration is well recognized. Retardation of epithelial recovery by persistent inflammation, release of enzymatic products from degranulating PMN, and stimulation of mononuclear leukocytes by cytokines all contribute to poor re-epithelialization. It has been shown that diabetic corneas manifest reduced rates of epithelial healing after denudement. Yet, in the diabetic patient, not only is the rate of corneal epithelial healing of clinical concern, abnormalities inherent in the diabetic corneal epithelial cytoarchitecture can cause substantial impediments to normal stromal healing. Histologically, diabetic corneas typically demonstrate thickening of the epithelial basal membrane (BM), decreased number of hemidesmosomes, and decreased number of nerve fiber endings. Studies of BM changes in diabetic corneas have yielded information regarding poor adhesion of the epithelial BM to the stroma. During vitrectomy in diabetic patients, when the cornea epithelium is removed, it separates as an intact sheet and the entire thickened BM, characteristic of diabetes, adheres to the epithelium. In contrast, when normal epithelium is removed by scraping, the BM remains adherent to the stroma. Because patients with diabetic retinopathy (DR) corneas have delayed wound healing, the expression of thymosin beta 4 (Tβ4) as a potent epithelial cell migration stimulator in DR corneas was investigated. Human DR corneas were analyzed and were found to express significantly less Tβ4 compared to normal corneas, suggesting that the use of Tβ4 may accelerate the wound-healing process in this model.
Interventions
DRUGThymosin Beta 4 (Tβ4)
There are 2 groups: active drug and placebo. The patients in the active arm receive an administration of 0.01% Tβ4 (w/w) eyedrops to the affected eye, 2 drops 4 times daily (breakfast, lunch, dinner, and bedtime) for 14 days. The first of 4 daily doses will be administered following surgery (vitrectomy).
OTHERPlacebo
There are 2 groups: active drug and placebo. The patients in the placebo arm receive an administration of 0.00% Tβ4(w/w) eyedrops to the affected eye, 2 drops four times a day (QID) (breakfast, lunch, dinner, and bedtime) for 14 days. The first of 4 daily doses will be administered following surgery (vitrectomy).
Sponsors
PPD Development, LP
ReGenTree, LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Type 1 or Type 2 diabetes mellitus. * Patients who have an expected minimum 50% likelihood of requiring corneal epithelial debridement in the opinion of the Investigator Size of wound should be 8 mm. * Signed written informed consent by patient or legal guardian.
Exclusion criteria
* Have current or history of herpetic eye disease in the past 3 years. * Display evidence of keratitis. * Have Sjögren's syndrome. * Have corneal scarring, opacity, or dystrophy. * Have a history of malignancy. * Have a history of HIV or AIDs * Are pregnant or lactating females. * Are females who can become pregnant. * Have a known hypersensitivity to the study drug. * May be regarded as unreliable for the study. * Have previously participated in this study. * Experience any complication during the vitrectomy procedure itself, which will exclude the patient from participating in this study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Treatment Emergent Adverse Events (TEAEs) After Treatment With Thymosin Beta 4 in the Target Eye of Diabetic Patients During Vitrectomy | 14 days | Number of participants with Number of Treatment Emergent Adverse Events (TEAEs) in the Target Eye in diabetic patients who had undergone epithelial debridement during vitrectomy and treated with thymosin beta 4 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Corneal Epithelial Wound Healing at Day 14 (End of Treatment) | 14 days | Number of diabetic patients who had undergone epithelial debridement during vitrectomy resulted in complete corneal wound closure of the affected eye at the end of treatment (Day 14) |
Countries
United States
Participant flow
Recruitment details
Recruitment started in January 2008 and ended February 2009 using 4 sites (Hospital Medical Centers). Only the first dose group was completed before suspending the trial due to low patient availability.The procedure of debridement was discontinued in most centers, thus making the availability of surgical subject extremely small.
Pre-assignment details
Prior to randomization, patients needed to meet specific inclusion and exclusion criteria.There was no run-in period.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Administration of 0.00% Thymosin beta 4 (Tβ4) weight/weight(w/w) eyedrops to the affected eye, 2 drops 4 times a day (breakfast, lunch, dinner, and bedtime) for 14 days. The first of 4 daily doses will be administered following surgery (vitrectomy). | 3 |
| Active Drug Administration of 0.01% Tβ4 weight/weight (w/w) eyedrops to the affected eye, 2 drops 4 times a day (breakfast, lunch, dinner, and bedtime) for 14 days. The first of 4 daily doses will be administered following surgery (vitrectomy). | 9 |
| Total | 12 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 |
Baseline characteristics
| Characteristic | Placebo | Active Drug | Total |
|---|---|---|---|
| Age, Continuous | 43.3 years STANDARD_DEVIATION 3.1 | 51.4 years STANDARD_DEVIATION 15 | 49.4 years STANDARD_DEVIATION 13.4 |
| Sex: Female, Male Female | 2 Participants | 4 Participants | 6 Participants |
| Sex: Female, Male Male | 1 Participants | 5 Participants | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 3 / 3 | 9 / 9 |
| serious Total, serious adverse events | 0 / 3 | 0 / 9 |
Outcome results
Primary
Number of Participants With Treatment Emergent Adverse Events (TEAEs) After Treatment With Thymosin Beta 4 in the Target Eye of Diabetic Patients During Vitrectomy
Number of participants with Number of Treatment Emergent Adverse Events (TEAEs) in the Target Eye in diabetic patients who had undergone epithelial debridement during vitrectomy and treated with thymosin beta 4
Time frame: 14 days
Population: Intent to Treat (ITT), Last Observation Carried Forward (LOCF)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Number of Participants With Treatment Emergent Adverse Events (TEAEs) After Treatment With Thymosin Beta 4 in the Target Eye of Diabetic Patients During Vitrectomy | 3 Participants |
| Active Drug | Number of Participants With Treatment Emergent Adverse Events (TEAEs) After Treatment With Thymosin Beta 4 in the Target Eye of Diabetic Patients During Vitrectomy | 9 Participants |
Secondary
Number of Participants With Corneal Epithelial Wound Healing at Day 14 (End of Treatment)
Number of diabetic patients who had undergone epithelial debridement during vitrectomy resulted in complete corneal wound closure of the affected eye at the end of treatment (Day 14)
Time frame: 14 days
Population: Analysis per protocol, ITT (Intent to treat), using LOCF (Last Observation Carried Over)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Number of Participants With Corneal Epithelial Wound Healing at Day 14 (End of Treatment) | 3 participants |
| Active Drug | Number of Participants With Corneal Epithelial Wound Healing at Day 14 (End of Treatment) | 9 participants |