Efficacy and Safety Study of Intravitreal Triamcinolone to Treat Diffuse Diabetic Macular Edema
Condition: Diabetes Mellitus; Macular Edema
MeSH terms: Macular Edema; Edema
Study type: Interventional
Phase: Phase 3

Summary: 
      The purpose of this study is to determine whether intravitreal injection of Triamcinolone
      Acetonide is effective in the treatment of Clinically Significant Diffuse Macular Edema due
      to Type 2 Diabetes Mellitus.
    

Detailed description: 
      Diabetes mellitus and its complications represent nowadays an important issue in Public
      Health terms. The WHO expectations indicate that around 2025 the European population with
      diabetes will reach about 12%, and it has been estimated that the percent in the USA will be
      around 10% (King, 1995).

      The severe complications of proliferant diabetic retinopathy and its disastrous effects on
      vision seem to be solved with retinal panphotocoagulation. The most relevant issue regarding
      diabetes´ ocular complications seems to be macular edema. We define macular edema as retinal
      thickening between 1500 microns central to fovea. It is found in about 10% diabetics, of whom
      about 40% will have an important visual acuity loss (Klein, 1984) In our environment,
      diabetes retinopathy affects nearly 21% of all the diabetics, and among them, about 6% has a
      clinically significant macular edema (Lopez, 2001).

      Until now the only treatment available with proved efficacy for diffuse edema was grid
      photocoagulation, stablished as standard treatment since the publication of results from
      "Early Treatment Diabetic Retinopathy Study" (Olk 1990). A maximum 3 laser treatments with 3
      to 4 months intervals between treatment has been accepted.

      Nevertheless, the results with the treatment haven´t been considered satisfactory as the main
      aim is to preserve visual function, and only 15% of the patients get any improvement (Mc
      Donald, 1985).

      Because of that more alternatives have been studied, among them victrectomy and intraocular
      corticosteroyd injections. Though, vitrectomy seems to provide significative improvements
      only if the patient has a thickened posterior hyaloid able to make a traction over the
      macular area (Tachi, 1996) and that doesn´t happen in the majority of diabetic patients.

      The identification of Vascular Endothelial Growth Factor (VEGF) as the main responsible agent
      of angiogenesis and its role in the pathogenia of diabetic macular edema has opened new
      approach methods in the treatment of this complication (Adamis 1994). This factor, also known
      as Vascular Permeability Factor (VPF), interacts with "tight junctions" of retinal
      endothelial cells, producing a disruption of hematoretinal barrier.

      It is known that corticosteroids are not only the more powerful antiangiogenetic agents, but
      are also capable of reversing the effects mentioned before over the retinal endothelial by
      acting at phosphorilation and expression of tight-junctions´ proteins. They also inhibit VEGF
      expression (Fisher 2001).

      It seems logical that its use has been proposed in the treatment of this diabetes
      complication. Though, its side effects, either local or systemical, and its intraocular
      biodisponibility issues have obligated the use of intravitreal administration.

      In 2001 was published the first work about intravitreal triamcinolone after vitrectomy in
      proliferative diabetes retinopathy patients, in an attempt to reduce the inflammatory
      response what sometimes occurs in these patients after surgery (Jonas, 2001). A series of 29
      eyes shows a good tolerance of the drug administered this way.

      The next year, and after the presentation at ARVO meeting, some other authors present a
      prospective work without control group with 16 eyes of patients who have been injected
      triamcinolone acetonide after grid laser failure, applied according to ETDRS criteria. The
      results show a visual acuity improvemente and a reduction of macular edema evaluated with
      ocular coherence tomography, with an effect loss in a 6 months interval (Martidis, 2002).

      Since then more clinical series have been published, but yet without any prospective,
      randomized and control group studies done.

      These series seem to show a positive effect of triamcionlone either in 25 mg dosage (Jonas,
      2002) or 4 mg dosage.

      It is remarkable that the majority of the studies have been published by Heidelberg Group,
      although series from other authors are also being published (Massin, 2004).

      There has also been published side effects as ocular hypertension and endophthalmitis, that
      seem not to be infectious in the majority of the cases (Roth, 2003) but due to its high
      prevalence they need to be studied in depth.

      This approach is being taken by some pharma industries with variations; intraocular
      controlled liberation implants of fluocionola acetonide or dexametasone biodegradable
      implants have been developed (Jaffe 2000).

      It is also being investigated the potential effect of Anecortave acetate, a cortisol
      derivate, and there are also some other alternatives under research: VEGF inhibitors as
      adaptamers, andibodies or fragments, PKC inhibitors or angiopoiteins, some of which are
      currently being evaluated in Phase III Clinical Trials.

      Despite the lack of clinical trials similar to the one proposed here, the topic has provoked
      a lot of interest in the international and national ophthalmological community and there are
      evidences of some of these treatments being used in our country.

      Comparisons:

      Study Group: TRIGON DEPOT (Bristol Mayers Squibb Labs) 4 mg intravitreal injection followed
      by ETDRS grid laser technique.

      Control Group: ETDRS grid laser technique.
    

Intervention name(s): Triamcinolone Acetonide; Grid laser; Sham Injection
Intervention type(s): Drug; Procedure; Procedure
Intervention description(s): Intravitreal Injection 4mg single dose; Grid laser as specified in ETDRS; Simulation procedure for triamcinolone injection
Other intervention name(s): Trigon Depot
Intervention MeSH terms: Triamcinolone; Triamcinolone Acetonide; Triamcinolone hexacetonide; Triamcinolone diacetate
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Diabetes, Macular Edema, Triamcinolone