A Randomized, Double-masked, Placebo-controlled Phase 1b/2a Study to Evaluate Clinical Efficacy and Safety of Nuvastatic™ in Patients With Non-proliferative Diabetic Retinopathy Without Center-involved Diabetic Macular Edema.

Brief Summary

Detailed Description

Diabetic retinopathy (DR) is a common complication of diabetes mellitus that leads to loss of vision and blindness among working age adults. During progression of DR, patients can develop diabetic macular edema (DME), which is characterized by the thickening of the macula caused by the breakdown of the blood-retinal barrier and consequent retinal vascular hyperpermeability. In 2010, the global prevalence of DR among adults with diabetes mellitus aged 20-79 years was estimated to be 34.6% for any DR and 6.81% for DME. DME is the leading cause of vision loss among patients with DR. It is associated with the type of diabetes, and increases with the duration and severity of disease. Other significant risk factors common to DR and DME include hyperglycemia and hypertension. DME negatively impacts patients' health-related quality of life and represents an economic burden due to the increased use of healthcare resources by affected patients. In DR, which is a complex multifactorial disease, basically the retinal neovascularization occurs with the disturbance of physiological angiogenesis due to creation of hypoxic condition, which induces the oxygen demand in the retina (Roth, 1977; Smith et al., 1994; Chen and Smith, 2007). Consequently, in response to induced hypoxia, excessive production and over expression of VEGF and other pro-angiogenic factors take place in the retina. This ultimately induces the situation so called "pathological neovascularization" (Aiello et al., 1994; Folkman, 2006). Retinal ischemia is a common precursor to vitreal neovascularization in retinal diseases (Tolentino and Adamis, 1998) and is strongly associated with a local inflammatory response in the ischemic retina (Barouch et al., 2000). While there is no curative treatment available for DME, laser photocoagulation represents an effective treatment to preserve vision. However, this treatment modality is limited by its inability to restore vision once it has been lost. The current standard of care for DME includes intravitreal anti-vascular endothelial growth factor (VEGF) therapeutics and corticosteroids. Clinical studies have confirmed that monthly intravitreal treatment with the anti-VEGF treatment can improve vision, with up to 45% of patients gaining ≥ 15 letters in best-corrected visual acuity (BCVA) after 24 months. Similar improvements were found after treatment with the anti-VEGF antibodies. Despite the proven efficacy of VEGF inhibitors, the requirement of frequent injections causes a high rate of treatment discontinuation among patients with DME and represents a major limitation. Thus, current pharmacological treatments target single pathogenic processes with a narrow therapeutic range and may cause adverse side effects leading to undesired systemic effects. The presence of potential side effects and the significant proportion of patients who do not respond to treatment suggest that there remains a need for the development of improved therapies for DR and DME. An ideal adjunctive agent for treating DR hence should be polymorphic and possess antiangiogenic, neuroprotective, anti-inflammatory, anti-oxidant as well as anti-ischaemic properties. We have assessed the efficacy of core ingredient of Nuvastatic™, Lanctos 75™ for the treatment and management of the diabetic retinopathic condition. These scientific studies have shown that the standardized extract of O. stamineus (Lanctos 75™) in mediates antiangiogenic actions via blocking VEGF pathway. We demonstrated the potent antiangiogenic activity of the standardized extract of O. stamineus and prevention activity of the extract against human breast tumor in xenograft model. In addition, it is reported that, the extract was found to specifically inhibit VEGF expression and VEGFR phosphorylation known to be up-regulated in new blood vessel formation which in turn leads to suppression of vascularization and thereby ultimately the growth of tumor will be affected. Rosmarinic acid present in the extract could be involved in cell cycle arrest in the G0/G1 and G1/S phases, exhibiting an anti-proliferative effect of thus suggesting that the proliferative vascular diseases including retinopathy might be the potential target for the pharmacological application of rosmarinic acid. Also, the key active ingredients in the extract are rosmarinic acid mainly, and sinensetin, eupatorin and betulinic acid, which are readily absorbed into the plasma and exert that conferred the synergistic pharmacological response such as anti-inflammatory, antioxidant, analgesic and neuroprotective effects.

Primary Outcomes

Secondary Outcomes

• To evaluate short-term visual outcomes on zone diagnosis(12 months)
• To evaluate short-term visual outcomes on DRSS(12 months)
• To evaluate short-term visual outcomes on severity(12 months)