Pulmonary Arterial Hypertension Improvement With Nutrition and Exercise (PHINE)

Pulmonary Arterial Hypertension Improvement With Nutrition and Exercise (PHINE) A Randomized Controlled Trial

The purpose of this study is to investigate the extent to which diet and exercise may improve PAH through the modulation of insulin sensitivity. The central hypothesis is that dysregulated glucose metabolism elicits a response in PAH patients that can be modified by exercise and diet, thereby leading to improvements in pulmonary vascular disease.

Study Overview

• Status: Active, not recruiting
• Conditions: Insulin Resistance; Pulmonary Arterial Hypertension
• Intervention / Treatment: Behavioral: Nutrition and Exercise

Detailed Description

Pulmonary arterial hypertension (PAH) leads to premature death as a consequence of increased pulmonary vascular resistance and right heart failure. PAH-targeted therapies developed over the past 20 years target excessive vasoconstriction. However, the pathobiology of PAH is more complicated, and includes dysregulated vascular cell proliferation, cellular metabolic abnormalities, and inflammation. Even with modern PAH therapies, current outcomes remain poor, with an estimated 3-year survival rate of only 55%. Thus, there is a clear need for more effective therapies, based on better understanding of the pathobiology of the disease.

Insulin resistance has emerged as a potential new mechanism in PAH. Animal models of insulin resistance are associated with PAH, which reverses with the administration of insulin sensitizing drugs. Over the past decade there has been an epidemiologic shift in PAH, where the disease is increasingly observed in older, obese, and diabetic subjects. Low levels of high-density lipoprotein cholesterol in PAH, a feature of insulin resistance, have been observed and found to be a strong independent predictor of PAH mortality. Elevated glycosylated hemoglobin (HbA1c) also correlates with PAH diagnosis and severity. As measured by the OGTT, idiopathic PAH patients have not only insulin resistance, but also an inability to mount an appropriate insulin response to a glucose challenge. These data point to dysfunction in the pancreatic beta cells of PAH patients. It is known that an exercise and low glycemic index diet intervention improves insulin sensitivity in pre-diabetic subjects.

• Study Type: Interventional
• Enrollment (Actual): 34
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic Foundation

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Age range between 18-75 years old
• Group 1 PAH, including idiopathic, heritable, drugs and toxin induced, and PAH associated with connective tissue disease, HIV infection and congenital heart disease
• NYHA Class II or III
• ≥ 1 PAH-targeted therapy with a stable dose for ≥ 2 months
• Stable dose of diuretics and rate of supplemental oxygen for the preceding 2 months

Exclusion Criteria:

• Decompensated Right Heart Failure
• NYHA Class IV
• Syncope within the previous 3 months
• Cardiac Arrhythmia (except for controlled atrial fibrillation or flutter)
• Baseline supplemental O2 > 4 LPM
• Portal Hypertension
• Pulmonary hypertension due to Lung Disease and Hypoxia
• Pulmonary Hypertension due to Left Heart Disease
• Chronic Thromboembolic Pulmonary Hypertension
• Pulmonary Hypertension associated with systemic diseases such as hematological disorders and sarcoidosis
• Type 2 Diabetes
• Evidence of cardiac ischemia on a graded exercise test

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Nutrition and Exercise; 5 days a week of moderate exercise and biweekly diet counseling on Low Glycemic Index/ Mediterranean Diet for 12 weeks.	Behavioral: Nutrition and Exercise; 5 times a week exercise training and biweekly diet counseling for 12 weeks.
No Intervention: Standard of Care; Counseling at baseline on diet as recommended by USDA and on the benefits of regular aerobic exercise.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Insulin Sensitivity	Assessed by the frequently-sampled intravenous glucose tolerance test. Units of assessment in min/uU*mL	5 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Right Ventricular Global Peak Longitudinal Strain	Assessed by the Doppler Echocardiography 2D longitudinal speckle tracking. Units of assessment in percent.	5 years

Collaborators and Investigators

• Sponsor: The Cleveland Clinic
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI)
• Investigators: Principal Investigator: Raed Dweik, MD, The Cleveland Clinic; Principal Investigator: Gustavo Heresi, MD, The Cleveland Clinic

Study record dates

Study Major Dates

• Study Start (Actual): September 27, 2017
• Primary Completion (Actual): February 18, 2022
• Study Completion (Estimated): June 30, 2026

Study Registration Dates

• First Submitted: August 31, 2017
• First Submitted That Met QC Criteria: September 15, 2017
• First Posted (Actual): September 19, 2017

Study Record Updates

• Last Update Posted (Estimated): September 24, 2025
• Last Update Submitted That Met QC Criteria: September 23, 2025
• Last Verified: September 1, 2025

More Information

Terms related to this study

• Keywords: Inflammation; Insulin Resistance; Glucose; Metabolism; Right Ventricular Function
• Additional Relevant MeSH Terms: Pathologic Processes; Metabolic Diseases; Respiratory Tract Diseases; Lung Diseases; Glucose Metabolism Disorders; Hyperinsulinism; Hypertension, Pulmonary; Pathological Conditions, Signs and Symptoms; Nutritional and Metabolic Diseases; Pulmonary Arterial Hypertension; Inflammation; Insulin Resistance; Motor Activity; Movement; Musculoskeletal Physiological Phenomena; Musculoskeletal and Neural Physiological Phenomena; Diet, Food, and Nutrition; Physiological Phenomena; Nutritional Physiological Phenomena; Population Characteristics; Health Status; Demography; Exercise; Nutritional Status
• Other Study ID Numbers: 16-260; R01HL130209 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No