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Interventions Against Insulin Resistance in Pulmonary Arterial Hypertension

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03617458
Recruitment Status : Recruiting
First Posted : August 6, 2018
Last Update Posted : June 16, 2020
Sponsor:
Collaborators:
Mayo Clinic
The Cleveland Clinic
Information provided by (Responsible Party):
Anna Hemnes, Vanderbilt University Medical Center

Tracking Information
First Submitted Date  ICMJE May 2, 2018
First Posted Date  ICMJE August 6, 2018
Last Update Posted Date June 16, 2020
Actual Study Start Date  ICMJE August 23, 2018
Estimated Primary Completion Date December 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 31, 2018)
  • Change from baseline in six minute walk distance (meters) [ Time Frame: baseline and 12 weeks ]
    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) [ Time Frame: baseline and 12 weeks ]
    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.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: July 31, 2018)
  • Change from baseline to week 12 in Body Weight (kilograms) [ Time Frame: baseline and end of 12 weeks ]
    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) [ Time Frame: baseline and end of 12 weeks ]
    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) [ Time Frame: baseline and end of 12 weeks ]
    Change from baseline six-minute walk test distance (meters) at week 12.
  • Change from baseline to week 12 in Borg Dyspnea Score [ Time Frame: baseline and end of 12 weeks ]
    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 [ Time Frame: baseline and end of 12 weeks ]
    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 [ Time Frame: baseline and end of 12 weeks ]
    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 [ Time Frame: baseline and end of 12 weeks ]
    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) [ Time Frame: baseline and end of 12 weeks ]
    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 [ Time Frame: baseline and end of 12 weeks ]
    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) [ Time Frame: baseline and end of 12 weeks ]
    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) [ Time Frame: baseline and end of 12 weeks ]
    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 [ Time Frame: baseline and end of 12 weeks ]
    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 [ Time Frame: baseline and end of 12 weeks ]
    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 [ Time Frame: baseline and end of 12 weeks ]
    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 [ Time Frame: baseline and end of 12 weeks ]
    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 [ Time Frame: baseline and end of 12 weeks ]
    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 [ Time Frame: baseline and end of 12 weeks ]
    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 [ Time Frame: baseline and end of 12 weeks ]
    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 [ Time Frame: baseline and end of 12 weeks ]
    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 [ Time Frame: baseline and end of 12 weeks ]
    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 [ Time Frame: baseline and end of 12 weeks ]
    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 [ Time Frame: baseline and end of 12 weeks ]
    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. [ Time Frame: baseline and end of 12 weeks ]
    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 (%). [ Time Frame: baseline and end of 12 weeks ]
    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 (%). [ Time Frame: baseline and end of 12 weeks ]
    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 [ Time Frame: baseline and end of 12 weeks ]
    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. [ Time Frame: baseline and end of 12 weeks ]
    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 [ Time Frame: baseline and end of 12 weeks ]
    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. [ Time Frame: baseline and end of 12 weeks ]
    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. [ Time Frame: baseline and end of 12 weeks ]
    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 [ Time Frame: baseline and end of 12 weeks ]
    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) [ Time Frame: baseline and end of 12 weeks ]
    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 [ Time Frame: baseline and end of 12 weeks ]
    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 [ Time Frame: baseline and end of 12 weeks ]
    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 [ Time Frame: baseline and end of 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 to week 12 in Patient Medication Regimen, as measured by percentage (%) of subjects with a change in medication regimen [ Time Frame: baseline and end of 12 weeks ]
    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 [ Time Frame: baseline to/and 12 weeks ]
    To assess the effect of a mHealth intervention or no intervention and/or metformin or placebo on incidence of death over 12 weeks.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Interventions Against Insulin Resistance in Pulmonary Arterial Hypertension
Official Title  ICMJE Interventions Against Insulin Resistance in Pulmonary Arterial Hypertension
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Factorial Assignment
Intervention 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: Triple (Care Provider, Investigator, Outcomes 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.
Primary Purpose: Treatment
Condition  ICMJE Pulmonary Artery Hypertension
Intervention  ICMJE
  • Drug: Metformin
    Metformin is a drug has been on the market for several decades and is considered first line therapy for diabetes mellitus type 2.
  • Drug: Placebo
    A treatment with no active ingredients or therapeutic effect.
  • Device: mHealth Intervention
    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.
  • Device: Usual Care
    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.
Study Arms  ICMJE
  • Active Comparator: Metformin + mHealth Intervention

    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).

    Interventions:
    • Drug: Metformin
    • Device: mHealth Intervention
  • Placebo Comparator: Placebo + Usual Care
    Patient will receive non active medicine and routine medical care.
    Interventions:
    • Drug: Placebo
    • Device: Usual Care
  • Active Comparator: Metformin + Usual 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).

    Interventions:
    • Drug: Metformin
    • Device: Usual Care
  • Placebo Comparator: Placebo + mHealth Intervention
    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.
    Interventions:
    • Drug: Placebo
    • Device: mHealth Intervention
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: June 15, 2020)
130
Original Estimated Enrollment  ICMJE
 (submitted: July 31, 2018)
160
Estimated Study Completion Date  ICMJE December 2022
Estimated Primary Completion Date December 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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)
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Study Coordinator 615-343-7396 kelly.burke@vanderbilt.edu
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03617458
Other Study ID Numbers  ICMJE 180198
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Anna Hemnes, Vanderbilt University Medical Center
Study Sponsor  ICMJE Vanderbilt University Medical Center
Collaborators  ICMJE
  • Mayo Clinic
  • The Cleveland Clinic
Investigators  ICMJE
Principal Investigator: Anna R Hemnes, MD Vanderbilt University Medical Center
PRS Account Vanderbilt University Medical Center
Verification Date June 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP