Sorbinil Retinopathy Trial (SRT)
Condition: Diabetic Retinopathy; Diabetes Mellitus
MeSH terms: Retinal Diseases; Diabetic Retinopathy
Study type: Interventional
Phase: Phase 3

Summary: 
      To evaluate the safety and efficacy of the investigational drug sorbinil, an aldose reductase
      inhibitor, in preventing the development of diabetic retinopathy and neuropathy in persons
      with insulin-dependent diabetes.
    

Detailed description: 
      During the last two decades, vision researchers have studied intensively the role of the
      enzyme aldose reductase (AR) in diabetic cataract and in other diabetic complications. The
      potentially damaging effects of AR in diabetes were first discovered in the lens fiber cells.
      In these cells, the enzyme catalyzes the reduction of high levels of glucose to sorbitol
      through the polyol pathway and initiates a sequence of events that eventually results in
      opacification of the lens. Because sorbitol (a sugar alcohol) and fructose (a subsequent
      product of glucose metabolism) cannot readily diffuse across cell membranes, they become
      trapped in lens fiber cells. There they accumulate at unusually high levels and exert a
      significant osmotic stress, causing an influx of water and swelling of the lens fibers. Major
      electrolytic and osmotic changes then occur that lead to lens opacity.

      More recently, the detection of AR in the pericytes of retinal capillaries -- cells that are
      involved very early in the evolution of diabetic retinopathy -- suggests that this enzyme may
      also play a role in the pathogenesis of this disorder. Scientists now know that AR is present
      in nerve tissue, and they speculate that in diabetes it induces the depletion of myo
      -inositol, which leads to the lessening of nerve conduction velocity in diabetic neuropathy.

      Chemicals that inhibit aldose reductase have proved effective in preventing damage to the
      lens, in preventing thickening of retinal capillary basement membranes in diabetic animals,
      and in improving nerve conduction velocity values in patients with diabetic neuropathy.
      Therefore, it is possible that AR inhibitors also may be able to prevent, delay, or halt the
      development or progression of diabetic retinopathy.

      To test this hypothesis, an AR inhibitor developed by Pfizer Inc., sorbinil, was studied in
      this clinical trial. (Other AR inhibitors underwent study in clinical trials sponsored by
      Ayerst and Alcon.) Initially, 402 patients were randomized into the double-masked treatment
      period using a dosage schedule of one 250-mg tablet daily. In 1985, recruitment was
      voluntarily halted by Pfizer because of several serious hypersensitivity reactions among
      patients taking sorbinil in clinical trials in the United States and Europe. In November
      1985, recruitment resumed, using a titrated dosage schedule of 25 mg daily for 2 weeks,
      followed by 75 mg daily for 2 weeks, then 250 mg daily for the duration. A total of 497
      patients participated in the study.

      Followup visits were scheduled weekly for the first 4 weeks, monthly for the next 2 months,
      and every 3 months thereafter. For patients assigned to the titration protocol, additional
      visits were made at weeks 5 and 6. A complete history was recorded and a physical examination
      was conducted every 15 months; electrocardiogram was recorded every 6 months. In addition,
      patients were cautioned to note any signs of hypersensitivity.

      Efficacy visits, scheduled at 9-month intervals after the first visit at 12 months, included
      fundus photographs, visual acuity examinations according to the Early Treatment Diabetic
      Retinopathy Study (ETDRS), red blood cell sorbitol measure, and assessment of coronary risk
      factor classification.

      The Sorbinil Retinopathy Trial (SRT) was a unique collaboration between private industry and
      the Federal government in designing, funding, and conducting a multicenter, randomized
      clinical trial. Pfizer Inc. supported 10 of the 11 participating Clinical Centers, provided
      the medication, and funded the Data Coordinating Center and Fundus Photograph Reading Center.
      The National Eye Institute funded the Policy, Data, and Safety Monitoring Committee and its
      own participating Clinical Center.
    

Intervention name(s): Sorbinil
Intervention type(s): Drug
Allocation: Randomized
Masking: Double
Primary purpose: Treatment