Clinical trial NCT03617458: Interventions Against Insulin Resistance in Pulmonary Arterial Hypertension
Official title: Interventions Against Insulin Resistance in Pulmonary Arterial Hypertension
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Pulmonary Artery Hypertension
Keywords: PAH
Lead sponsor: Vanderbilt University Medical Center
Sponsor class: OTHER
Collaborators: name: Mayo Clinic
name: The Cleveland Clinic
First posted: 2018-08-06
Enrollment: 73
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: FACTORIAL
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.
Primary purpose: TREATMENT

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.

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)

Primary outcomes:
measure: Change From Baseline in Six Minute Walk Distance (Meters)
timeFrame: baseline and 12 weeks
measure: Change From Baseline to Week 12 in World Health Organization Functional Class (WHO FC)
timeFrame: baseline and 12 weeks
Secondary outcomes:
measure: Change From Baseline to Week 12 in Body Weight (Kilograms)
timeFrame: baseline and end of 12 weeks
measure: Change From Baseline to Week 12 in Body Mass Index (BMI)
timeFrame: baseline and end of 12 weeks
measure: Change From Baseline to Week 12 in Absolute Six-Minute Walk Distance (Meters)
timeFrame: baseline and end of 12 weeks
measure: Change From Baseline to Week 12 in Borg Dyspnea Score
timeFrame: baseline and end of 12 weeks
measure: Change From Baseline to Week 12 in Emphasis-10 Quality of Life Survey Score
timeFrame: baseline and end of 12 weeks
measure: Change From Baseline to Week 12 in Daily Step Count, as Measured by the Mean Daily Step Count
timeFrame: baseline and end of 12 weeks
measure: 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
timeFrame: baseline and end of 12 weeks
measure: Change From Baseline to Week 12 in Daily Aerobic Time (Minutes)
timeFrame: baseline and end of 12 weeks
measure: Change From Baseline to Week 12 in Total Daily Activity Assessed in Step Counts Per Minute
timeFrame: baseline and end of 12 weeks
measure: Change From Baseline to Week 12 in Resting Heart Rate (Beats Per Minute)
timeFrame: baseline and end of 12 weeks
measure: Change From Baseline to Week 12 in Homeostatic Model Assessment (HOMA)-Insulin Resistance (IR)
timeFrame: baseline and end of 12 weeks
measure: Number of Participants With Abnormal Laboratory Values of Plasma Estradiol Metabolites
timeFrame: baseline and end of 12 weeks
measure: Number of Participants With Abnormal Laboratory Values of Urine Estradiol Metabolites
timeFrame: baseline and end of 12 weeks
measure: Number of Participants With Abnormal Laboratory Values of Plasma Lipid Profile
timeFrame: baseline and end of 12 weeks
measure: Number of Participants With Abnormal Laboratory Values of Plasma Free Fatty Acid Profiles
timeFrame: baseline and end of 12 weeks
measure: Number of Participants With Abnormal Laboratory Values of Plasma Acylcarnitine Profiles
timeFrame: baseline and end of 12 weeks
measure: Change From Baseline to Week 12 in Plasma Brain Natriuretic Peptide (BNP) Laboratory Value Measured in pg/ml
timeFrame: baseline and end of 12 weeks
measure: Change From Baseline to Week 12 in Quadriceps Skeletal Muscle Triglyceride Content, as Measured by % Triglycerides
timeFrame: baseline and end of 12 weeks
measure: 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
timeFrame: baseline and end of 12 weeks
measure: Change From Baseline to Week 12 in Quadriceps Skeletal Muscle Strength During the Muscle Strength and Function Test, as Measured by Maximum Contraction Strength
timeFrame: baseline and end of 12 weeks
measure: Change From Baseline to Week 12 in Quadriceps Skeletal Muscle Contractile Tissue Cross-sectional
timeFrame: baseline and end of 12 weeks
measure: Change From Baseline to Week 12 in RV Myocardial Muscle Triglyceride Content, as Measured by % Triglycerides
timeFrame: baseline and end of 12 weeks
measure: Change From Baseline to Week 12 in Tricuspid Annular Plane Systolic Excursion (TAPSE), Expressed in mm.
timeFrame: baseline and end of 12 weeks
measure: Change From Baseline in Right Ventricle (RV) and Left Ventricle (LV) Ejection Fraction Values as Assessed by Echocardiogram Results, Expressed in Percentage (%).
timeFrame: baseline and end of 12 weeks
measure: Change From Baseline in Right Ventricle (RV) Fractional Area, as Assessed by Echocardiogram Results, Expressed in Percentage (%).
timeFrame: baseline and end of 12 weeks
measure: Change From Baseline in Tricuspid Annular Velocity (S'), as Assessed by Echocardiogram Results, Expressed in cm/Sec
timeFrame: baseline and end of 12 weeks
measure: Change From Baseline in Tricuspid Regurgitant (TR) Velocity, as Assessed by Echocardiogram Results, Expressed in m/Sec.
timeFrame: baseline and end of 12 weeks
measure: Change From Baseline in Estimated Right Ventricle (RV) and Right Atrial (RA) Pressure, as Assessed by Echocardiogram Results, Expressed in mmHg
timeFrame: baseline and end of 12 weeks
measure: Change From Baseline in Right Ventricle (RV) and Left Ventricle (LV) Diastolic Function as Assessed by Doppler Inflow Patterns on Echocardiogram.
timeFrame: baseline and end of 12 weeks
measure: Change From Baseline in Right Ventricle (RV) Free Wall Longitudinal Strain, as Assessed by Echocardiogram Results, and Expressed as Percent (%) Change in Myocardial Deformation.
timeFrame: baseline and end of 12 weeks
measure: Number of Participants With a Change in Screening Clinical Characteristics
timeFrame: baseline and end of 12 weeks
measure: Number of Patients With Treatment - Emergent Adverse Events (Safety and Tolerability of mHealth Intervention and Drug Treatment in PAH Subjects)
timeFrame: baseline and end of 12 weeks
measure: Patient Satisfaction of Treatment Interventions, as Measured by Change in Emphasis-10 Survey Score
timeFrame: baseline and end of 12 weeks
measure: Dropout Rate Incidence
timeFrame: baseline and end of 12 weeks
measure: Number of Patients With a PAH-related Hospitalization Incidence
timeFrame: baseline and end of 12 weeks
measure: Change From Baseline to Week 12 in Patient Medication Regimen, as Measured by Percentage (%) of Subjects With a Change in Medication Regimen
timeFrame: baseline and end of 12 weeks
measure: Incidence of Death
timeFrame: baseline to/and 12 weeks
Other outcomes:
Locations:
city: Nashville
country: United States
facility: Vanderbilt University Medical Center
state: Tennessee
Study officials:
affiliation: Vanderbilt University Medical Center
name: Anna R Hemnes, MD
role: PRINCIPAL_INVESTIGATOR
References:
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.
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.
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.