Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12616001467426
Ethics application status
Approved
Date submitted
21/09/2016
Date registered
21/10/2016
Date last updated
7/07/2017
Type of registration
Prospectively registered

Titles & IDs
Public title
Exercise Training in Pulmonary Hypertension.
Scientific title
Exercise Training in Pulmonary Hypertension (ExTra_PH): A randomised controlled trial examining short and long-term outcomes of an outpatient-based exercise training in pulmonary hypertension
Secondary ID [1] 284142 0
Nil
Universal Trial Number (UTN)
U1111-1175-3680
Trial acronym
ExTra_PH
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Pulmonary hypertension 291225 0
Condition category
Condition code
Respiratory 291573 291573 0 0
Other respiratory disorders / diseases
Physical Medicine / Rehabilitation 291574 291574 0 0
Physiotherapy
Cardiovascular 300207 300207 0 0
Diseases of the vasculature and circulation including the lymphatic system

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Exercise training: Twice weekly, group-based, 8-week exercise-based rehabilitation program run in an hospital outpatient setting.
Exercise training will be supervised by a physiotherapist or an accredited exercise physiologist. Each subject will commence the first session by undertaking a minimum of 10 min of cycling and 10 min of treadmill training. Interval training (60s exercise, 120s rest) will be used if participants are unable to complete 10 min of continuous exercise. The duration of cycling and treadmill exercise will be up-titrated with the aim that each subject is completing 20 min each of cycling and treadmill exercise by the end of week 4. The exercise group will commence training at 70% of six-minute walk test (6MWT) speed which will be titrated up to 90% of 6MWT as tolerated over the first 4 weeks of training, at which point training heart rate (HR) and rate of perceived exertion (RPE) will be determined. Training intensity will be maintained at this HR and RPE for the remainder of the training period. Cycle intensity will be calculated using the 6MWT distance from standard equations.

Participants will be monitored so that HR during training will be less than 90% of peak 6MWT HR, SaO2> 85% and RPE <13. If required, supplemental oxygen will be provided during exercise sessions to maintain SpO2> 85%.The exercise training session should take approx. 45-60 min to complete.

The number of exercise sessions attended by each participant over the 8-wk intervention will be recorded.

Following the exercise training program, participants will be prescribed a standard home-exercise training program. The home program will consist of the participant being asked to walk 3-5 times per week for 20-30 minutes. Participants will be asked to walk at an RPE similar to that which they achieved during the exercise training program.

Compliance with the home exercise program will be monitored at subsequent follow-up clinical visits over a 2 year period.
Intervention code [1] 288836 0
Rehabilitation
Intervention code [2] 288837 0
Treatment: Other
Comparator / control treatment
Standard treatment: Standard care involving routine medical care and undertaking usual daily physical activities.
Control group
Active

Outcomes
Primary outcome [1] 291526 0
Exercise Capacity will be measured using the 6-min walk test (6MWT).
Timepoint [1] 291526 0
Pre and post 8-week study period
Secondary outcome [1] 327873 0
Exercise capacity as measured using a incremental cardiopulmonary exercise test to determine peak exercise capacity
Timepoint [1] 327873 0
Pre and post 8-week study period
Secondary outcome [2] 327874 0
Quality of life using the Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR)
Timepoint [2] 327874 0
Pre and post 8-week study period
Secondary outcome [3] 327875 0
Cardiac Function will be measured using echocardiography and cardiac Magnetic Resonance Imaging (MRI) at rest and during a submaximal exercise load (MRI only)
Timepoint [3] 327875 0
Pre and post 8-week study period
Secondary outcome [4] 327876 0
Disease severity as assessed using the New York Heart Association Functional class
Timepoint [4] 327876 0
Pre and post 8-week study period
Secondary outcome [5] 327877 0
Adverse events (e.g. syncope, dizziness, desaturation, arrhythmia, etc) will be recorded for the duration of the exercise training program for both intervention and control groups. For the intervention group details regarding adverse events will be collected by the therapist running the exercise program. For the participants in the control group data will be collected during a routine weekly phone call made by the therapist.
Timepoint [5] 327877 0
During 8-week study period
Secondary outcome [6] 327878 0
Long term outcomes will be assessed by clinical worsening using a standard definition of:
PH-related death OR listing for/completed lung transplantation
OR hospitalization for PH OR clinical worsening leading to initiation of new chronic PH-specific treatment
OR WHO functional classification deterioration AND a > 15% decrease in 6MWT from baseline.

Reference:
Frost AE, Badesch DB, Miller DP, Benza RL, et al. Evaluation of the predictive value of a clinical worsening definition using 2-year outcomes in patients with pulmonary arterial hypertension: a REVEAL Registry analysis. Chest. 2013;144(5):1521-9.
Timepoint [6] 327878 0
Outcomes will be assessed during routine clinical visits during the 2 -year period following the intervention. Routine clinical visits typically occur every 3 to 6 months and clinical worsening will be evaluated on the return clinical visit.

Eligibility
Key inclusion criteria
1) Confirmed diagnosis of pulmonary hypertension based on right heart catheterization procedure. Mean pulmonary artery pressure > 25 mmHg and pulmonary capillary wedge pressure of < 15 mmHg
2) On stable pulmonary hypertension medical therapies and exacerbation-free in the previous 3 months
3) Participants will be New York Heart Association (NYHA) Class II-III
Minimum age
18 Years
Maximum age
80 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1) Individuals < 18 years of age
2) Pregnant Females
3) Patients who have changed pulmonary hypertension medication in the previous 3 months
4) Patients with significant co-morbidities including left sided heart failure
5) Patients with recent (within one month) history of syncope or light-headedness during exercise
6) Patients with significant musculoskeletal or neurological conditions likely to affect their exercise performance
7) Individuals who would be excluded from performing an exercise as per American College of Sports Medicine Guidelines

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Participants will be recruited from the tertiary pulmonary hypertension centre located at The Prince Charles Hospital, Brisbane. Concealed allocation will be used to randomise eligible participants to control and exercise groups using sequentially numbered, opaque, sealed envelopes.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Subjects will be allocated to exercise or control using permuted blocked randomisation and a 1:1 allocation.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?


The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Not Applicable
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
Correlational analysis will be used to examine the relationship between measures of disease severity (obtained from resting echocardiography and exercise MRI) and gas exchange measures determine from the 6MWT and incremental exercise test.

Comparisons between the two groups will be made using a two-way analysis of variance with repeated measures (or equivalent parametric test). Baseline measurements are likely to influence post-intervention outcomes, and therefore we will use analysis of covariance (ANCOVA) for the between group comparisons.

To examine the effects of exercise training we will compare the pre and post measurements of dependent measures. We will use an intention-to-treat analysis to avoid bias in estimating the treatment effect for this study. Specifically we will use a generalised linear mixed model approach which can accommodate missing data points often encountered in longitudinal datasets, does not need the same number of observations per subject and provides an ideal way of dealing with missing values or dropouts.

Power calculations for the primary outcome measure are as follows:
Six minute walk distance: Using an effect size of 0.84 (based on the mean effect size from published RCT's of exercise training in pulmonary hypertension) and an probability of Type I error of 5%, the proposed study is powered at 83%.



References:

Mereles, D., N. Ehlken, S. Kreuscher, S. Ghofrani, M.M. Hoeper, M. Halank, F.J. Meyer, G. Karger, J. Buss, J. Juenger, N. Holzapfel, C. Opitz, J. Winkler, F.F. Herth, H. Wilkens, H.A. Katus, H. Olschewski, and E. Grunig, Exercise and respiratory training improve exercise capacity and quality of life in patients with severe chronic pulmonary hypertension. Circulation, 2006. 114(14): p. 1482-9.
Ley, S., C. Fink, F. Risse, N. Ehlken, C. Fischer, J. Ley-Zaporozhan, H.U. Kauczor, H. Klose, and E. Gruenig, Magnetic resonance imaging to assess the effect of exercise training on pulmonary perfusion and blood flow in patients with pulmonary hypertension. Eur Radiol, 2013. 23(2): p. 324-31.
Ehlken, N., M. Lichtblau, H. Klose, J. Weidenhammer, C. Fischer, R. Nechwatal, S. Uiker, M. Halank, K. Olsson, W. Seeger, H. Gall, S. Rosenkranz, H. Wilkens, D. Mertens, H.J. Seyfarth, C. Opitz, S. Ulrich, B. Egenlauf, and E. Grunig, Exercise training improves peak oxygen consumption and haemodynamics in patients with severe pulmonary arterial hypertension and inoperable chronic thrombo-embolic pulmonary hypertension: a prospective, randomized, controlled trial. Eur Heart J, 2016. 37(1): p. 35-44.
Chan, L., L.M. Chin, M. Kennedy, J.G. Woolstenhulme, S.D. Nathan, A.A. Weinstein, G. Connors, N.A. Weir, B. Drinkard, J. Lamberti, and R.E. Keyser, Benefits of intensive treadmill exercise training on cardiorespiratory function and quality of life in patients with pulmonary hypertension. Chest, 2013. 143(2): p. 333-43.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
1/11/2016
Actual
1/11/2016
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
50
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
QLD
Recruitment hospital [1] 4189 0
The Prince Charles Hospital - Chermside

Funding & Sponsors
Funding source category [1] 291832 0
Government body
Name [1] 291832 0
Queensland Health
Country [1] 291832 0
Australia
Primary sponsor type
Individual
Name
Professor Norm Morris
Address
Griffith University
School of Allied Health Sciences
Gold Coast Campus
Parklands Drive
Southport QLD 4222
Country
Australia
Secondary sponsor category [1] 293578 0
Individual
Name [1] 293578 0
Menaka Sabaratnam
Address [1] 293578 0
Gold Coast University Hospital
Parklands Drive
Southport QLD 4222
Country [1] 293578 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 293348 0
The Prince Charles Human Research Ethics Committee
Ethics committee address [1] 293348 0
The Prince Charles Hospital
627 Rode Rd
Chermside QLD 4032
Ethics committee country [1] 293348 0
Australia
Date submitted for ethics approval [1] 293348 0
09/09/2015
Approval date [1] 293348 0
26/11/2015
Ethics approval number [1] 293348 0
HREC/15/QPCH/238

Summary
Brief summary
The aim of the study is to provide guidance to clinicians in relation to the safety and effectiveness of exercise training for pulmonary hypertension (PH) patients. More specifically, the study will have the following aims:
1) To examine the short-term outcomes and safety of exercise training in patients with PH
2) To examine the impact of exercise training on cardiac function at rest and during exercise using cardiac magnetic resonance imaging
3) To examine the long-term outcomes including adverse events and clinical worsening following exercise training.


The study hypotheses are:
1) Exercise training will have beneficial effects in terms of improved exercise capacity, quality of life and a reduction in disease severity, with no increase in adverse events
2) Exercise training will result in improved cardiac function as measured using cardiac MRI, both at rest and during submaximal exercise
3) Participants who undertake exercise training will have a longer period without clinical worsening, using a minimum 2-year follow-up period
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 46442 0
Prof Norman Morris
Address 46442 0
Griffith University
School of Allied Health Sciences
Gold Coast Campus
Parklands Drive
Southport QLD 4222
Country 46442 0
Australia
Phone 46442 0
+61 7 5552 8921
Fax 46442 0
Email 46442 0
[email protected]
Contact person for public queries
Name 46443 0
Prof Norman Morris
Address 46443 0
Griffith University
School of Allied Health Sciences
Gold Coast Campus
Parklands Drive
Southport QLD 4222
Country 46443 0
Australia
Phone 46443 0
+61 7 5552 8921
Fax 46443 0
Email 46443 0
[email protected]
Contact person for scientific queries
Name 46444 0
Prof Norman Morris
Address 46444 0
Griffith University
School of Allied Health Sciences
Gold Coast Campus
Parklands Drive
Southport QLD 4222
Country 46444 0
Australia
Phone 46444 0
+61 7 5552 8921
Fax 46444 0
Email 46444 0
[email protected]

No information has been provided regarding IPD availability


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
SourceTitleYear of PublicationDOI
Dimensions AIClinical Trials Targeting Metabolism in Pulmonary Arterial Hypertension2018https://doi.org/10.21693/1933-088x-17.3.110
N.B. These documents automatically identified may not have been verified by the study sponsor.