Clinical trial NCT05584722: Risk and Resilience in Pulmonary Arterial Hypertension and Genetically Susceptible Individuals
Official title: Risk and Resilience in Pulmonary Arterial Hypertension and Genetically Susceptible Individuals
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Idiopathic Pulmonary Arterial Hypertension
Heritable Pulmonary Arterial Hypertension
Unaffected Mutation Carriers: Healthy Participants With a Known BMPR2 Gene Mutation and Normal Pulmonary Pressure and RV Function on Echo
Healthy Individuals With no Cardiopulmonary Disease
Keywords: pulmonary hypertension
Lead sponsor: Vanderbilt University Medical Center
Sponsor class: OTHER
First posted: 2022-10-18
Enrollment: 150
Sex: ALL
Minimum age (years): 15
Maximum age (years): 80
Standard ages: CHILD
ADULT
OLDER_ADULT
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: PROBABILITY_SAMPLE
Study population: * Diagnosed with idiopathic or heritable, pulmonary arterial hypertension (PAH), defined according to standard criteria
* Unaffected Mutation Carriers: Healthy participants with a known BMPR2 gene mutation and normal pulmonary pressure and RV function on echo
* Healthy Controls: Healthy individuals without cardiopulmonary disease.

Brief summary: Pulmonary arterial hypertension (PAH) is a severe disease with a delayed diagnosis and markedly elevated mortality. High-risk populations, such as those with known genetic defects, provide a unique opportunity to determine the features of susceptibility and resilience to PAH. This proposal will fundamentally overturn the prevailing understanding of PAH by creating molecularly-driven signatures of susceptibility and resilience, provide novel insight into disease severity, and potentially identify new therapeutic targets.

Funding Source - FDA OOPD

Detailed description: Pulmonary arterial hypertension (PAH) is an orphan disease with a delayed diagnosis and markedly elevated mortality from right heart failure. Despite nearly a dozen FDA-approved drugs for PAH, median survival is only seven years. All approved therapies target one of three vasodilatory pathways, and none are disease modifying. This study has two objectives: 1) Understand dynamic and static relationships between molecular markers and PAH progression and resilience; 2) Identify molecular features of PAH risk and resilience in individuals harboring a PAH-causing mutation. It is unknown why some at risk individuals develop PAH and others do not. BMPR2 mutations are present in about 30% of patients with PAH but clinical penetrance is only 20%. Unaffected BMPR2 mutation carriers (UMCs) are a unique and understudied population that may also provide clues to disease trajectory in patients with clinical PAH. Longitudinal natural history studies with molecular profiling in PAH are lacking. Most molecular profiling studies in PAH are cross-sectional which limits understanding of how disease progression and disease markers relate over time. The Investigators propose a strategy of dense clinical and molecular phenotyping at multiple timepoints to overcome inferential limitations of cross-sectional studies. This application will leverage the clinical and research infrastructure built at Vanderbilt over the past 35 years in our study of PAH patients. The investigators share an extensive published record of recruiting patients with this rare disease and related UMCs. The Investigators hypothesize that a comprehensive understanding of risk and resilience over time in patients and genetically susceptible individuals will provide insight into disease severity and identify novel therapeutic targets in patients with PAH. Aim 1 will identify static and dynamic molecular features of disease progression and resilience. 1a: Perform serial clinical, proteomic, and gene expression profiling in HPAH, IPAH, and healthy controls 3 times over 4 years. Bioinformatic and network medicine analyses will identify proteins and RNAs associated with changes in clinical outcomes, functional capacity, and RV function in the parent cohort and two external validation cohorts.1b: Test whether adding molecular risk/resilience markers will improve the performance of a widely used PAH risk prediction tool (REVEAL 2.0 Risk Score). Aim 2 will identify the clinical and molecular factors that promote resilience and susceptibility to PAH in a longitudinal cohort of UMCs. UMCs will undergo serial clinical and molecular phenotyping as in Aim 1. Proteins/genes that mirror PAH are "risk factors" and those that mirror a healthy population are "resilience factors". Explanatory models will be developed and tested in validation cohorts. The Investigators will test UMC risk and resilience features for associations with clinical outcomes in PAH patients and risk prediction performance. These studies will identify signatures of risk and resilience to PAH progression and penetrance, offering an initial step toward personalizing care and surveillance guided by biologic data.

Eligibility criteria: Inclusion Criteria:

* Children and Adults, aged 15 - 80
* Diagnosed with idiopathic or heritable, pulmonary arterial hypertension (PAH), defined according to standard criteria
* Unaffected Mutation Carriers: Healthy participants with a known BMPR2 gene mutation and normal pulmonary pressure and RV function on echo
* Healthy Controls: Healthy individuals without cardiopulmonary disease.
* WHO functional class I-III
* 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.

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
* Functional class IV heart failure
* Requirement of \> 2 diuretic adjustment in the prior three months.

Primary outcomes:
measure: Change in Quality of Life as measured by the emPHasis-10
timeFrame: Baseline to 32 months
measure: Change in Quality of Life as measured by the Pediatric Quality of Life Inventory Version 4.0
timeFrame: Baseline to 32 months
measure: Change in meters walked in six-minute walk distance (meters)
timeFrame: Baseline to 32 months
measure: Change in diffusing capacity for carbon monoxide (DLCO) on the Pulmonary Function Test
timeFrame: Baseline to 32 months
measure: Change in Tricuspid Annular Plane Systolic Excursion (TAPSE), expressed in mm.
timeFrame: Baseline to 32 months
measure: Change in Tricuspid Annular Velocity (S'), as assessed by echocardiogram results, expressed in cm/sec
timeFrame: Baseline to 32 months
measure: Change in Estimated Right Ventricle (RV) Systolic Pressure, as assessed by echocardiogram results, expressed in mmHg
timeFrame: Baseline to 32 months
measure: Change in Right Ventricle (RV) Free Wall Longitudinal Strain, as assessed by echocardiogram results, and expressed as percent (%) change in myocardial deformation.
timeFrame: Baseline to 32 months
measure: Change in Daily Step Count as measured by the mHealth device mean daily step count
timeFrame: Baseline to 32 months
measure: Change in Resting Heart Rate (beats per minute)
timeFrame: Baseline to 32 months
measure: Intensity of activity
timeFrame: Baseline to 32 months
measure: Number of patients with a PAH-related Hospitalization Incidence
timeFrame: Baseline to 32 months
measure: Change in Patient Medication Regimen, as measured by percentage (%) of subjects with a change in medication regimen
timeFrame: Baseline to 32 months
measure: Number of patients with an incidence of death
timeFrame: Baseline to 32 months
measure: Number of patients with an incidence of lung transplantation
timeFrame: Baseline to 32 months
Secondary outcomes:
Other outcomes:
Locations:
city: Nashville
country: United States
facility: Vanderbilt University Medical Center
state: Tennessee
Study officials:
affiliation: Vanderbilt Medical Center
name: Evan Brittain, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Vanderbilt Medical Center
name: Anna Hemnes, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Vanderbilt Medical Center
name: Eric Austin, MD
role: PRINCIPAL_INVESTIGATOR
References: