A Pilot Study of Moderate Hyperbilirubinemia in Type 1 Diabetes Mellitus

• ClinicalTrials.gov Identifier: NCT01421355
• Recruitment Status: Completed
• First Posted: August 22, 2011
• Results First Posted: July 21, 2014
• Last Update Posted: July 21, 2014
• Sponsor: Brigham and Women's Hospital
• Collaborator: National Institutes of Health (NIH)
• Information provided by (Responsible Party): Mark Alan Creager, MD, Brigham and Women's Hospital

Study Description

Brief Summary:

Specific Aim: To establish the feasibility of studying the change in endothelial function caused by induced moderate hyperbilirubinemia in type 1 diabetes. Atazanavir, a drug that inhibits bilirubin conjugation, will be used to induce moderate hyperbilirubinemia. Endothelial function will be measured before and after atazanavir therapy. In addition, plasma markers of antioxidant capacity and oxidant stress will be measured as proof-of-concept that induced moderate hyperbilirubinemia has favorable effects on oxidative stress in type 1 diabetes.

Condition or disease	Intervention/treatment	Phase
Type 1 Diabetes Mellitus	Drug: Atazanavir	Phase 1

Detailed Description:

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 15 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Official Title: A Pilot Study of Moderate Hyperbilirubinemia in Type 1 Diabetes Mellitus
• Study Start Date: May 2012
• Actual Primary Completion Date: February 2014
• Actual Study Completion Date: February 2014

Arms and Interventions

Arm	Intervention/treatment
Experimental: Atazanavir 300 mg BID; Atazanavir 300 mg BID for 4 days.	Drug: Atazanavir; 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.

Outcome Measures

Primary Outcome Measures :

1. Change in Brachial Artery Diameter [ Time Frame: Day 0 and Day 4 ]
   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.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. Symptoms of diabetes plus casual plasma glucose concentration ≥ 200 mg/dl (11.1 mmol/l), or;
2. FPG ≥ 126 mg/dl (7.0 mmol/l), or;

3. 2-h postload glucose ≥ 200 mg/dl (11.1 mmol/l) during an OGTT. In addition, subjects would be required to be at increased risk of cardiovascular events, defined as:

   • microalbuminuria, or;
   • T1DM duration of > 20 years.

Exclusion Criteria:

1. HIV infection
2. Gilbert's syndrome
3. Hepatic failure or active hepatitis,
4. Unstable cardiovascular disease, including angina, heart failure or arrhythmia
5. drug abuse including alcoholism or addiction to cocaine, heroin or amphetamines
6. Use of medications that significantly with atazanavir
7. Pregnancy, or inability to practice adequate contraception

Contacts and Locations

Locations

United States, Massachusetts

Brigham and Women's Hospital

Boston, Massachusetts, United States, 02115

Sponsors and Collaborators

Brigham and Women's Hospital

National Institutes of Health (NIH)

Investigators

• Principal Investigator: Joshua Beckman, MD; Brigham and Women's Hospital

More Information

• Responsible Party: Mark Alan Creager, MD, Mark A. Creager, MD, Brigham and Women's Hospital
• ClinicalTrials.gov Identifier: NCT01421355
• Other Study ID Numbers: 1R03DK094510-01 ( U.S. NIH Grant/Contract )
• First Posted: August 22, 2011
• Results First Posted: July 21, 2014
• Last Update Posted: July 21, 2014
• Last Verified: June 2014

Additional relevant MeSH terms:

Diabetes Mellitus; Diabetes Mellitus, Type 1; Hyperbilirubinemia; Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Autoimmune Diseases; Immune System Diseases; Pathologic Processes; Atazanavir Sulfate; HIV Protease Inhibitors; Viral Protease Inhibitors; Protease Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Anti-HIV Agents; Anti-Retroviral Agents; Antiviral Agents; Anti-Infective Agents