A Randomized Controlled Multicenter Trial of Exercise Training in Pulmonary Hypertension in European Countries

Pulmonary Hypertension Clinical Trial

— EU-TRAIN-01  

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03345212
• Other study ID #: EU-TRAIN-01
• Status: Completed
• Phase: N/A
• Start date: February 2016
• Est. completion date: December 2019

Study information

• Verified date: December 2019
• Source: Heidelberg University
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical 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.

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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 129
• Est. completion date: December 2019
• Est. primary completion date: December 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• 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

• 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 (ß-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

Exclusion Criteria:

• 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

• 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

Related Conditions & MeSH terms

• Hypertension
• Hypertension, Pulmonary
• Pulmonary Hypertension

Intervention

Other:
• Exercise training
The rehabilitation program comprises interval ergometer training, dumbbell training, respiratory therapy, mental training and guided walks for 5-7 times/week.

Locations

Country	Name	City	State
Germany	Centre for pulmonary hypertension of the Thoraxclinic at the University Hospital Heidelberg	Heidelberg

Sponsors (1)

Lead Sponsor	Collaborator
Heidelberg University

Country where clinical trial is conducted

Germany, 

References & Publications (9)

Becker-Grünig 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, Grünig 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. — View Citation

Ehlken 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, Grünig 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. — View Citation

Grünig 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. — View Citation

Grünig 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. — View Citation

Grünig E, Maier F, Ehlken N, Fischer C, Lichtblau M, Blank N, Fiehn C, Stöckl 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. — View Citation

Halank M, Einsle F, Lehman S, Bremer H, Ewert R, Wilkens H, Meyer FJ, Grünig E, Seyfarth HJ, Kolditz M, Wieder G, Höffken G, Köllner 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. — View Citation

Kabitz HJ, Bremer HC, Schwoerer A, Sonntag F, Walterspacher S, Walker DJ, Ehlken N, Staehler G, Windisch W, Grünig 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. — View Citation

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, Grünig 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. Epub 2006 Sep 18. — View Citation

Nagel C, Prange F, Guth S, Herb J, Ehlken N, Fischer C, Reichenberger F, Rosenkranz S, Seyfarth HJ, Mayer E, Halank M, Grünig 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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	6 MWD	Change in 6-MWD between baseline and 15 weeks in the training vs. the control Group; meters	15 weeks
Secondary	Change in WHO functional class in training vs. control group	WHO functional class	15 weeks
Secondary	Change in Quality of life in training vs. control group	Quality of life (SF-36)	15 weeks
Secondary	Change in Borg scale 6-MWD training vs. control group	Borg scale 6-MWD	15 weeks
Secondary	Change in tricuspid annular plane systolic excursion	Echocardiographic parameter training vs. control Group; mm	15 weeks
Secondary	Change in tissue Doppler imaging	Echocardiographic Parameter training vs. control group	15 weeks
Secondary	Change in left ventricular pump function	Echocardiographic Parameter training vs. control Group; qualitative	15 weeks
Secondary	Change in right ventricular pump function	Echocardiographic Parameter training vs. control Group; qualitative	15 weeks
Secondary	Change in thickness of interventricular septum	Echocardiographic Parameter training vs. control Group; mm	15 weeks
Secondary	Change insize of inferior vena cava	Echocardiographic Parameter training vs. control Group; mm	15 weeks
Secondary	Change in systolic pulmonary arterial pressure	Echocardiographic Parameter training vs. control Group; mmHg	15 weeks
Secondary	Change in left ventricular eccentricity index	Echocardiographic Parameter training vs. control group	15 weeks
Secondary	Change in Tei index	Echocardiographic Parameter training vs. control group	15 weeks
Secondary	Change in right ventricular area	Echocardiographic Parameter training vs. control group	15 weeks
Secondary	Change in right atrial area	Echocardiographic Parameter training vs. control Group; square cm	15 weeks
Secondary	Change in workload	Cardiopulmonary exercise testing (spiroergometry) training vs. control Group; Watts	15 weeks
Secondary	Change in heart rate	Cardiopulmonary exercise testing (spiroergometry) training vs. control Group; bpm	15 weeks
Secondary	Change in ventilation	Cardiopulmonary exercise testing (spiroergometry) training vs. control Group; L/min	15 weeks
Secondary	Change in carbon dioxide output	Cardiopulmonary exercise testing (spiroergometry) training vs. control Group	15 weeks
Secondary	Change in spiroergometry parameters in training vs. control group	Cardiopulmonary exercise testing (spiroergometry): VO2 at anaerobic threshold determined by V-slope method	15 weeks
Secondary	Change in VCO2 at anaerobic threshold	Cardiopulmonary exercise testing (spiroergometry): determined by V-slope method	15 weeks
Secondary	Change in oxygen uptake	Cardiopulmonary exercise testing (spiroergometry); L/min/kg	15 weeks
Secondary	Change in diffusion-limited carbon monoxide (DLCO)	Lung function; Diffusion capacity	15 weeks
Secondary	Change in alveolar volume (VA)	Lung function	15 weeks
Secondary	Change in residual volume (RV)	Lung function	15 weeks
Secondary	Change in total lung volume (TLC)	Lung function	15 weeks
Secondary	Change in forced expiratory flow	Lung function	15 weeks
Secondary	Change in peak expiratory flow rate	Lung function	15 weeks
Secondary	Change in forced expiratory volume in one second (FEV1)	Lung function; total and in percentage	15 weeks
Secondary	Change in forced vital capacity (FVC)	Lung function	15 weeks
Secondary	Change in NTproBNP	Laboratory marker for the impairment of the right heart	15 weeks
Secondary	Change in interleukins	Laboratory marker for the impairment of the right heart	15 weeks
Secondary	Change in inflammatory markers	Laboratory marker for the impairment of the right heart	15 weeks
Secondary	Change in carbon dioxide partial pressure	Blood gas Analysis	15 weeks
Secondary	Change in oxygen saturation of the blood (SaO2)	Blood gas analysis	15 weeks
Secondary	Change in additional oxygen supplementation (yes/no and quantity)	Blood gas analysis	15 weeks
Secondary	Change in oxygen partial pressure	Blood gas analysis	15 weeks
Secondary	Change in oxygen saturation	Safety Parameter; L/min	15 weeks
Secondary	Assessment of clinical laboratory Investigation alerts (values out of range)	Safety parameter	15 weeks
Secondary	Assessment of adverse Events	Safety Parameter; unrelated and related to procedure	15 weeks
Secondary	Assessment of serious adverse events	Safety parameter	15 weeks
Secondary	frequency of hospitalizations	Safety parameter	15 weeks
Secondary	length of hospitalizations	Safety parameter	15 weeks
Secondary	Change in resting heart rate	Safety parameter	15 weeks
Secondary	Change in blood pressure	Safety parameter	15 weeks
Secondary	frequency of pathological findings in long-term ECG	Safety parameter	15 weeks
Secondary	Qualitative Review of electrocardiogram (ECG)	Safety Parameter; pathological findings	15 weeks
Secondary	Assessment of survival	Training and control Group; transplant-free and Overall survival	1 year
Secondary	Change of the right ventricular size	Optional: Changes in MRI parameters	15 weeks
Secondary	Change of the right ventricular pump function	Optional: Changes in MRI parameters	15 weeks
Secondary	Change of the left ventricular size	Optional: Changes in MRI parameters	15 weeks
Secondary	Change of the left ventricular pump function	Optional: Changes in MRI parameters	15 weeks
Secondary	Change in microRNA expression	Optional: Epigenetic changes	15 weeks
Secondary	Change in DNA-methylation	Optional: Epigenetic changes	15 weeks
Secondary	Assessment of relationship of DNA mutations and disease progression	Optional: Investigation of DNA mutations relationship to disease progression	15 weeks
Secondary	Assessment of relationship of DNA mutations and training effects	Optional: Investigation of DNA mutations	15 weeks