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Interventions Against Insulin Resistance in Pulmonary Arterial Hypertension

Primary Purpose

Pulmonary Artery Hypertension

Status
Active
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Metformin
Placebo
mHealth Intervention
Usual Care
Sponsored by
Vanderbilt University Medical Center
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Pulmonary Artery Hypertension focused on measuring PAH

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:• Adults aged 18 or older.

  • Diagnosed with idiopathic, heritable, or drug- or toxin-associated pulmonary arterial hypertension (PAH) according to World Health Organization consensus recommendations.
  • Stable PAH-specific medication regimen for three months prior to enrollment. Subjects with only a single diuretic adjustment in the prior three months will be included. Adjustments in IV prostacyclin for side effect management are allowed.
  • Subjects must own a Bluetooth capable modern smartphone capable of receiving and sending text messages and an active data plan.
  • WHO Functional Class I-III
  • Ambulatory

Exclusion Criteria:

  • Prohibited from normal activity due to wheelchair bound status, bed bound status, reliance on a cane/walker, activity-limiting angina, activity-limiting osteoarthritis, or other condition that limits activity
  • Pregnancy
  • Diagnosis of PAH etiology other than idiopathic, heritable, or associated with drugs or toxins
  • FEV1> or = 65% predicted AND normal chest imaging
  • WHO Functional class IV heart failure
  • Requirement of > 1 diuretic adjustment in the prior 30 days
  • Preferred form of activity is not measured by an activity tracker (swimming, ice skating, stair master, or activities on wheels such as bicycling or rollerblading)
  • Type I diabetes mellitus
  • Prior diagnosis of cirrhosis
  • Untreated hypo- or hyper-thyroidism
  • estimated glomerular filtration rate (eGFR) by modification of diet in renal disease (MDRD) <60 milliliters per minute (mL/min)

Sites / Locations

  • Vanderbilt University Medical Center

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Active Comparator

Placebo Comparator

Active Comparator

Placebo Comparator

Arm Label

Metformin + mHealth Intervention

Placebo + Usual Care

Metformin + Usual Care

Placebo + mHealth Intervention

Arm Description

Patients will receive active ingredient medicine with mHealth texting platform, which are messages designed to facilitate self-awareness, reinforce step targets, and link physical activity with a reward or memorable cue. Subjects will receive metformin 500mg. Patients will titrate the medication as follows: 500mg po daily x 5 days, 500mg po twice a day (BID) x 5 days, 500mg po three times a day (TID) x 5 days,1000mg po BID x 69 days (12 weeks total).

Patient will receive non active medicine and routine medical care.

Patient will receive active ingredient medicine with routine medical care. Subjects will receive metformin 500mg. Patients will titrate the medication as follows: 500mg po daily x 5 days, 500mg po BID x 5 days, 500mg po TID x 5 days,1000mg po BID x 69 days (12 weeks total).

Patient will receive non active medicine and the mHealth texting platform, which are messages designed to facilitate self-awareness, reinforce step targets, and link physical activity with a reward or memorable cue.

Outcomes

Primary Outcome Measures

Change from baseline in six minute walk distance (meters)
The change in meters walked for the six-minute walk distance from baseline to week 12
Change from baseline to week 12 in World Health Organization Functional Class (WHO FC)
Change from baseline in WHO functional class at week 12. The World Health Organization (WHO) functional class system was created to define the severity of an individual's symptoms and how they impact on day-to-day activities.

Secondary Outcome Measures

Change from baseline to week 12 in Body Weight (kilograms)
Change in body weight as measured by assessing weight in kilograms at baseline and at week 12.
Change from baseline to week 12 in Body Mass Index (BMI)
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 to week 12 in Absolute Six-Minute Walk Distance (meters)
Change from baseline six-minute walk test distance (meters) at week 12.
Change from baseline to week 12 in Borg Dyspnea Score
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.
Change from baseline to week 12 in Emphasis-10 Quality of Life Survey Score
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 baseline to week 12 in Daily Step Count, as measured by the mean daily step count
Change from the baseline mean daily step count at week 12. Data obtained by the mHealth device.
Change from Baseline to week 12 in Daily Step Count Goal Attainment, as measured by the percentage (%) of subjects who meet their daily step count goal
Assess the frequency (% of days) that the daily step target was achieved over time. Data obtained by the mHealth device.
Change from baseline to week 12 in Daily Aerobic Time (minutes)
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.
Change from baseline to week 12 in total daily activity assessed in step counts per 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.
Change from baseline to week 12 in Resting Heart Rate (beats per minute)
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 to week 12 in Homeostatic model assessment (HOMA)-Insulin Resistance (IR)
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.
Number of participants with abnormal laboratory values of Plasma Estradiol Metabolites
As measured by plasma estradiol in pg/ml, DHEA in mcg/ml, total testosterone in ng/dl, bioavailable testosterone in ng/dl, progesterone in ng/ml, and sex hormone binding globulin (SHBG) in nmol/L at baseline and week 12. These laboratory values will be aggregated to assess the number of participants with abnormal laboratory values.
Number of participants with abnormal laboratory values of Urine Estradiol Metabolites
As measured by the laboratory values Estrone (E1), Estradiol (E2), 2-OHE1, 2-OHE2, 2-MeOE1, 2-MeOE2, 4-OHE1, 4-MeOE1, 4-MeOE2, 16a-OHE1, 17-epiE3, Estriol (E3), 16-ketoE2, 16-epiE3 with pM per mg of urine creatinine. These laboratory values will be assessed at baseline and week 12 and then aggregated to assess the number of participants with abnormal laboratory values.
Number of participants with abnormal laboratory values of Plasma Lipid Profile
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.
Number of participants with abnormal laboratory values of Plasma Free Fatty Acid Profiles
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.
Number of participants with abnormal laboratory values of Plasma Acylcarnitine Profiles
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 to week 12 in Plasma Brain Natriuretic Peptide (BNP) Laboratory Value measured in pg/ml
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 to week 12 in Quadriceps Skeletal Muscle Triglyceride Content, as measured by % triglycerides
Change from baseline quadriceps Skeletal Muscle Triglyceride Content at week 12 as measured by % triglycerides.
Change from baseline to week 12 in Quadriceps Skeletal Muscle Fatigue, as measured by total time to muscle fatigue during the muscle strength and function test
Change from baseline quadriceps Skeletal Muscle Fatigue at week 12 as measured by total time to muscle fatigue during the muscle strength and function test.
Change from baseline to week 12 in Quadriceps Skeletal Muscle Strength During the Muscle Strength and Function Test, as measured by maximum contraction strength
Change from baseline quadriceps Skeletal Muscle Strength during the Muscle Strength and Function Test at week 12 as measured by maximum contraction strength.
Change from baseline to week 12 in quadriceps skeletal muscle contractile tissue cross-sectional
Change from baseline in quadriceps skeletal muscle contractile tissue cross-sectional at week 12 as measured by the relative change in the maximum cross-sectional area of muscle tissue of the quadriceps muscle group, measured in the axial anatomical plane.
Change from baseline to week 12 in RV Myocardial Muscle Triglyceride Content, as measured by % triglycerides
Change from baseline in right ventricle Myocardial Muscle Triglyceride Content results at week 12 as measured by % triglycerides.
Change from baseline to week 12 in Tricuspid Annular Plane systolic Excursion (TAPSE), expressed in mm.
Change from baseline in Tricuspid Annular Plane systolic Excursion (TAPSE) expressed in mm on echocardiogram results at week 12.
Change from baseline in Right Ventricle (RV) and Left Ventricle (LV) Ejection Fraction values as assessed by echocardiogram results, expressed in percentage (%).
Change from baseline in RV and Left Ventricle (LV) Ejection Fraction values on echocardiogram results at week 12 and expressed in percentage (%).
Change from baseline in Right Ventricle (RV) Fractional Area, as assessed by echocardiogram results, 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'), as assessed by echocardiogram results, expressed in cm/sec
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, as assessed by echocardiogram results, expressed in m/sec.
Change from baseline in Tricuspid Regurgitant (TR) Velocity on echocardiogram results at week 12 and expressed in m/sec.
Change from baseline in Estimated Right Ventricle (RV) and Right Atrial (RA) Pressure, as assessed by echocardiogram results, expressed in mmHg
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 (RV) and Left Ventricle (LV) Diastolic Function as assessed by Doppler inflow patterns on echocardiogram.
Change from baseline in right and left ventricular diastolic function as assessed by Doppler inflow patterns on echocardiogram results at week 12
Change from baseline in Right Ventricle (RV) Free Wall Longitudinal Strain, as assessed by echocardiogram results, and expressed as percent (%) change in myocardial deformation.
Change from baseline in right ventricle free wall longitudinal strain on echocardiogram results at week 12 and expressed as percent (%) change in myocardial deformation.
Number of participants with a change in Screening Clinical Characteristics
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 patients with Treatment - Emergent Adverse Events (Safety and Tolerability of mHealth intervention and drug treatment in PAH subjects)
Number of treatment-related adverse events as assessed by telephone calls at baseline, week one, week three, week nine, week twelve, and week seventeen.
Patient Satisfaction of treatment interventions, as measured by change in emphasis-10 survey score
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.
Dropout Rate Incidence
To assess the effect of a mHealth intervention or no intervention and/or metformin or placebo on dropout rates over 12 weeks.
Number of patients with a PAH-related Hospitalization Incidence
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 to week 12 in Patient Medication Regimen, as measured by percentage (%) of subjects with a change in medication regimen
Change from baseline in patient medication regimen at week 12 as measured by percentage (%) of subjects with a change in medication regimen.
Incidence of Death
To assess the effect of a mHealth intervention or no intervention and/or metformin or placebo on incidence of death over 12 weeks.

Full Information

First Posted
May 2, 2018
Last Updated
October 9, 2023
Sponsor
Vanderbilt University Medical Center
Collaborators
Mayo Clinic, The Cleveland Clinic
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1. Study Identification

Unique Protocol Identification Number
NCT03617458
Brief Title
Interventions Against Insulin Resistance in Pulmonary Arterial Hypertension
Official Title
Interventions Against Insulin Resistance in Pulmonary Arterial Hypertension
Study Type
Interventional

2. Study Status

Record Verification Date
October 2023
Overall Recruitment Status
Active, not recruiting
Study Start Date
August 23, 2018 (Actual)
Primary Completion Date
September 9, 2023 (Actual)
Study Completion Date
July 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Vanderbilt University Medical Center
Collaborators
Mayo Clinic, The Cleveland Clinic

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
The primary objective of this study is to determine the impact of two interventions against insulin resistance on the composite endpoint of 10% improvement in baseline six minute walk distance or improvement in World Health Organization (WHO) functional class in humans with pulmonary artery hypertension (PAH).
Detailed Description
The investigators propose to test the hypothesis that interventions to improve insulin resistance will improve exercise capacity and World Health Organization (WHO) functional class in PAH. The investigators propose three specific aims to test this 1) A prospective 2x2 factorial design 12-week clinical trial of metformin or placebo and activity intervention or usual care to assess effect on six minute walk and WHO functional class, 2) Assessment of the interventions in Aim 1 in a subset of patients on right ventricle (RV) and peripheral muscle function and lipid content and markers of pulmonary vascular disease to define how these interventions may work in PAH and 3) Identify and prospectively test peripheral blood markers of metformin response in PAH. The broad goals of this work are to demonstrate the efficacy and mechanisms of interventions against insulin resistance in PAH and to identify which patients are most likely to benefit from these interventions, moving to precision medicine in PAH. The investigators are planning a factorial design trial. Patients will be randomized twice. The first is metformin or placebo and is quadruple randomized. The second is mobile health (mHealth) intervention via texts or standard of care and is not blinded to the patients, but is to the investigator and thus is triple randomized.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Pulmonary Artery Hypertension
Keywords
PAH

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Factorial Assignment
Model Description
This is a phase II, 2x2 factorial randomized, blinded trial testing metformin versus placebo and a mHealth intervention (mHealth) versus usual care of 12 weeks.
Masking
Care ProviderInvestigatorOutcomes Assessor
Masking Description
The investigators propose a phase II, 2x2 factorial randomized, blinded trial testing metformin versus placebo and a mobile health intervention (mHealth) versus usual care of 12 weeks.
Allocation
Randomized
Enrollment
82 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Metformin + mHealth Intervention
Arm Type
Active Comparator
Arm Description
Patients will receive active ingredient medicine with mHealth texting platform, which are messages designed to facilitate self-awareness, reinforce step targets, and link physical activity with a reward or memorable cue. Subjects will receive metformin 500mg. Patients will titrate the medication as follows: 500mg po daily x 5 days, 500mg po twice a day (BID) x 5 days, 500mg po three times a day (TID) x 5 days,1000mg po BID x 69 days (12 weeks total).
Arm Title
Placebo + Usual Care
Arm Type
Placebo Comparator
Arm Description
Patient will receive non active medicine and routine medical care.
Arm Title
Metformin + Usual Care
Arm Type
Active Comparator
Arm Description
Patient will receive active ingredient medicine with routine medical care. Subjects will receive metformin 500mg. Patients will titrate the medication as follows: 500mg po daily x 5 days, 500mg po BID x 5 days, 500mg po TID x 5 days,1000mg po BID x 69 days (12 weeks total).
Arm Title
Placebo + mHealth Intervention
Arm Type
Placebo Comparator
Arm Description
Patient will receive non active medicine and the mHealth texting platform, which are messages designed to facilitate self-awareness, reinforce step targets, and link physical activity with a reward or memorable cue.
Intervention Type
Drug
Intervention Name(s)
Metformin
Intervention Description
Metformin is a drug has been on the market for several decades and is considered first line therapy for diabetes mellitus type 2.
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
A treatment with no active ingredients or therapeutic effect.
Intervention Type
Device
Intervention Name(s)
mHealth Intervention
Intervention Description
Our Health Insurance Portability and Accountability Act (HIPPA) compliant texting platform is linked to the Fitbit Application Program Interface. Real time activity data will be transmitted from the subject's smartphone to our mHealth platform via cellular network.Subjects assigned to the texting arm will receive 3 texts/day in sync with their preferred morning, lunch, and evening leisure schedule, which is defined at enrollment. These texts will use personal, disease-specific, and provider information to deliver 2 types of messages customized to the current step count and sent in equal proportion. Messages are designed to facilitate self-awareness, reinforce step targets, and link physical activity with a reward or memorable cue.
Intervention Type
Device
Intervention Name(s)
Usual Care
Intervention Description
Our HIPPA compliant texting platform is linked to the Fitbit Application Program Interface. Real time activity data will be transmitted from the subject's smartphone to our mHealth platform via cellular network.
Primary Outcome Measure Information:
Title
Change from baseline in six minute walk distance (meters)
Description
The change in meters walked for the six-minute walk distance from baseline to week 12
Time Frame
baseline and 12 weeks
Title
Change from baseline to week 12 in World Health Organization Functional Class (WHO FC)
Description
Change from baseline in WHO functional class at week 12. The World Health Organization (WHO) functional class system was created to define the severity of an individual's symptoms and how they impact on day-to-day activities.
Time Frame
baseline and 12 weeks
Secondary Outcome Measure Information:
Title
Change from baseline to week 12 in Body Weight (kilograms)
Description
Change in body weight as measured by assessing weight in kilograms at baseline and at week 12.
Time Frame
baseline and end of 12 weeks
Title
Change from baseline to week 12 in Body Mass Index (BMI)
Description
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.
Time Frame
baseline and end of 12 weeks
Title
Change from baseline to week 12 in Absolute Six-Minute Walk Distance (meters)
Description
Change from baseline six-minute walk test distance (meters) at week 12.
Time Frame
baseline and end of 12 weeks
Title
Change from baseline to week 12 in Borg Dyspnea Score
Description
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.
Time Frame
baseline and end of 12 weeks
Title
Change from baseline to week 12 in Emphasis-10 Quality of Life Survey Score
Description
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.
Time Frame
baseline and end of 12 weeks
Title
Change from baseline to week 12 in Daily Step Count, as measured by the mean daily step count
Description
Change from the baseline mean daily step count at week 12. Data obtained by the mHealth device.
Time Frame
baseline and end of 12 weeks
Title
Change from Baseline to week 12 in Daily Step Count Goal Attainment, as measured by the percentage (%) of subjects who meet their daily step count goal
Description
Assess the frequency (% of days) that the daily step target was achieved over time. Data obtained by the mHealth device.
Time Frame
baseline and end of 12 weeks
Title
Change from baseline to week 12 in Daily Aerobic Time (minutes)
Description
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.
Time Frame
baseline and end of 12 weeks
Title
Change from baseline to week 12 in total daily activity assessed in step counts per minute
Description
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.
Time Frame
baseline and end of 12 weeks
Title
Change from baseline to week 12 in Resting Heart Rate (beats per minute)
Description
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.
Time Frame
baseline and end of 12 weeks
Title
Change from baseline to week 12 in Homeostatic model assessment (HOMA)-Insulin Resistance (IR)
Description
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.
Time Frame
baseline and end of 12 weeks
Title
Number of participants with abnormal laboratory values of Plasma Estradiol Metabolites
Description
As measured by plasma estradiol in pg/ml, DHEA in mcg/ml, total testosterone in ng/dl, bioavailable testosterone in ng/dl, progesterone in ng/ml, and sex hormone binding globulin (SHBG) in nmol/L at baseline and week 12. These laboratory values will be aggregated to assess the number of participants with abnormal laboratory values.
Time Frame
baseline and end of 12 weeks
Title
Number of participants with abnormal laboratory values of Urine Estradiol Metabolites
Description
As measured by the laboratory values Estrone (E1), Estradiol (E2), 2-OHE1, 2-OHE2, 2-MeOE1, 2-MeOE2, 4-OHE1, 4-MeOE1, 4-MeOE2, 16a-OHE1, 17-epiE3, Estriol (E3), 16-ketoE2, 16-epiE3 with pM per mg of urine creatinine. These laboratory values will be assessed at baseline and week 12 and then aggregated to assess the number of participants with abnormal laboratory values.
Time Frame
baseline and end of 12 weeks
Title
Number of participants with abnormal laboratory values of Plasma Lipid Profile
Description
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.
Time Frame
baseline and end of 12 weeks
Title
Number of participants with abnormal laboratory values of Plasma Free Fatty Acid Profiles
Description
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.
Time Frame
baseline and end of 12 weeks
Title
Number of participants with abnormal laboratory values of Plasma Acylcarnitine Profiles
Description
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.
Time Frame
baseline and end of 12 weeks
Title
Change from baseline to week 12 in Plasma Brain Natriuretic Peptide (BNP) Laboratory Value measured in pg/ml
Description
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.
Time Frame
baseline and end of 12 weeks
Title
Change from baseline to week 12 in Quadriceps Skeletal Muscle Triglyceride Content, as measured by % triglycerides
Description
Change from baseline quadriceps Skeletal Muscle Triglyceride Content at week 12 as measured by % triglycerides.
Time Frame
baseline and end of 12 weeks
Title
Change from baseline to week 12 in Quadriceps Skeletal Muscle Fatigue, as measured by total time to muscle fatigue during the muscle strength and function test
Description
Change from baseline quadriceps Skeletal Muscle Fatigue at week 12 as measured by total time to muscle fatigue during the muscle strength and function test.
Time Frame
baseline and end of 12 weeks
Title
Change from baseline to week 12 in Quadriceps Skeletal Muscle Strength During the Muscle Strength and Function Test, as measured by maximum contraction strength
Description
Change from baseline quadriceps Skeletal Muscle Strength during the Muscle Strength and Function Test at week 12 as measured by maximum contraction strength.
Time Frame
baseline and end of 12 weeks
Title
Change from baseline to week 12 in quadriceps skeletal muscle contractile tissue cross-sectional
Description
Change from baseline in quadriceps skeletal muscle contractile tissue cross-sectional at week 12 as measured by the relative change in the maximum cross-sectional area of muscle tissue of the quadriceps muscle group, measured in the axial anatomical plane.
Time Frame
baseline and end of 12 weeks
Title
Change from baseline to week 12 in RV Myocardial Muscle Triglyceride Content, as measured by % triglycerides
Description
Change from baseline in right ventricle Myocardial Muscle Triglyceride Content results at week 12 as measured by % triglycerides.
Time Frame
baseline and end of 12 weeks
Title
Change from baseline to week 12 in Tricuspid Annular Plane systolic Excursion (TAPSE), expressed in mm.
Description
Change from baseline in Tricuspid Annular Plane systolic Excursion (TAPSE) expressed in mm on echocardiogram results at week 12.
Time Frame
baseline and end of 12 weeks
Title
Change from baseline in Right Ventricle (RV) and Left Ventricle (LV) Ejection Fraction values as assessed by echocardiogram results, expressed in percentage (%).
Description
Change from baseline in RV and Left Ventricle (LV) Ejection Fraction values on echocardiogram results at week 12 and expressed in percentage (%).
Time Frame
baseline and end of 12 weeks
Title
Change from baseline in Right Ventricle (RV) Fractional Area, as assessed by echocardiogram results, expressed in percentage (%).
Description
Change from baseline in right ventricle Fractional Area on echocardiogram results at week 12 and expressed in percentage (%).
Time Frame
baseline and end of 12 weeks
Title
Change from baseline in Tricuspid Annular Velocity (S'), as assessed by echocardiogram results, expressed in cm/sec
Description
Change from baseline in Tricuspid Annular Velocity (S') on echocardiogram results at week 12 and expressed in cm/sec.
Time Frame
baseline and end of 12 weeks
Title
Change from baseline in Tricuspid Regurgitant (TR) Velocity, as assessed by echocardiogram results, expressed in m/sec.
Description
Change from baseline in Tricuspid Regurgitant (TR) Velocity on echocardiogram results at week 12 and expressed in m/sec.
Time Frame
baseline and end of 12 weeks
Title
Change from baseline in Estimated Right Ventricle (RV) and Right Atrial (RA) Pressure, as assessed by echocardiogram results, expressed in mmHg
Description
Change from baseline in the estimated right ventricle and right atrial pressure on echocardiogram results at week 12 and expressed in mmHg.
Time Frame
baseline and end of 12 weeks
Title
Change from baseline in Right Ventricle (RV) and Left Ventricle (LV) Diastolic Function as assessed by Doppler inflow patterns on echocardiogram.
Description
Change from baseline in right and left ventricular diastolic function as assessed by Doppler inflow patterns on echocardiogram results at week 12
Time Frame
baseline and end of 12 weeks
Title
Change from baseline in Right Ventricle (RV) Free Wall Longitudinal Strain, as assessed by echocardiogram results, and expressed as percent (%) change in myocardial deformation.
Description
Change from baseline in right ventricle free wall longitudinal strain on echocardiogram results at week 12 and expressed as percent (%) change in myocardial deformation.
Time Frame
baseline and end of 12 weeks
Title
Number of participants with a change in Screening Clinical Characteristics
Description
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.
Time Frame
baseline and end of 12 weeks
Title
Number of patients with Treatment - Emergent Adverse Events (Safety and Tolerability of mHealth intervention and drug treatment in PAH subjects)
Description
Number of treatment-related adverse events as assessed by telephone calls at baseline, week one, week three, week nine, week twelve, and week seventeen.
Time Frame
baseline and end of 12 weeks
Title
Patient Satisfaction of treatment interventions, as measured by change in emphasis-10 survey score
Description
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.
Time Frame
baseline and end of 12 weeks
Title
Dropout Rate Incidence
Description
To assess the effect of a mHealth intervention or no intervention and/or metformin or placebo on dropout rates over 12 weeks.
Time Frame
baseline and end of 12 weeks
Title
Number of patients with a PAH-related Hospitalization Incidence
Description
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.
Time Frame
baseline and end of 12 weeks
Title
Change from baseline to week 12 in Patient Medication Regimen, as measured by percentage (%) of subjects with a change in medication regimen
Description
Change from baseline in patient medication regimen at week 12 as measured by percentage (%) of subjects with a change in medication regimen.
Time Frame
baseline and end of 12 weeks
Title
Incidence of Death
Description
To assess the effect of a mHealth intervention or no intervention and/or metformin or placebo on incidence of death over 12 weeks.
Time Frame
baseline to/and 12 weeks

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:• Adults aged 18 or older. Diagnosed with idiopathic, heritable, or drug- or toxin-associated pulmonary arterial hypertension (PAH) according to World Health Organization consensus recommendations. Stable PAH-specific medication regimen for three months prior to enrollment. Subjects with only a single diuretic adjustment in the prior three months will be included. Adjustments in IV prostacyclin for side effect management are allowed. Subjects must own a Bluetooth capable modern smartphone capable of receiving and sending text messages and an active data plan. WHO Functional Class I-III Ambulatory Exclusion Criteria: Prohibited from normal activity due to wheelchair bound status, bed bound status, reliance on a cane/walker, activity-limiting angina, activity-limiting osteoarthritis, or other condition that limits activity Pregnancy Diagnosis of PAH etiology other than idiopathic, heritable, or associated with drugs or toxins FEV1> or = 65% predicted AND normal chest imaging WHO Functional class IV heart failure Requirement of > 1 diuretic adjustment in the prior 30 days Preferred form of activity is not measured by an activity tracker (swimming, ice skating, stair master, or activities on wheels such as bicycling or rollerblading) Type I diabetes mellitus Prior diagnosis of cirrhosis Untreated hypo- or hyper-thyroidism estimated glomerular filtration rate (eGFR) by modification of diet in renal disease (MDRD) <60 milliliters per minute (mL/min)
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Anna R Hemnes, MD
Organizational Affiliation
Vanderbilt University Medical Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
Vanderbilt University Medical Center
City
Nashville
State/Province
Tennessee
ZIP/Postal Code
37232
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
1863023
Citation
D'Alonzo GE, Barst RJ, Ayres SM, Bergofsky EH, Brundage BH, Detre KM, Fishman AP, Goldring RM, Groves BM, Kernis JT, et al. Survival in patients with primary pulmonary hypertension. Results from a national prospective registry. Ann Intern Med. 1991 Sep 1;115(5):343-9. doi: 10.7326/0003-4819-115-5-343.
Results Reference
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PubMed Identifier
22281797
Citation
Benza RL, Miller DP, Barst RJ, Badesch DB, Frost AE, McGoon MD. An evaluation of long-term survival from time of diagnosis in pulmonary arterial hypertension from the REVEAL Registry. Chest. 2012 Aug;142(2):448-456. doi: 10.1378/chest.11-1460.
Results Reference
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PubMed Identifier
22723290
Citation
Mathai SC, Puhan MA, Lam D, Wise RA. The minimal important difference in the 6-minute walk test for patients with pulmonary arterial hypertension. Am J Respir Crit Care Med. 2012 Sep 1;186(5):428-33. doi: 10.1164/rccm.201203-0480OC. Epub 2012 Jun 21.
Results Reference
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Interventions Against Insulin Resistance in Pulmonary Arterial Hypertension

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