Interventions Against Insulin Resistance in Pulmonary Arterial Hypertension

Change in body weight as measured by assessing weight in kilograms at baseline and at week 12.

Change from baseline BMI at week 12. BMI is defined as a measure of body fat based on height and weight that applies to adult men and women.

Change from baseline six-minute walk test distance (meters) at week 12.

Change from baseline Borg dyspnea score at week 12.

The Borg dyspnea score is a measure of the physical activity intensity level based on the subject's perceived exertion. Subjects will rate at resting and peak exercise. Targets exercise capacity. The Borg Dyspnea Scale is a single-item measure of perceived breathlessness (dyspnea). Scores range from 0 to 10, where 0 indicates no breathlessness and 10 indicates maximal breathlessness. Higher scores represent worse outcomes (greater dyspnea), while lower scores represent better outcomes.

Change from baseline Emphasis-10 quality of life survey score at week 12. Survey completed at baseline and 12 weeks.

The emPHasis-10 is a short and easy questionnaire that consists of 10 items which address breathlessness, fatigue, control and confidence. Each item is scored on a semantic differential six-point scale (0-5), with contrasting adjectives at each end. A total emPHasis-10 score is derived using simple aggregation of the 10 items. emPHasis-10 scores range from 0 to 50, higher scores indicate worse quality of life.

Change from the baseline mean daily step count at week 12. Data obtained by the mHealth device.

Change from baseline daily aerobic time at week 12. Aerobic time is defined as total time in minutes spent walking continuously for > 10 minutes without breaking for > 1 minute.

This variable will be assessed by FitBit and is expressed in step counts per minute. Mean value from the last week in the study will be evaluated and mean change from baseline will be calculated.

Monitored regularly using activity tracking device (per second when active, per 5 seconds when inactive). Subject's resting and peak exercise heart rate will also be recorded at baseline and week 12. Targets exercise capacity. Heart rate is expressed as beats per minute.

Change from baseline insulin resistance at week 12. Insulin resistance will be quantified using the homeostatic model assessment of insulin resistance (HOMA-IR), which estimates insulin resistance through fasting plasma insulin and glucose ratios. Targets mechanism of improved exercise capacity. Copilot said:

Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) is an index used to estimate insulin resistance based on fasting glucose and fasting insulin levels. HOMA-IR values generally range from 0 to no fixed upper limit, with higher values indicating greater insulin resistance (worse outcome) and lower values indicating greater insulin sensitivity (better outcome).

As measured by total cholesterol, triglycerides, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and non - high-density lipoprotein cholesterol with mg/dl as the units of measure at baseline and week 12. These laboratory values will be aggregated to assess number of participants with abnormal laboratory values.

As measured by plasma free fatty acid profiles at baseline and week 12. Free fatty acids will be measured in mmol/L. This laboratory value will be assessed by the number of patients with abnormal laboratory values.

As measured by plasma acylcarnitine profiles at baseline and week 12. We will be measuring the laboratory values of C2, C3, C3-dicarboxylic, C4, C4- hydroxyl, C4-dicarboxylic, C5, C5:1, C5 - hydroxy, C5-dicarboxylic, C6, C8, C10, C10:1, C10:2, C12, C14, C14:1, C14:2, C14-hydroxy, C16, C16:1, C161:-hydroxy, C16-hydroxy, C18, C18:1, C18:2, C18-hydroxy, C18:1-hydroxy, C18:2-hydroxy in the unit of measure nmol/L. These laboratory values will be aggregated to assess the number of participants with abnormal laboratory values.

Change from baseline B-type natriuretic peptide (BNP) level at week 12. BNP is a marker of myocardial stress which decreases with exercise training and measured in pg/ml. Targets mechanism of improved exercise capacity.

Change from baseline in Tricuspid Annular Plane systolic Excursion (TAPSE) expressed in mm on echocardiogram results at week 12.

Change from baseline Left Ventricle (LV) Ejection Fraction values on echocardiogram results at week 12 and expressed in percentage (%).

Change from baseline in right ventricle Fractional Area on echocardiogram results at week 12 and expressed in percentage (%).

Change from baseline in Tricuspid Annular Velocity (S') on echocardiogram results at week 12 and expressed in cm/sec.

Change from baseline in Tricuspid Regurgitant (TR) Velocity on echocardiogram results at week 12 and expressed in m/sec.

Change from baseline in the estimated right ventricle and right atrial pressure on echocardiogram results at week 12 and expressed in mmHg.

Change from baseline in right ventricle free wall longitudinal strain on echocardiogram results at week 12 and expressed as percent (%) change in myocardial deformation.

To compare and define the screening clinical characteristics of responders and non-responders to mHealth intervention or no intervention and/or metformin at week 12. We will be taking into account all patient screening data including demographic information, medical history, current medication regimen, physical exam, 6MWT, echocardiogram, MRS, skeletal muscle function test, emphasis-10 survey, WHO functional class, and laboratory values. These results will be aggregated and the results compared to the same characteristics at the end of week 12.

We will be assessing the number of participants with a change in screening clinical characteristics.

Number of treatment-related adverse events as assessed by telephone calls at baseline, week one, week three, week nine, week twelve, and week seventeen.

We will be assessing patient satisfaction of treatment interventions by looking at the number of participants with an increase or decrease in overall score on the emphasis-10 questionnaire from screening and at the end of 12 weeks.

The emPHasis-10 is a short and easy questionnaire that consists of 10 items which address breathlessness, fatigue, control and confidence. Each item is scored on a semantic differential six-point scale (0-5), with contrasting adjectives at each end. A total emPHasis-10 score is derived using simple aggregation of the 10 items. EmPHasis-10 scores range from 0 to 50, higher scores indicate worse quality of life.

To assess the effect of a mHealth intervention or no intervention and/or metformin or placebo on dropout rates over 12 weeks.

To assess the effect of a mHealth intervention or no intervention and/or metformin or placebo on PAH-related hospitalization incidences over 12 weeks. Number of patients will be assessed.

Change from baseline in patient medication regimen at week 12 as measured by percentage (%) of subjects with a change in medication regimen.

To assess the effect of a mHealth intervention or no intervention and/or metformin or placebo on incidence of death over 12 weeks.