Repeatability and Sensitivity to Change of Non-invasive Endpoints in PAH (RESPIRE)

February 14, 2019 updated by: Andy J Swift, University of Sheffield

A Prospective Study Comparing the REpeatability and Sensitivity to Change of Non-invasive Endpoints in Pulmonary arterIal hypeRtEnsion

Pulmonary arterial hypertension (PAH) is progressive life limiting disease with a median survival of less than 3 years without treatment. Current drug trials in PAH commonly use simple tests for example the 6-minute walk test, blood tests such as N-terminal pro-brain-type natriuretic peptide (NT-pro-BNP) and BNP, and haemodynamic measures such as PAP and PVR obtained by RHC as endpoints. These tests are surrogate markers of disease severity in patients with pulmonary hypertension. There is now evidence suggesting that magnetic resonance imaging (MRI) may be helpful in the follow up of patients with PAH with high accuracy for the detection of treatment failure, this is because MRI can track changes occurring in the heart by direct visualisation of cardiopulmonary morphology and function, an advantage over existing methods. However, the reproducible of MRI measurements in patients with PAH is not known, and the comparative repeatability of MRI in relation to traditional candidate endpoints such as walk tests and blood tests used in drug trials is not known.

Study Overview

Status

Unknown

Conditions

Intervention / Treatment

Detailed Description

Background:

Pulmonary arterial hypertension (PAH) is a rare but severe and progressive disorder, with a prevalence of approximately 50 in 1,000,000 of the population. The condition is incurable with high morbidity and mortality despite the development of effective treatment options. The emergence of goal orientated therapy initially focused interest on prognostic markers that can both inform the clinician regarding disease severity at presentation and be used to follow-up response to therapy and aid in decisions regarding listing for transplantation. A number of effective therapies are available but are very expensive and there is an urgent need for non-invasive and specific markers to assess treatment response and guide therapy. Accurate follow up with reproducible measurements of the heart and pulmonary vasculature are essential in order to accurately characterise treatment response.

Magnetic resonance imaging (MRI) a non-ionising and non-invasive technique provides accurate and reproducible information on cardiac morphology and function. MR imaging is becoming an established technique in the evaluation of patients with PAH, allowing direct visualisation and accurate analysis of the structure and function of the right ventricle (RV). There is a pressing need to validate and standardise MRI methods in pulmonary hypertension to allow clinical translation nationally and internationally and to support trials of novel disease modifying therapies.

Aims:

The aim of this study is to determine the repeatability and capability of detecting change of MR imaging measurements in comparison with walk tests and blood tests in patients with PAH, and define the optimal MRI analysis protocol for use in clinical practice and in future studies in PAH.

Objectives:

  • Determine the inter-observer and inter-scan variability of MRI in healthy volunteers and patients with PAH
  • Compare the inter-observer and inter-scan variability of MRI with walk tests and blood tests, in healthy volunteers and patients with PAH
  • Determine the capability of MRI to detect change in PAH patients with start or change of therapy in comparison to walk test and blood test data.
  • Compare MRI endpoints with associated clinical data including haemodynamic measures obtained by right heart catheterisation

Plan of investigation:

Participants:

Participants from the following groups will be recruited:

  • Treatment naïve patients with PAH
  • Patients with PAH undergoing changes in their treatment regime
  • Patients with PAH who are NOT undergoing changes in their treatment regime
  • Healthy volunteers will be recruited.

PAH treatment will be as per standard of care. No new therapies are being tested.

Sample sizes:

Recruit sufficient incident treatment naïve patients with PAH and patients with PAH on monotherapy whose treatment is to be changed to achieve approximately 40 completers. This number is based on prior MRI reproducibility studies investigating the reproducibility of right ventricular measurements in healthy subjects and in those with cardiovascular disease. It is planned that at least 30% of patients will be treatment naïve. 20 healthy volunteer subjects will be recrited

Visit schedule Patients with pulmonary arterial hypertension Baseline study visit: During the baseline visit, blood draw, 6 minute walk test (+/- shuttle walk test) and cardiopulmonary MRI will be performed.

Follow-up visit: A follow-up visit will then occur at any time between 1 and 12 months after baseline. Patients with PAH, will be admitted for a one or two day visit. Cardiopulmonary MRI, blood draw, 6 minute walk test (+/- shuttle walk test) in the morning. Patients will take their usual medications approximately 1 hour prior to their MRI. These investigations will be repeated in the afternoon in the same way and in the same order. Patients will refrain from, exercise, caffeinated drinks and alcohol, between investigations.

Healthy volunteers Recruited by open advertisement within the hospital and university. Male or female subjects aged 18-60 years. Subjects will attend for a half day baseline visit for MRI, walk tests and blood tests. The follow up visit, including MRI, blood draw and walk test(s) will be as described for patients with PAH.

End points:

The MRI protocol will include measurement of candidate markers from the right heart and pulmonary vasculature:

I. Biventricular volume, mass and function. Analysis from both the 4 chamber and short axis images. Analyses will include and exclude trabecular mass.

II. Interventricular septal curvature and left ventricular eccentricity III. Pulmonary arterial flow, pulmonary arterial area change and pulsatility IV. Dynamic contrast enhanced perfusion imaging (first pass pulmonary transit time, full-width-half-maximum, delayed enhancement washout time) V. Myocardial and pulmonary tissue characteristics pre and post contrast T1 mapping of heart and lungs and myocardial late gadolinium enhancement pattern VI. Other MRI endpoints including composite measures

Analysis of MRI will be undertaken blinded to the patient's covariate data (walk tests and blood tests). Two experienced (one primary, one secondary) independent observers will analyse all the MRI studies. In the event of discrepancy between observers, the images will be reviewed by a third observer (radiologist) and all three observers should reach consensus.

Biomarker and walk test evaluation - The patient will be bled via a needle or cannula. Whenever possible, blood tests will precede the walk test and MRI. Candidate prognostic biomarkers, Pro NT BNP and BNP, will be tested. Incremental shuttle walk test and the 6 minute walk test will be performed >45 minutes apart and both tests will be repeated in the afternoon to determine the between measurement reproducibility for comparison with MRI. Walk tests will be performed in accordance with standard protocols.

Study Type

Interventional

Enrollment (Actual)

44

Phase

  • Not Applicable

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Child
  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Patients with PAH

Inclusion Criteria:

  • PAH subject is diagnosed with Group 1 pulmonary arterial hypertension, including IPAH, hereditable and CTD, and PAH associated with portal hypertension
  • Mean pulmonary arterial pressure ≥ 25 mmHg
  • Pulmonary arterial wedge pressure ≤ 15 mmHg

Exclusion Criteria:

  • Inability to perform the study protocol
  • Significant comorbidity where in the opinion of the clinician this is a significant contributor to the patients PAH
  • Pregnancy
  • Allergy to contrast medium
  • Contraindication to MRI (as per standard screening questionnaire)
  • Significant lung disease.
  • Known Hep B,C, HIV

Healthy volunteers

Inclusion criteria:

  • Male or female aged between 18 years and 60 years
  • Currently healthy as determined by a responsible physician
  • No significant history of lung or cardiac disease and normal BNP.
  • Capable of giving written informed consent.
  • Subject is >50kg with a body mass index within the range 18.0 to 32kg/m2.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Diagnostic
  • Allocation: Non-Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Single

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: Healthy volunteers
MRI 6 minute walk test, incremental shuttle walk test, NT-Pro BNP and BNP
Device: MRI
Evaluation of the utility of candidate endpoints in PAH trials
Other Names:
  • 6 minute walk test, incremental shuttle walk test, NT-ProBNP and BNP
Active Comparator: Treatment naive patients

MRI 6 minute walk test, incremental shuttle walk test, NT-Pro BNP and BNP

Patients diagnosed with PAH initiating PAH therapy for the first time
Device: MRI
Evaluation of the utility of candidate endpoints in PAH trials
Other Names:
  • 6 minute walk test, incremental shuttle walk test, NT-ProBNP and BNP
Active Comparator: Treatment change patients

MRI 6 minute walk test, incremental shuttle walk test, NT-Pro BNP and BNP

Patients diagnosed with PAH, currently on PAH therapy who are undergoing an escalation of PAH therapy
Device: MRI
Evaluation of the utility of candidate endpoints in PAH trials
Other Names:
  • 6 minute walk test, incremental shuttle walk test, NT-ProBNP and BNP
Active Comparator: Stable patients

MRI 6 minute walk test, incremental shuttle walk test, NT-Pro BNP and BNP

Patients with PAH who are NOT undergoing changes in their treatment regime
Device: MRI
Evaluation of the utility of candidate endpoints in PAH trials
Other Names:
  • 6 minute walk test, incremental shuttle walk test, NT-ProBNP and BNP

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Repeatability of endpoints
Time Frame: Measurements repeated within 24 hours
Repeatability of MRI, 6 minute walk test, incremental shuttle walk test, NT-Pro BNP and BNP
Measurements repeated within 24 hours
Sensitivity to change of endpoints
Time Frame: Follow up visits performed at 1-12 months
Sensitivity to change of MRI, 6 minute walk test, incremental shuttle walk test, NT-Pro BNP and BNP
Follow up visits performed at 1-12 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of Sheffield

Collaborators

GlaxoSmithKline

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

September 15, 2015

Primary Completion (Actual)

September 24, 2018

Study Completion (Anticipated)

May 20, 2019

Study Registration Dates

First Submitted

February 8, 2019

First Submitted That Met QC Criteria

February 11, 2019

First Posted (Actual)

February 15, 2019

Study Record Updates

Last Update Posted (Actual)

February 18, 2019

Last Update Submitted That Met QC Criteria

February 14, 2019

Last Verified

February 1, 2019

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • STH18285

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

Undecided

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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