Hypertension, Pulmonary
Conditions
Keywords
pulmonary hypertension & insulin resistance
Brief summary
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.
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.
Interventions
DRUGbosentan
Bosentan 62.5 mg BID for 4 weeks, then 125mg BID for duration of study.
DRUGPioglitazone
Pioglitazone 15 mg a day for 4 weeks then Pioglitazone 30 mg a day for the duration fo the study.
Sponsors
Stanford University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Insulin Resistance Profile Change - Triglyceride:HDL Cholesterol Ratio | baseline and 16 weeks | insulin resistance measured -triglyceride: HDL cholesterol ratio measures at 16 weeks compared with baseline. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 6 Minute Walk Test | Baseline and 16 weeks | 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. |
| NYHA (New York Heart Association Classification) Changes | Baseline and 16 weeks | 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} |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Bosentan Bosentan 62.5 twice daily for 4 weeks, then 125 mg twice daily.
bosentan: Bosentan 62.5 mg BID for 4 weeks, then 125mg BID for duration of study. | 1 |
| Pioglitazone Pioglitazone 15 mg a day for 4 weeks then Pioglitazone 30 mg a day for the duration of the study.
Pioglitigone: Pioglitazone 15 mg a day for 4 weeks then Pioglitazone 30 mg a day for the duration fo the study. | 1 |
| Total | 2 |
Baseline characteristics
| Characteristic | Bosentan | Pioglitazone | Total |
|---|---|---|---|
| Age, Continuous | 61 years | 51 years | 56 years |
| Region of Enrollment United States | 1 participants | 1 participants | 2 participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 1 Participants | 1 Participants | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 1 | 0 / 1 |
| serious Total, serious adverse events | 0 / 1 | 0 / 1 |
Outcome results
Primary
Insulin Resistance Profile Change - Triglyceride:HDL Cholesterol Ratio
insulin resistance measured -triglyceride: HDL cholesterol ratio measures at 16 weeks compared with baseline.
Time frame: baseline and 16 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Bosentan | Insulin Resistance Profile Change - Triglyceride:HDL Cholesterol Ratio | -0.22 ratio |
| Pioglitazone | Insulin Resistance Profile Change - Triglyceride:HDL Cholesterol Ratio | -1.96 ratio |
Secondary
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.
Time frame: Baseline and 16 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Bosentan | 6 Minute Walk Test | -71 meters |
| Pioglitazone | 6 Minute Walk Test | -23 meters |
Secondary
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}
Time frame: Baseline and 16 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Bosentan | NYHA (New York Heart Association Classification) Changes | 0 NYHA class |
| Pioglitazone | NYHA (New York Heart Association Classification) Changes | 0 NYHA class |