Pulmonary HypertensionEU-TRAIN-01NCT03345212
A Randomized Controlled Multicenter Trial of Exercise Training in Pulmonary Hypertension in European Countries
A study testing Exercise training in people with Pulmonary Hypertension, run by Heidelberg University at 1 site in Germany.
Trial summary
Chronic pulmonary hypertension (PH) is associated with impaired exercise capacity, quality of life and right ventricular function. The disease is characterized by an increase of pulmonary vascular resistance and pulmonary arterial pressure, leading to right heart insufficiency. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Pulmonary Hypertension
- What is being tested?
- Exercise training
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 129 participants
- Where
- 1 siteGermany
- Study dates
- Feb 2016to Dec 2019
- Phase
- Interventional
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Female and male patients of any ethnic origin ≥ 18 years
- WHO functional class II-IV
- PH diagnosed by right heart catheter showing:
- Baseline mean pulmonary arterial pressure (mPAP) ≥ 25 mmHg
- Baseline pulmonary vascular resistance (PVR) ≥ 240 dyn x s x cm-5
- Baseline pulmonary capillary wedge pressure (PCWP) ≤ 15 mm Hg
Show all 10Show fewer
- Patients receiving optimized conventional PH therapy including intensified treatment with diuretics and who have been stable for 2 months before entering the study
- Except for diuretics, medical treatment should not be expected to change during the entire 15-week study period
- Negative pregnancy test (β-HCG) at the start of the trial and appropriate contraception throughout the study for women with child-bearing potential
- Able to understand and willing to sign the Informed Consent Form
Who cannot join
- PH of any cause other than permitted in the entry criteria, e.g. concomitantly to portal hypertension, complex congenital heart disease, reversed shunt, HIV infection, suspected pulmonary veno-occlusive disease based on pulmonary edema during a previous vasoreactivity test or on abnormal findings compatible with that diagnosis (septal lines or pulmonary edema at high resolution computer tomography), congenital or acquired valvular defects with clinically relevant myocardial function disorders not related to pulmonary hypertension or unclear diagnosis
- Pregnancy
- Patients with signs of right heart decompensation
- Walking disability
- Acute infection
- Pyrexia
Show all 18Show fewer
- Any change in disease-targeted therapy within the last 2 months
- Any subject who is scheduled to receive an investigational drug during the course of this study
- Severe lung disease: FEV1/FVC <0.5 and total lung capacity < 70% of the normal value
- Active liver disease, porphyria or elevations of serum transaminases >3 x ULN (upper limit of normal) or bilirubin > 1.5 x ULN
- Hemoglobin concentration of less than 75 % of the lower limit of normal
- Systolic blood pressure < 85 mmHg
- Active myocarditis, instable angina pectoris, exercise induced ventricular arrhythmias, decompensated heart failure, hypertrophic obstructive cardiomyopathy, highly impaired left ventricular function
- History or suspicion of inability to cooperate adequately. will be excluded from the study.
- Additional exclusion criteria for MRI (optional)
- Acute psychosis or other states of mind, which seem to impair patient's ability to comprehend instructions
- Patients with metal cardiac valves or other metal implants, incorporated ferromagnetic materials or MRI-incompatible active medicinal products
- Claustrophobia
Trial locations and contacts
1 site in 1 country.
Germany1 site
Centre for pulmonary hypertension of the Thoraxclinic at the University Hospital Heidelberg
Heidelberg, 69126
About this study
Official title: Implementation and Effect of Exercise and Respiratory Training on 6-minute Walking Distance in Patients With Severe Chronic Pulmonary Hypertension: a Randomized Controlled Multicenter Trial in European Countries
Chronic pulmonary hypertension (PH) is associated with impaired exercise capacity, quality of life and right ventricular function. The disease is characterized by an increase of pulmonary vascular resistance and pulmonary arterial pressure, leading to right heart insufficiency.
Despite optimized combination-medical therapy most patients remain symptomatic, have reduced exercise capacity, quality of life and reduced survival rates, with an annual mortality rate of approximately 5 -15 % or even higher.
Read more
Previous training studies have suggested that exercise training as add-on to medical treatment is highly effective improving exercise capacity, quality of life and symptoms.
The current guidelines recommend exercise training only in specialized centres including both PH and rehabilitation specialists who are experienced in exercise training of severely compromised patients.
A specialized PH-training program has been performed in Heidelberg since 2003 including >1200 patients with various forms of chronic PH. The exercise training program is performed in a special setting with an in-hospital start of the rehabilitation program. It is characterized by a low-dose closely supervised exercise training in small groups with additional psychological support and mental training.
This training program for patients with PH will be implemented in European centers to add exercise training to the existing PH therapies. The effect of the training on physical exercise capacity will be assessed by 6-minute walking distance (6-MWD). Further clinical parameters will be assessed to evaluate the effect on exercise capacity, quality of life and symptoms.
The aim of this study is to guide European PH-centers to become specialized centers for training in PH.
126 patients will be included, who either receive exercise training or continue their daily sedentary life style (1:1 randomization) for 15 weeks.
As inpatient settings are not available in all healthcare systems the training program will be adapted from the specific training program for PH patients developed in Heidelberg to a procedure, which is feasible in the local participating centres. Another objective of this study is to assess if the particular adopted training program specified for each participating centre and country is still safe and effective.
Read the detailed description
Pulmonary hypertension (PH) is defined as a mean pulmonary arterial pressure ≥25 mmHg. PH is often diagnosed at an advanced stage (WHO functional class III-IV) with a massive increase of the mean pulmonary arterial pressure. A crucial parameter determining the symptoms and prognosis of the patients is the cardiac reserve. This parameter is defined by the pulmonary vascular resistance and the right ventricular adaptation. Severe PH is characterized by a decreased cardiac output at rest, an increased afterload and consecutive cor pulmonale.
Within the last years there has been a huge progress in the scientific fields of genetics, pathogenesis, pathophysiology and therapy of PH. This has also been documented in the PH world conferences. New disease-targeted medication has been developed such as endothelin receptor antagonists (bosentan, ambrisentan, sitaxentan, macitentan), prostacyclin derivates (inhaled and intravenous iloprost, epoprostenol, treprostinil), phosphodiesterase-5-inhibitors (sildenafil, tadalafil) and the soluble guanylate cyclase inhibitor riociguat. Despite these advances in treatment, the disease may not be treated causally or even be cured. In most cases however, disease progression may be slowed down. The use of PH-targeted treatment and supporting therapies such as anticoagulation and diuretics improve the symptoms and impede the progression of the disease. Nevertheless, the prognosis of the patients remains impaired. The first randomized controlled study investigating the effect of exercise training in PH showed a significant improvement of exercise capacity and quality of life. Further uncontrolled trials using a low-dose exercise and respiratory therapy in different etiologies of PH showed an improvement in exercise capacity, quality of life, muscle function and further prognostic parameters. A recent randomized controlled study could support these findings. Studies also showed an improvement in muscle capillarization of the quadriceps muscle.
The training program consists of interval ergometer training, respiratory therapy, muscle training and mental gait training. The interval ergometer training allows performing aerobic exercise training with a low cardio-circulatory stress. In patients with left heart insufficiency, this training has been successfully implemented. Respiratory therapy has been established in the rehabilitation of patients with lung disease within the last years. The different techniques aim to improve ventilation, strengthen the respiratory muscles, mobilize the thorax and enhance secretolysis. The training program also contains mental (gait) training. This training was adapted from mental imagery techniques used by sport psychologists in professional athletes. Mental imagery techniques have shown to improve physical and cognitive functions.
Due to the beneficial results, exercise training and rehabilitation has received a 1A recommendation at the PH world symposium in Nice in 2013. This decision was mainly based on three randomized controlled trials that investigated a limited number of patients. To unequivocally demonstrate safety and positive effects of exercise training in different settings large multicenter RCTs are essential. An exercise program has not yet been implemented in most European countries, partly due to limited access to rehabilitation programs and institutions.
The aim of this large, multicenter, prospective, randomized controlled trial is to investigate the effect of exercise training and rehabilitation on physical exercise capacity across different European countries. Physical exercise capacity will be measured by exercise induced change of 6-minute walking distance (6-MWD) compared to baseline and the control group without training. As inpatient settings are not available in all healthcare systems the training program will be adapted from the specific training program for PH patients developed in Heidelberg in a system, which is feasible for the local participating centres. Another objective of this study is to assess if the adopted training program specified for each participating centre and country is still safe and effective.
- Conditions
- Pulmonary Hypertension
- Being tested
- Exercise training
- Medical subject headings
- Hypertension, Pulmonary
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Exercise trainingOther
The rehabilitation program comprises interval ergometer training, dumbbell training, respiratory therapy, mental training and guided walks for 5-7 times/week.
| Study group | Role | What they receive |
|---|---|---|
| Control group | No intervention | Patients in this group continue their sedentary life-style throughout the study period. Patients will be advised to perform no specific exercise training during the trial. After 15 weeks, the patients are offered to take part in the training program as well. |
| Training group | Experimental | Standard rehabilitation therapy includes dietary measures, massages and relaxation techniques. Additionally, patients perform exercise and respiratory therapy and mental gait training.
Patients will be informed about group allocation. Receives: Other: Exercise training |
What is being measured
The primary outcome is the main question the study is designed to answer.
6 MWD
Change in 6-MWD between baseline and 15 weeks in the training vs. the control Group; meters
Measured: 15 weeks
Secondary outcomes (55)
Change in WHO functional class in training vs. control group
WHO functional class
Measured: 15 weeks
Change in Quality of life in training vs. control group
Quality of life (SF-36)
Measured: 15 weeks
Change in Borg scale 6-MWD training vs. control group
Borg scale 6-MWD
Measured: 15 weeks
Change in tricuspid annular plane systolic excursion
Echocardiographic parameter training vs. control Group; mm
Measured: 15 weeks
Change in tissue Doppler imaging
Echocardiographic Parameter training vs. control group
Measured: 15 weeks
Change in left ventricular pump function
Echocardiographic Parameter training vs. control Group; qualitative
Measured: 15 weeks
Change in right ventricular pump function
Echocardiographic Parameter training vs. control Group; qualitative
Measured: 15 weeks
Change in thickness of interventricular septum
Echocardiographic Parameter training vs. control Group; mm
Measured: 15 weeks
Change insize of inferior vena cava
Echocardiographic Parameter training vs. control Group; mm
Measured: 15 weeks
Change in systolic pulmonary arterial pressure
Echocardiographic Parameter training vs. control Group; mmHg
Measured: 15 weeks
Change in left ventricular eccentricity index
Echocardiographic Parameter training vs. control group
Measured: 15 weeks
Change in Tei index
Echocardiographic Parameter training vs. control group
Measured: 15 weeks
Change in right ventricular area
Echocardiographic Parameter training vs. control group
Measured: 15 weeks
Change in right atrial area
Echocardiographic Parameter training vs. control Group; square cm
Measured: 15 weeks
Change in workload
Cardiopulmonary exercise testing (spiroergometry) training vs. control Group; Watts
Measured: 15 weeks
Change in heart rate
Cardiopulmonary exercise testing (spiroergometry) training vs. control Group; bpm
Measured: 15 weeks
Change in ventilation
Cardiopulmonary exercise testing (spiroergometry) training vs. control Group; L/min
Measured: 15 weeks
Change in carbon dioxide output
Cardiopulmonary exercise testing (spiroergometry) training vs. control Group
Measured: 15 weeks
Change in spiroergometry parameters in training vs. control group
Cardiopulmonary exercise testing (spiroergometry): VO2 at anaerobic threshold determined by V-slope method
Measured: 15 weeks
Change in VCO2 at anaerobic threshold
Cardiopulmonary exercise testing (spiroergometry): determined by V-slope method
Measured: 15 weeks
Change in oxygen uptake
Cardiopulmonary exercise testing (spiroergometry); L/min/kg
Measured: 15 weeks
Change in diffusion-limited carbon monoxide (DLCO)
Lung function; Diffusion capacity
Measured: 15 weeks
Change in alveolar volume (VA)
Lung function
Measured: 15 weeks
Change in residual volume (RV)
Lung function
Measured: 15 weeks
Change in total lung volume (TLC)
Lung function
Measured: 15 weeks
Change in forced expiratory flow
Lung function
Measured: 15 weeks
Change in peak expiratory flow rate
Lung function
Measured: 15 weeks
Change in forced expiratory volume in one second (FEV1)
Lung function; total and in percentage
Measured: 15 weeks
Change in forced vital capacity (FVC)
Lung function
Measured: 15 weeks
Change in NTproBNP
Laboratory marker for the impairment of the right heart
Measured: 15 weeks
Change in interleukins
Laboratory marker for the impairment of the right heart
Measured: 15 weeks
Change in inflammatory markers
Laboratory marker for the impairment of the right heart
Measured: 15 weeks
Change in carbon dioxide partial pressure
Blood gas Analysis
Measured: 15 weeks
Change in oxygen saturation of the blood (SaO2)
Blood gas analysis
Measured: 15 weeks
Change in additional oxygen supplementation (yes/no and quantity)
Blood gas analysis
Measured: 15 weeks
Change in oxygen partial pressure
Blood gas analysis
Measured: 15 weeks
Change in oxygen saturation
Safety Parameter; L/min
Measured: 15 weeks
Assessment of clinical laboratory Investigation alerts (values out of range)
Safety parameter
Measured: 15 weeks
Assessment of adverse Events
Safety Parameter; unrelated and related to procedure
Measured: 15 weeks
Assessment of serious adverse events
Safety parameter
Measured: 15 weeks
frequency of hospitalizations
Safety parameter
Measured: 15 weeks
length of hospitalizations
Safety parameter
Measured: 15 weeks
Change in resting heart rate
Safety parameter
Measured: 15 weeks
Change in blood pressure
Safety parameter
Measured: 15 weeks
frequency of pathological findings in long-term ECG
Safety parameter
Measured: 15 weeks
Qualitative Review of electrocardiogram (ECG)
Safety Parameter; pathological findings
Measured: 15 weeks
Assessment of survival
Training and control Group; transplant-free and Overall survival
Measured: 1 year
Change of the right ventricular size
Optional: Changes in MRI parameters
Measured: 15 weeks
Change of the right ventricular pump function
Optional: Changes in MRI parameters
Measured: 15 weeks
Change of the left ventricular size
Optional: Changes in MRI parameters
Measured: 15 weeks
Change of the left ventricular pump function
Optional: Changes in MRI parameters
Measured: 15 weeks
Change in microRNA expression
Optional: Epigenetic changes
Measured: 15 weeks
Change in DNA-methylation
Optional: Epigenetic changes
Measured: 15 weeks
Assessment of relationship of DNA mutations and disease progression
Optional: Investigation of DNA mutations relationship to disease progression
Measured: 15 weeks
Assessment of relationship of DNA mutations and training effects
Optional: Investigation of DNA mutations
Measured: 15 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted17 Nov 2017
- Study startFeb 2016
- Primary completionDec 2018
- Study completionDec 2019
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (9)Papers the sponsor has linked to this study.
- Other trials for Pulmonary HypertensionStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Diagnosis
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 129 participants (actual)
Sponsor and investigators
- Lead sponsor
- Heidelberg University
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Prof. Dr. med. Ekkehard Gruenig, Heidelberg University
- Investigators
- Ekkehard Grünig, MD, Principal investigator, Centre for pulmonary hypertension of the Thoraxclinic at the University Hospital Heidelberg
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03345212
- Sponsor's protocol ID
- EU-TRAIN-01
- Acronym
- EU-TRAIN-01
- Status last verified
- Dec 2019
- First submitted
- 27 Jul 2017
- Last updated
- 19 Dec 2019
- Results posted
- No
- Data monitoring committee
- No
Publications
Mereles D, Ehlken N, Kreuscher S, Ghofrani S, Hoeper MM, Halank M, Meyer FJ, Karger G, Buss J, Juenger J, Holzapfel N, Opitz C, Winkler J, Herth FF, Wilkens H, Katus HA, Olschewski H, Grunig E. Exercise and respiratory training improve exercise capacity and quality of life in patients with severe chronic pulmonary hypertension. Circulation. 2006 Oct 3;114(14):1482-9. doi: 10.1161/CIRCULATIONAHA.106.618397. Epub 2006 Sep 18.
PubMed 16982941Grunig E, Ehlken N, Ghofrani A, Staehler G, Meyer FJ, Juenger J, Opitz CF, Klose H, Wilkens H, Rosenkranz S, Olschewski H, Halank M. Effect of exercise and respiratory training on clinical progression and survival in patients with severe chronic pulmonary hypertension. Respiration. 2011;81(5):394-401. doi: 10.1159/000322475. Epub 2011 Feb 9.
PubMed 21311162Grunig E, Lichtblau M, Ehlken N, Ghofrani HA, Reichenberger F, Staehler G, Halank M, Fischer C, Seyfarth HJ, Klose H, Meyer A, Sorichter S, Wilkens H, Rosenkranz S, Opitz C, Leuchte H, Karger G, Speich R, Nagel C. Safety and efficacy of exercise training in various forms of pulmonary hypertension. Eur Respir J. 2012 Jul;40(1):84-92. doi: 10.1183/09031936.00123711. Epub 2012 Feb 9.
PubMed 22323570Grunig E, Maier F, Ehlken N, Fischer C, Lichtblau M, Blank N, Fiehn C, Stockl F, Prange F, Staehler G, Reichenberger F, Tiede H, Halank M, Seyfarth HJ, Wagner S, Nagel C. Exercise training in pulmonary arterial hypertension associated with connective tissue diseases. Arthritis Res Ther. 2012 Jun 18;14(3):R148. doi: 10.1186/ar3883.
PubMed 22709477Nagel C, Prange F, Guth S, Herb J, Ehlken N, Fischer C, Reichenberger F, Rosenkranz S, Seyfarth HJ, Mayer E, Halank M, Grunig E. Exercise training improves exercise capacity and quality of life in patients with inoperable or residual chronic thromboembolic pulmonary hypertension. PLoS One. 2012;7(7):e41603. doi: 10.1371/journal.pone.0041603. Epub 2012 Jul 25.
PubMed 22848542Becker-Grunig T, Klose H, Ehlken N, Lichtblau M, Nagel C, Fischer C, Gorenflo M, Tiede H, Schranz D, Hager A, Kaemmerer H, Miera O, Ulrich S, Speich R, Uiker S, Grunig E. Efficacy of exercise training in pulmonary arterial hypertension associated with congenital heart disease. Int J Cardiol. 2013 Sep 20;168(1):375-81. doi: 10.1016/j.ijcard.2012.09.036. Epub 2012 Oct 5.
PubMed 23041100Halank M, Einsle F, Lehman S, Bremer H, Ewert R, Wilkens H, Meyer FJ, Grunig E, Seyfarth HJ, Kolditz M, Wieder G, Hoffken G, Kollner V. Exercise capacity affects quality of life in patients with pulmonary hypertension. Lung. 2013 Aug;191(4):337-43. doi: 10.1007/s00408-013-9472-6. Epub 2013 May 17.
PubMed 23681593Kabitz HJ, Bremer HC, Schwoerer A, Sonntag F, Walterspacher S, Walker DJ, Ehlken N, Staehler G, Windisch W, Grunig E. The combination of exercise and respiratory training improves respiratory muscle function in pulmonary hypertension. Lung. 2014 Apr;192(2):321-8. doi: 10.1007/s00408-013-9542-9. Epub 2013 Dec 13.
PubMed 24338088Ehlken N, Lichtblau M, Klose H, Weidenhammer J, Fischer C, Nechwatal R, Uiker S, Halank M, Olsson K, Seeger W, Gall H, Rosenkranz S, Wilkens H, Mertens D, Seyfarth HJ, Opitz C, Ulrich S, Egenlauf B, Grunig E. 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 Jan 1;37(1):35-44. doi: 10.1093/eurheartj/ehv337. Epub 2015 Jul 31.
PubMed 26231884
Study at a glance
From the registry record, last updated by the sponsor on 19 Dec 2019. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Implementation and Effect of Exercise and Respiratory Training on 6-minute Walking Distance in Patients With Severe Chronic Pulmonary Hypertension: a Randomized Controlled Multicenter Trial in European Countries
- ClinicalTrials.gov ID
- NCT03345212
- Acronym / sponsor ID
- EU-TRAIN-01 / EU-TRAIN-01
- Conditions
- Pulmonary Hypertension
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 129 participants (actual)
- Lead sponsor
- Heidelberg UniversityUniversity, hospital or other
- Study start
- Feb 2016 (actual)
- Primary completion
- Dec 2018 (actual)
- Study completion
- Dec 2019 (actual)
- First posted
- 17 Nov 2017 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Chronic pulmonary hypertension (PH) is associated with impaired exercise capacity, quality of life and right ventricular function. The disease is characterized by an increase of pulmonary vascular resistance and pulmonary arterial pressure, leading to right heart insufficiency.
Despite optimized combination-medical therapy most patients remain symptomatic, have reduced exercise capacity, quality of life and reduced survival rates, with an annual mortality rate of approximately 5 -15 % or even higher.
Previous training studies have suggested that exercise training as add-on to medical treatment is highly effective improving exercise capacity, quality of life and symptoms.
The current guidelines recommend exercise training only in specialized centres including both PH and rehabilitation specialists who are experienced in exercise training of severely compromised patients.
A specialized PH-training program has been performed in Heidelberg since 2003 including >1200 patients with various forms of chronic PH. The exercise training program is performed in a special setting with an in-hospital start of the rehabilitation program. It is characterized by a low-dose closely supervised exercise training in small groups with additional psychological support and mental training.
This training program for patients with PH will be implemented in European centers to add exercise training to the existing PH therapies. The effect of the training on physical exercise capacity will be assessed by 6-minute walking distance (6-MWD). Further clinical parameters will be assessed to evaluate the effect on exercise capacity, quality of life and symptoms.
The aim of this study is to guide European PH-centers to become specialized centers for training in PH.
126 patients will be included, who either receive exercise training or continue their daily sedentary life style (1:1 randomization) for 15 weeks.
As inpatient settings are not available in all healthcare systems the training program will be adapted from the specific training program for PH patients developed in Heidelberg to a procedure, which is feasible in the local participating centres. Another objective of this study is to assess if the particular adopted training program specified for each participating centre and country is still safe and effective.
Detailed description
Pulmonary hypertension (PH) is defined as a mean pulmonary arterial pressure ≥25 mmHg. PH is often diagnosed at an advanced stage (WHO functional class III-IV) with a massive increase of the mean pulmonary arterial pressure. A crucial parameter determining the symptoms and prognosis of the patients is the cardiac reserve. This parameter is defined by the pulmonary vascular resistance and the right ventricular adaptation. Severe PH is characterized by a decreased cardiac output at rest, an increased afterload and consecutive cor pulmonale.
Within the last years there has been a huge progress in the scientific fields of genetics, pathogenesis, pathophysiology and therapy of PH. This has also been documented in the PH world conferences. New disease-targeted medication has been developed such as endothelin receptor antagonists (bosentan, ambrisentan, sitaxentan, macitentan), prostacyclin derivates (inhaled and intravenous iloprost, epoprostenol, treprostinil), phosphodiesterase-5-inhibitors (sildenafil, tadalafil) and the soluble guanylate cyclase inhibitor riociguat. Despite these advances in treatment, the disease may not be treated causally or even be cured. In most cases however, disease progression may be slowed down. The use of PH-targeted treatment and supporting therapies such as anticoagulation and diuretics improve the symptoms and impede the progression of the disease. Nevertheless, the prognosis of the patients remains impaired. The first randomized controlled study investigating the effect of exercise training in PH showed a significant improvement of exercise capacity and quality of life. Further uncontrolled trials using a low-dose exercise and respiratory therapy in different etiologies of PH showed an improvement in exercise capacity, quality of life, muscle function and further prognostic parameters. A recent randomized controlled study could support these findings. Studies also showed an improvement in muscle capillarization of the quadriceps muscle.
The training program consists of interval ergometer training, respiratory therapy, muscle training and mental gait training. The interval ergometer training allows performing aerobic exercise training with a low cardio-circulatory stress. In patients with left heart insufficiency, this training has been successfully implemented. Respiratory therapy has been established in the rehabilitation of patients with lung disease within the last years. The different techniques aim to improve ventilation, strengthen the respiratory muscles, mobilize the thorax and enhance secretolysis. The training program also contains mental (gait) training. This training was adapted from mental imagery techniques used by sport psychologists in professional athletes. Mental imagery techniques have shown to improve physical and cognitive functions.
Due to the beneficial results, exercise training and rehabilitation has received a 1A recommendation at the PH world symposium in Nice in 2013. This decision was mainly based on three randomized controlled trials that investigated a limited number of patients. To unequivocally demonstrate safety and positive effects of exercise training in different settings large multicenter RCTs are essential. An exercise program has not yet been implemented in most European countries, partly due to limited access to rehabilitation programs and institutions.
The aim of this large, multicenter, prospective, randomized controlled trial is to investigate the effect of exercise training and rehabilitation on physical exercise capacity across different European countries. Physical exercise capacity will be measured by exercise induced change of 6-minute walking distance (6-MWD) compared to baseline and the control group without training. As inpatient settings are not available in all healthcare systems the training program will be adapted from the specific training program for PH patients developed in Heidelberg in a system, which is feasible for the local participating centres. Another objective of this study is to assess if the adopted training program specified for each participating centre and country is still safe and effective.
Study design
- Primary purpose
- Diagnosis
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Control group | No intervention | –Patients in this group continue their sedentary life-style throughout the study period. Patients will be advised to perform no specific exercise training during the trial. After 15 weeks, the patients are offered to take part in the training program as well. |
| Training group | Experimental | Other: Exercise trainingStandard rehabilitation therapy includes dietary measures, massages and relaxation techniques. Additionally, patients perform exercise and respiratory therapy and mental gait training. Patients will be informed about group allocation. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (10 listed)
- Female and male patients of any ethnic origin ≥ 18 years
- WHO functional class II-IV
- PH diagnosed by right heart catheter showing:
- Patients receiving optimized conventional PH therapy including intensified treatment with diuretics and who have been stable for 2 months before entering the study
- Except for diuretics, medical treatment should not be expected to change during the entire 15-week study period
Key exclusion criteria (18 listed)
- PH of any cause other than permitted in the entry criteria, e.g. concomitantly to portal hypertension, complex congenital heart disease, reversed shunt, HIV infection, suspected pulmonary veno-occlusive disease based on pulmonary edema during a previous vasoreactivity test or on abnormal findings compatible with that diagnosis (septal lines or pulmonary edema at high resolution computer tomography), congenital or acquired valvular defects with clinically relevant myocardial function disorders not related to pulmonary hypertension or unclear diagnosis
- Pregnancy
- Patients with signs of right heart decompensation
- Walking disability
- Acute infection
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Exercise trainingThe rehabilitation program comprises interval ergometer training, dumbbell training, respiratory therapy, mental training and guided walks for 5-7 times/week. | Other | Training group |
Primary outcome
6 MWD
Time frame: 15 weeks
Change in 6-MWD between baseline and 15 weeks in the training vs. the control Group; meters
55 secondary outcomes
Change in WHO functional class in training vs. control group
Time frame: 15 weeks
Change in Quality of life in training vs. control group
Time frame: 15 weeks
Change in Borg scale 6-MWD training vs. control group
Time frame: 15 weeks
Change in tricuspid annular plane systolic excursion
Time frame: 15 weeks
Change in tissue Doppler imaging
Time frame: 15 weeks
Change in left ventricular pump function
Time frame: 15 weeks
Change in right ventricular pump function
Time frame: 15 weeks
Change in thickness of interventricular septum
Time frame: 15 weeks
Change insize of inferior vena cava
Time frame: 15 weeks
Change in systolic pulmonary arterial pressure
Time frame: 15 weeks
Change in left ventricular eccentricity index
Time frame: 15 weeks
Change in Tei index
Time frame: 15 weeks
Change in right ventricular area
Time frame: 15 weeks
Change in right atrial area
Time frame: 15 weeks
Change in workload
Time frame: 15 weeks
Change in heart rate
Time frame: 15 weeks
Change in ventilation
Time frame: 15 weeks
Change in carbon dioxide output
Time frame: 15 weeks
Change in spiroergometry parameters in training vs. control group
Time frame: 15 weeks
Change in VCO2 at anaerobic threshold
Time frame: 15 weeks
Change in oxygen uptake
Time frame: 15 weeks
Change in diffusion-limited carbon monoxide (DLCO)
Time frame: 15 weeks
Change in alveolar volume (VA)
Time frame: 15 weeks
Change in residual volume (RV)
Time frame: 15 weeks
Change in total lung volume (TLC)
Time frame: 15 weeks
Change in forced expiratory flow
Time frame: 15 weeks
Change in peak expiratory flow rate
Time frame: 15 weeks
Change in forced expiratory volume in one second (FEV1)
Time frame: 15 weeks
Change in forced vital capacity (FVC)
Time frame: 15 weeks
Change in NTproBNP
Time frame: 15 weeks
Change in interleukins
Time frame: 15 weeks
Change in inflammatory markers
Time frame: 15 weeks
Change in carbon dioxide partial pressure
Time frame: 15 weeks
Change in oxygen saturation of the blood (SaO2)
Time frame: 15 weeks
Change in additional oxygen supplementation (yes/no and quantity)
Time frame: 15 weeks
Change in oxygen partial pressure
Time frame: 15 weeks
Change in oxygen saturation
Time frame: 15 weeks
Assessment of clinical laboratory Investigation alerts (values out of range)
Time frame: 15 weeks
Assessment of adverse Events
Time frame: 15 weeks
Assessment of serious adverse events
Time frame: 15 weeks
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 19 Dec 2019.
- Background: PubMed 16982941Mereles D, Ehlken N, Kreuscher S, Ghofrani S, Hoeper MM, Halank M, Meyer FJ, Karger G, Buss J, Juenger J, Holzapfel N, Opitz C, Winkler J, Herth FF, Wilkens H, Katus HA, Olschewski H, Grunig E. Exercise and respiratory training improve exercise capacity and quality of life in patients with severe chronic pulmonary hypertension. Circulation. 2006 Oct 3;114(14):1482-9. doi: 10.1161/CIRCULATIONAHA.106.618397. Epub 2006 Sep 18.
- Background: PubMed 21311162Grunig E, Ehlken N, Ghofrani A, Staehler G, Meyer FJ, Juenger J, Opitz CF, Klose H, Wilkens H, Rosenkranz S, Olschewski H, Halank M. Effect of exercise and respiratory training on clinical progression and survival in patients with severe chronic pulmonary hypertension. Respiration. 2011;81(5):394-401. doi: 10.1159/000322475. Epub 2011 Feb 9.
- Background: PubMed 22323570Grunig E, Lichtblau M, Ehlken N, Ghofrani HA, Reichenberger F, Staehler G, Halank M, Fischer C, Seyfarth HJ, Klose H, Meyer A, Sorichter S, Wilkens H, Rosenkranz S, Opitz C, Leuchte H, Karger G, Speich R, Nagel C. Safety and efficacy of exercise training in various forms of pulmonary hypertension. Eur Respir J. 2012 Jul;40(1):84-92. doi: 10.1183/09031936.00123711. Epub 2012 Feb 9.
- Background: PubMed 22709477Grunig E, Maier F, Ehlken N, Fischer C, Lichtblau M, Blank N, Fiehn C, Stockl F, Prange F, Staehler G, Reichenberger F, Tiede H, Halank M, Seyfarth HJ, Wagner S, Nagel C. Exercise training in pulmonary arterial hypertension associated with connective tissue diseases. Arthritis Res Ther. 2012 Jun 18;14(3):R148. doi: 10.1186/ar3883.
- Background: PubMed 22848542Nagel C, Prange F, Guth S, Herb J, Ehlken N, Fischer C, Reichenberger F, Rosenkranz S, Seyfarth HJ, Mayer E, Halank M, Grunig E. Exercise training improves exercise capacity and quality of life in patients with inoperable or residual chronic thromboembolic pulmonary hypertension. PLoS One. 2012;7(7):e41603. doi: 10.1371/journal.pone.0041603. Epub 2012 Jul 25.
- Background: PubMed 23041100Becker-Grunig T, Klose H, Ehlken N, Lichtblau M, Nagel C, Fischer C, Gorenflo M, Tiede H, Schranz D, Hager A, Kaemmerer H, Miera O, Ulrich S, Speich R, Uiker S, Grunig E. Efficacy of exercise training in pulmonary arterial hypertension associated with congenital heart disease. Int J Cardiol. 2013 Sep 20;168(1):375-81. doi: 10.1016/j.ijcard.2012.09.036. Epub 2012 Oct 5.
- Background: PubMed 23681593Halank M, Einsle F, Lehman S, Bremer H, Ewert R, Wilkens H, Meyer FJ, Grunig E, Seyfarth HJ, Kolditz M, Wieder G, Hoffken G, Kollner V. Exercise capacity affects quality of life in patients with pulmonary hypertension. Lung. 2013 Aug;191(4):337-43. doi: 10.1007/s00408-013-9472-6. Epub 2013 May 17.
- Background: PubMed 24338088Kabitz HJ, Bremer HC, Schwoerer A, Sonntag F, Walterspacher S, Walker DJ, Ehlken N, Staehler G, Windisch W, Grunig E. The combination of exercise and respiratory training improves respiratory muscle function in pulmonary hypertension. Lung. 2014 Apr;192(2):321-8. doi: 10.1007/s00408-013-9542-9. Epub 2013 Dec 13.
- Background: PubMed 26231884Ehlken N, Lichtblau M, Klose H, Weidenhammer J, Fischer C, Nechwatal R, Uiker S, Halank M, Olsson K, Seeger W, Gall H, Rosenkranz S, Wilkens H, Mertens D, Seyfarth HJ, Opitz C, Ulrich S, Egenlauf B, Grunig E. 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 Jan 1;37(1):35-44. doi: 10.1093/eurheartj/ehv337. Epub 2015 Jul 31.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Ekkehard Grünig, MD principal investigator
Centre for pulmonary hypertension of the Thoraxclinic at the University Hospital Heidelberg
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Exercise training in people with Pulmonary Hypertension, run by Heidelberg University at 1 site in Germany.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 10 inclusion and 18 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 19 Dec 2019. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Germany. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
6 MWD (time frame: 15 weeks). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03345212, which also lists 9 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 19 Dec 2019.