A Pilot Study of Moderate Hyperbilirubinemia in Type 1 Diabetes Mellitus
|Study Design:||Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
|Official Title:||A Pilot Study of Moderate Hyperbilirubinemia in Type 1 Diabetes Mellitus|
- Change in Brachial Artery Diameter [ Time Frame: Day 0 and Day 4 ] [ Designated as safety issue: No ]The primary endpoint is the difference in the change in brachial artery diameter in response to a flow stimulus at visit 2 and 3. It is anticipated that a response will occur following atazanavir therapy compared with baseline. The principal secondary endpoints are the serum measures of oxidant stress and antioxidant capacity.
|Study Start Date:||May 2012|
|Study Completion Date:||February 2014|
|Primary Completion Date:||February 2014 (Final data collection date for primary outcome measure)|
Experimental: Atazanavir 300 mg BID
Atazanavir 300 mg BID for 4 days.
The study design is a single arm, open label trial. Treatment is atazanavir 300 mg BID per day for 4 days. The Brigham and Women's Hospital Investigational Drug Service (IDS) will dispense study drug.
Diabetes mellitus (DM) is associated with a markedly increased risk of both macro- and microvascular disease. Excess pro-oxidants and insufficient antioxidants each contributes to oxidant stress in DM. Oxidant stress induces endothelial dysfunction, a major determinant of vascular damage. In DM, hyperglycemia and elevated free fatty acids (FFAs) induce generation of reactive oxygen species (ROS) by stimulating protein kinase C (PKC) and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (Figure 1). In addition, hyperglycemia activates the renin-angiotensin system, and angiotensin II (Ang II) additively stimulates PKC and NADPH oxidase.
Bilirubin, long regarded as metabolic waste, is, in fact, a potent antioxidant scavenger of ROS. It also directly inhibits both protein kinase C and the NADPH oxidase system, augmenting its antioxidant activity (Figure 1). Moreover, bilirubin inhibits Ang II-mediated vasoconstriction and ROS generation. Experimental models suggest that hyperbilirubinemia may preserve diabetes-associated endothelial function and prevent vasculopathy. Furthermore, epidemiological studies demonstrate that higher bilirubin levels are associated with a reduced risk of vascular disease in DM. Bilirubin therefore emerges as a potentially critical molecule to protect against diabetic vascular and renal damage. However, limited translational research has addressed raising bilirubin levels as a preventive therapy for vascular disease in DM.
Accordingly, the investigators seek to establish the feasibility of studying the change in endothelial function caused by induced moderate hyperbilirubinemia in type 1 diabetes. the investigators will take advantage of the recently described use of atazanavir to safely achieve moderate hyperbilirubinemia. Atazanavir is a protease inhibitor used to treat HIV infection that competitively inhibits hepatic 1A1 isoform of uridine diphosphoglucose glucuronosyltransferase (UGT1A1), limiting bilirubin clearance and inducing hyperbilirubinemia (Figure 2). This mimics Gilbert's syndrome, a benign unconjugated hyperbilirubinemia due to partial genetic deficiency of UGT1A1.
This work has the potential to identify iatrogenic moderate hyperbilirubinemia as a strategy to interrupt key mechanisms of type 1 diabetes-associated macro- and microvascular disease.
This is a physiologic study. The design is a single arm and open label. There are three study visits: a screening visit, a baseline visit, and a final visit. The treatment is atazanavir 300 mg PO bid. The treatment period is 4 days. The primary study outcome is forearm vascular function. The principal secondary outcomes are serum antioxidant defense capacity and measures of oxidant stress.
The investigators aim to study 20 subjects to completion over the 12 month funding period. The investigators anticipate enrolling 40 subjects before 20 complete the study.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01421355
|United States, Massachusetts|
|Brigham and Women's Hospital|
|Boston, Massachusetts, United States, 02115|
|Principal Investigator:||Joshua Beckman, MD||Brigham and Women's Hospital|