Assessing the Utility of Submaximal CPET in Treatment Management of PAH

Assessing the Utility of Shape Submaximal Cardiopulmonary Exercise Testing in Detecting, Diagnosis and Treatment Management of Pulmonary Arterial Hypertension.

Pulmonary hypertension (PH) is associated with worsening breathlessness and exercise capacity, right-heart failure, and adverse outcomes including increased mortality. Moreover, PH disease progression can be rapid; pharmaceutical intervention in early-stage Pulmonary Hypertension (PH) can improve symptoms and functional capacity, and delayed diagnosis and treatment of Pulmonary Hypertension (PH) likely reduces survival.

Study Overview

• Status: Not yet recruiting
• Conditions: Pulmonary Arterial Hypertension
• Intervention / Treatment: Device: Shape II CPET

Detailed Description

Pulmonary hypertension (PH) is a devastating disease characterized by progressive dyspnea/exercise intolerance, right-heart failure, and carries a high risk of morbidity and early mortality. PH disease progression can be rapid, and any delay in the diagnosis and treatment of PH likely reduces survival. Given its clinical and prognostic significance, early and accurate diagnosis of PH to allow prompt and optimal establishment of clinical care is of critical importance. While traditional maximal/comprehensive cardiopulmonary exercise testing (CPET) has been validated in PH, it has limitations that have hindered its applicability to routine clinical assessment and monitoring. Our preliminary data suggest that the signature ventilatory and pulmonary gas exchange derangements of PH become apparent during even submaximal exercise. Our comprehensive proof-of-concept study (133 patients) supports our hypothesis that the addition of pulmonary gas exchange responses to a standardized 3-minute submaximal exercise test (Shape CPET) to standard echocardiographic evidence of PH (i.e Right ventricular systolic pressure( RVSP) >50 mmHg, suspicion of Right ventricular (RV) dysfunction) improves the sensitivity for PH detection by almost 40%. The Shape CPET system is compact and utilizes pattern-recognition software that automates interpretation, making the system ideally suitable for widespread adoption. The overarching objective of this small business innovation research (SBIR) proposal is to categorically establish the Shape CPET as a tool that: 1) improves early detection of PH; and 2) provides an objective evidence-based measure of PH therapy efficacy that can be easily used in academic and community practices. Investigators have established a 10-center consortium of academic and community PH centers for this SBIR proposal. Specific Aim 1 will assess the clinical utility of submaximal cardiopulmonary exercise testing as a complementary tool for the identification of pulmonary hypertension. Specific Aim 2 will assess whether pharmacotherapy-induced improvements in pulmonary hypertension severity and disease status are reflected in the physiological responses to a standardized submaximal cardiopulmonary exercise test. The investigators hypothesize that the Shape CPET will prove to be an efficacious adjunct to traditional clinical metrics to track changes in pulmonary vascular function over time and responses to therapy aimed at alleviating PAH.

• Study Type: Observational
• Enrollment (Estimated): 550

Contacts and Locations

Study Locations

• United States
  • California
    • Torrance, California, United States, 90502-2006
      • Harbor-UCLA Medical Center
      • Contact: Tatiana Gomes; Phone Number: 310-222-3560; Email: tatiana.gomes@lundquist.org
      • Principal Investigator: Ronald Oudiz, MD
  • Colorado
    • Denver, Colorado, United States, 80206-2761
      • National Jewish Health
      • Contact: Jami Henriksen; Phone Number: 303-398-1096; Email: henriksenj@NJhealth.org
      • Principal Investigator: Marjorie P George, MD
  • Florida
    • Jacksonville, Florida, United States, 32224-1865
      • Mayo Clinic
      • Contact: Taylor Galloway; Phone Number: 904-953-0543; Email: galloway.taylor@mayo.edu
      • Principal Investigator: Brian Taylor, Phd
  • Georgia
    • Atlanta, Georgia, United States, 30312-1213
      • WellStar Health System
      • Contact: Brandon D Pickens; Phone Number: 470-793-4046; Email: brandon.pickens@wellstar.org
      • Principal Investigator: Paul Guichard, DO
    • Columbus, Georgia, United States, 31904-7955
      • Southeastern Cardiology
      • Contact: Tanya Milton; Phone Number: 706-243-4500; Email: hchampion@southeasterncardiology.com
      • Principal Investigator: Hunter Champion, MD, Phd
  • New York
    • New York, New York, United States, 10021-9800
      • Weill Cornell Medicine
      • Principal Investigator: Evelyn Horn, MD
      • Contact: Dolores T Reynolds; Phone Number: 646-962-5555; Email: dtr2001@med.cornell.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Probability Sample

Study Population

The population will be consenting legal adults (minimum age 21 and no limit on maximum age) unless imposed by individual site standard of care (SoC). with no contraindications to exercise testing will be recruited. Suspected of pulmonary hypertension PH.

Description

Inclusion Criteria Study Aim 1:

• Subject referred for clinical assessment due to unexplained or worsening dyspnea and/or suspected Pulmonary Hypertension (PH).
• Subject is able and willing to provide appropriate Informed consent.
• Subject is greater than or equal to 21 years old
• Subject is not dependent on supplemental O2 to allow for CPET/sub-max-Shape exercise testing
• Subject is capable of performing a sub-max, incremental step exercise protocol, both physically and mentally, with no absolute contraindications to exercise testing, such as those causing symptoms or hemodynamic compromise Contraindications include syncope, active endocarditis, myocarditis or pericarditis, symptomatic severe aortic stenosis, uncontrolled heart failure (HF), uncontrolled cardiac arrhythmia, acute pulmonary embolus or pulmonary infarction, thrombosis of lower extremities, suspected dissecting aneurysm, uncontrolled asthma, pulmonary edema, respiratory failure, acute non-pulmonary disorder that may affect exercise performance or be aggravated by exercise such as infarction, renal failure or thyrotoxicosis, medical impairment with inability to cooperate with protocol instructions

Inclusion Criteria Study Aim 2:

• Subject must have been enrolled in Study Aim 1
• Dyspnea subject who has undergone echo examination and presented with suspicion of pulmonary arterial hypertension (PAH) category world health organization (WHO) I (mean pulmonary artery pressure (PAP) ≥ 20 mmHg; pulmonary vascular resistance (PVR) > 2 WU and pulmonary capillary wedge pressure (PCWP) ≤ 15 mmHg

Exclusion Criteria Study Aim 1:

• Resting Hypoxemia (oxygen saturation (Sp02) <85%)
• The subject's mean arterial blood pressure is less than 70 mmHg despite fluid resuscitation and pressor therapy.
• The subject has positive pregnancy test (verified in a manner consistent with institution's standard of care)
• The subject has joint limitations to performing incremental exercise with gas exchange monitoring.

Exclusion Criteria Study Aim 2:

• Normal pulmonary hemodynamics on right heart Catheterization (RHC) ( mean pulmonary arterial pressure (mPAP) ≤ 20mmHG)
• RHC evidence of precapillary PH (mPAP >20 mmHg, PAWP ≤15 mmHg, PVR >2 WU) but has a diagnosis of group III, IV or V PH
• RHC evidence isolated postcapillary PH (mPAP >20 mmHg, PAWP >15 mmHg, PVR ≤2 WU) or combined pre- and postcapillary PH (mPAP >20 mmHg, pulmonary arterial wedge pressure (PAWP) >15 mmHg, PVR >2 WU)

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
PAH Patients; Pulmonary hypertension (PH) is associated with worsening breathlessness and exercise capacity, right-heart failure, and adverse outcomes including increased mortality. Moreover, PH disease progression can be rapid; pharmaceutical intervention in early-stage PH can improve symptoms and functional capacity, and delayed diagnosis and treatment of PH likely reduces survival.	Device: Shape II CPET; Submaximal Cardiopulmonary exercise test equipment

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Demonstrate the Submaximal Cardiopulmonary exercise testing (Shape CPET) is an effective complementary tool in the resting echocardiogram for detection of Pulmonary Hypertension.	Identify Shape(CPET) gas exchange metrics, alone and in combination with echocardiographic (ECHO) measures to test for a correlation with Right heart catheterization (RHC) derived diagnostic determinations using standard uni- and multivariate analytic tools correlations with ECHO area under the curve (AUC) of receiver operating character (ROC) curves of Shape CPET+ ECHO vs those of Echo only screening will be used to examine if combining Shape with ECHO can improve the Echo only screening tool. Identify variants of the fuzzy random forest walk algorithm. This approach, patients are divided into two groups: a training and test set. The algorithm creates "leaves" of unique variable combinations that "bag" all patients in the training set into categories of classification (pulmonary arterial hypertension). The combinatorial routine that best leads to the classification in the training set is applied to the testing set whose results are compared to the reference standard.	10-12 months
Demonstrate the percent change in submaximal Shape Cardiopulmonary exercise testing (Shape CPET) metrics and the 6 minute walk time distance (6MWTd)	Identify the percent changes in the Shape variables and 6-minute walk time distance (6MWTd) from baseline to first post treatment (90 days) and to second post treatment (180 days) will be averaged and compared statistically using two-way, paired "t" tests with a significance level set at p<.05.	3 months and 6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The correlation of select non-invasive Shape Cardiopulmonary exercise test (CPET) metric to invasive hemodynamic variables	Correlation of the Shape cardiopulmonary exercise test (CPET) variables with right heart catheterization (RHC) derived diagnostic determinations using standard uni- and multivariate analytic tools correlations with echocardiogram area under the curve (AUC) of receiver operating characteristics (ROC) curves of Shape CPET + Echocardiograph (Echo) vs those of Echo only screening will be used to examine if combining Shape with echocardiography can improve the Echo only screening tool	10-12 months
Assessment of Pharmacotherapy-induced improvement or sensitivity of changes in pulmonary hypertension severity and disease status	Identify changes from baseline to subsequent visits in values of Shape CPET variable in the physiological responses to a PAH functional class, 6MWTd and time to clinical worsening (TTCW). The TTCW or the "time to clinical worsening" is based upon 1) an increase in functional capacitance (FC); 2) a 15 % decrease in 6-minute walk test distance (6MWTd) 3) hospitalization in days 4) death in days.	3 months and 6 months

Collaborators and Investigators

• Sponsor: Shape Medical Systems, Inc.
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI)

Study record dates

Study Major Dates

• Study Start (Estimated): April 1, 2024
• Primary Completion (Estimated): September 30, 2024
• Study Completion (Estimated): December 30, 2024

Study Registration Dates

• First Submitted: June 29, 2023
• First Submitted That Met QC Criteria: August 2, 2023
• First Posted (Actual): August 7, 2023

Study Record Updates

• Last Update Posted (Actual): March 13, 2024
• Last Update Submitted That Met QC Criteria: March 12, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Respiratory Tract Diseases; Lung Diseases; Hypertension, Pulmonary; Hypertension; Pulmonary Arterial Hypertension; Familial Primary Pulmonary Hypertension
• Other Study ID Numbers: SHP0422; R44HL162169 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: Yes
• product manufactured in and exported from the U.S.: No