Insulin Resistance in Pulmonary Arterial Hypertension

The Effect of Bosentan and Pioglitazone on Insulin Resistance in Pulmonary Arterial Hypertension

The purpose of this study is to evaluate 1) the incidence of insulin resistance (a pre-diabetic state) in patients with pulmonary hypertension, and 2) test the utility of a validated PH therapy (Tracleer) versus Pioglitazone in the treatment of those patients found to have insulin resistance.

Study Overview

• Status: Terminated
• Conditions: Hypertension, Pulmonary
• Intervention / Treatment: Drug: bosentan; Drug: Pioglitazone

Detailed Description

The Effect of Bosentan and Pioglitazone on Insulin Resistance in Pulmonary Arterial Hypertension ,is a study evaluating the incidence of insulin resistance in patients with pulmonary hypertension and testing the utility of a validated PH therapy(Tracleer) versus Pioglitazone in the treatment of those patients found to have insulin resistance.Patients with PAH must be stable on therapy for at least 3 months are considered for enrollment in this study.With the exception of PAH, subjects must be free of major medical illnesses, including diabetes mellitus ,malignancy or significant hepatic or renal disease.

• Study Type: Interventional
• Enrollment (Actual): 2
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • Stanford, California, United States, 94305
      • Stanford University School of Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

Patients with Pulmonary Arterial Hypertension (PAH) must be stable on therapy for at least 3 months prior to enrollment in the trial. We will include patients with idiopathic PAH and Familial PAH as well as PAH associated with collagen vascular disease or drug or toxin exposure. With the exception of PAH, subjects must be free of major medical illnesses, including diabetes mellitus (must have fasting plasma glucose < 126 mg/dL and taking no anti-hyperglycemic agent), malignancy or significant hepatic or renal disease. Subjects may be hypertensive and on anti-hypertensive medications as long as blood pressure is < 150/100 mm Hg. Subjects may also be dyslipidemic and/or taking drugs to improve abnormalities of lipid metabolism, but they will be excluded if they are taking medications known to alter insulin sensitivity, including glucocorticoids, niacin, anti-retrovirals, thiazolidinediones, or metformin. Use of oral contraceptives or estrogen and/or progesterone replacement therapy is permitted. Weight must be stable and the subjects agree not to change their eating habits or exercise regimen during the study period. There will be no restrictions with regard to race or socioeconomic status, and the racial/ethnic composition of the study population will be reflective of the communities surrounding the Stanford University Medical Center.

Exclusion Criteria:

* Vulnerable subject status.

• Concurrent Endothelin-1 antagonist therapy
• Concurrent Thiazolidinedione therapy
• New York Heart Class III or IV
• PAH related to other etiologies.
• Diabetes Mellitus with Fasting Glucose Levels > 126 mg/dL
• Allergy or hypersensitivity to pioglitazone or bosentan administration.
• Current treatment with statin therapy.
• Initiation of PAH therapy (prostacyclin analogues, phosphodiesterase-5 inhibitors) within three months of enrollment.
• Inability or unwillingness to avoid systemic steroid containing medications for four months. Inhaled steroid use is acceptable.
• Current or recent use or planned treatment with: glyburide, cyclosporine, nilotinib, nisoldipine, ranolazine, thioridazine
• Hepatic transaminases > 2x the upper limit of normal at the center at screening.
• Current or recent (< 6 months) chronic heavy alcohol consumption.
• Current use of another investigational drug (non-FDA approved) for PAH.
• Lung transplant recipients.
• History of myositis.
• Renal failure (Cr 2.0).
• Hospitalized or acutely ill.
• Chronic liver disease (cirrhosis, chronic hepatitis, etc.).
• Abnormalities of the arm or hand or radical mastectomy (preventing brachial artery ultrasound).
• Pregnant or lactating women.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: bosentan; Bosentan 62.5 twice daily for 4 weeks, then 125 mg twice daily.	Drug: bosentan; Bosentan 62.5 mg BID for 4 weeks, then 125mg BID for duration of study.; Other Names: Tracleer
Active Comparator: Pioglitazone; Pioglitazone 15 mg a day for 4 weeks then Pioglitazone 30 mg a day for the duration of the study.	Drug: Pioglitazone; Pioglitazone 15 mg a day for 4 weeks then Pioglitazone 30 mg a day for the duration fo the study.; Other Names: Actos

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Insulin Resistance Profile Change - Triglyceride:HDL Cholesterol Ratio	insulin resistance measured -triglyceride: HDL cholesterol ratio measures at 16 weeks compared with baseline.	baseline and 16 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
6 Minute Walk Test	6 minute walk test measures the distance that a patient can walk on a flat, hard surface in a period of 6 minutes.It assess the disease severity of the subject at 16 week compared to the baseline.	Baseline and 16 weeks
NYHA (New York Heart Association Classification) Changes	New York Heart Classification(NYHA) changes measured at 16 weeks compared with baseline. NYHA Classification: NYHA class I:no symptoms and no limitation in ordinary physical activity NYHA class II:Mild symptoms (mild shortness of breath and/or angina) and slight limitation during ordinary activity NYHA class III:Marked limitation in activity due to symptoms, even during less-than-ordinary activity, NYHA class IV:Severe limitations. Experiences symptoms even while at rest. {Higher NYHA class represent worse symptoms}	Baseline and 16 weeks

Collaborators and Investigators

• Sponsor: Stanford University
• Investigators: Principal Investigator: Roham T. Zamanian, Stanford University

Study record dates

Study Major Dates

• Study Start: September 1, 2008
• Primary Completion (Actual): May 1, 2010
• Study Completion (Actual): May 1, 2010

Study Registration Dates

• First Submitted: January 16, 2009
• First Submitted That Met QC Criteria: January 20, 2009
• First Posted (Estimate): January 21, 2009

Study Record Updates

• Last Update Posted (Actual): March 31, 2017
• Last Update Submitted That Met QC Criteria: February 13, 2017
• Last Verified: February 1, 2017

More Information

Terms related to this study

• Keywords: pulmonary hypertension & insulin resistance
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Glucose Metabolism Disorders; Metabolic Diseases; Respiratory Tract Diseases; Lung Diseases; Hyperinsulinism; Hypertension; Insulin Resistance; Pulmonary Arterial Hypertension; Hypertension, Pulmonary; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Endothelin Receptor Antagonists; Pioglitazone; Bosentan
• Other Study ID Numbers: SU-09052008-1295; IRB#7432