ClinicalTrials.gov
ClinicalTrials.gov Menu

A Randomized Controlled Multicenter Trial of Exercise Training in Pulmonary Hypertension in European Countries (EU-TRAIN-01)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT03345212
Recruitment Status : Recruiting
First Posted : November 17, 2017
Last Update Posted : November 27, 2017
Sponsor:
Information provided by (Responsible Party):
Prof. Dr. med. Ekkehard Gruenig, Heidelberg University

Brief 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.


Condition or disease Intervention/treatment Phase
Pulmonary Hypertension Other: Exercise training Not Applicable

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 Type : Interventional  (Clinical Trial)
Estimated Enrollment : 126 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Diagnostic
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
Actual Study Start Date : February 2016
Actual Primary Completion Date : July 2017
Estimated Study Completion Date : December 2018

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
No Intervention: Control group
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.
Experimental: Training group

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.

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




Primary Outcome Measures :
  1. 6 MWD [ Time Frame: 15 weeks ]
    Change in 6-MWD between baseline and 15 weeks in the training vs. the control Group; meters


Secondary Outcome Measures :
  1. Change in WHO functional class in training vs. control group [ Time Frame: 15 weeks ]
    WHO functional class

  2. Change in Quality of life in training vs. control group [ Time Frame: 15 weeks ]
    Quality of life (SF-36)

  3. Change in Borg scale 6-MWD training vs. control group [ Time Frame: 15 weeks ]
    Borg scale 6-MWD

  4. Change in tricuspid annular plane systolic excursion [ Time Frame: 15 weeks ]
    Echocardiographic parameter training vs. control Group; mm

  5. Change in tissue Doppler imaging [ Time Frame: 15 weeks ]
    Echocardiographic Parameter training vs. control group

  6. Change in left ventricular pump function [ Time Frame: 15 weeks ]
    Echocardiographic Parameter training vs. control Group; qualitative

  7. Change in right ventricular pump function [ Time Frame: 15 weeks ]
    Echocardiographic Parameter training vs. control Group; qualitative

  8. Change in thickness of interventricular septum [ Time Frame: 15 weeks ]
    Echocardiographic Parameter training vs. control Group; mm

  9. Change insize of inferior vena cava [ Time Frame: 15 weeks ]
    Echocardiographic Parameter training vs. control Group; mm

  10. Change in systolic pulmonary arterial pressure [ Time Frame: 15 weeks ]
    Echocardiographic Parameter training vs. control Group; mmHg

  11. Change in left ventricular eccentricity index [ Time Frame: 15 weeks ]
    Echocardiographic Parameter training vs. control group

  12. Change in Tei index [ Time Frame: 15 weeks ]
    Echocardiographic Parameter training vs. control group

  13. Change in right ventricular area [ Time Frame: 15 weeks ]
    Echocardiographic Parameter training vs. control group

  14. Change in right atrial area [ Time Frame: 15 weeks ]
    Echocardiographic Parameter training vs. control Group; square cm

  15. Change in workload [ Time Frame: 15 weeks ]
    Cardiopulmonary exercise testing (spiroergometry) training vs. control Group; Watts

  16. Change in heart rate [ Time Frame: 15 weeks ]
    Cardiopulmonary exercise testing (spiroergometry) training vs. control Group; bpm

  17. Change in ventilation [ Time Frame: 15 weeks ]
    Cardiopulmonary exercise testing (spiroergometry) training vs. control Group; L/min

  18. Change in carbon dioxide output [ Time Frame: 15 weeks ]
    Cardiopulmonary exercise testing (spiroergometry) training vs. control Group

  19. Change in spiroergometry parameters in training vs. control group [ Time Frame: 15 weeks ]
    Cardiopulmonary exercise testing (spiroergometry): VO2 at anaerobic threshold determined by V-slope method

  20. Change in VCO2 at anaerobic threshold [ Time Frame: 15 weeks ]
    Cardiopulmonary exercise testing (spiroergometry): determined by V-slope method

  21. Change in oxygen uptake [ Time Frame: 15 weeks ]
    Cardiopulmonary exercise testing (spiroergometry); L/min/kg

  22. Change in diffusion-limited carbon monoxide (DLCO) [ Time Frame: 15 weeks ]
    Lung function; Diffusion capacity

  23. Change in alveolar volume (VA) [ Time Frame: 15 weeks ]
    Lung function

  24. Change in residual volume (RV) [ Time Frame: 15 weeks ]
    Lung function

  25. Change in total lung volume (TLC) [ Time Frame: 15 weeks ]
    Lung function

  26. Change in forced expiratory flow [ Time Frame: 15 weeks ]
    Lung function

  27. Change in peak expiratory flow rate [ Time Frame: 15 weeks ]
    Lung function

  28. Change in forced expiratory volume in one second (FEV1) [ Time Frame: 15 weeks ]
    Lung function; total and in percentage

  29. Change in forced vital capacity (FVC) [ Time Frame: 15 weeks ]
    Lung function

  30. Change in NTproBNP [ Time Frame: 15 weeks ]
    Laboratory marker for the impairment of the right heart

  31. Change in interleukins [ Time Frame: 15 weeks ]
    Laboratory marker for the impairment of the right heart

  32. Change in inflammatory markers [ Time Frame: 15 weeks ]
    Laboratory marker for the impairment of the right heart

  33. Change in carbon dioxide partial pressure [ Time Frame: 15 weeks ]
    Blood gas Analysis

  34. Change in oxygen saturation of the blood (SaO2) [ Time Frame: 15 weeks ]
    Blood gas analysis

  35. Change in additional oxygen supplementation (yes/no and quantity) [ Time Frame: 15 weeks ]
    Blood gas analysis

  36. Change in oxygen partial pressure [ Time Frame: 15 weeks ]
    Blood gas analysis

  37. Change in oxygen saturation [ Time Frame: 15 weeks ]
    Safety Parameter; L/min

  38. Assessment of clinical laboratory Investigation alerts (values out of range) [ Time Frame: 15 weeks ]
    Safety parameter

  39. Assessment of adverse Events [ Time Frame: 15 weeks ]
    Safety Parameter; unrelated and related to procedure

  40. Assessment of serious adverse events [ Time Frame: 15 weeks ]
    Safety parameter

  41. frequency of hospitalizations [ Time Frame: 15 weeks ]
    Safety parameter

  42. length of hospitalizations [ Time Frame: 15 weeks ]
    Safety parameter

  43. Change in resting heart rate [ Time Frame: 15 weeks ]
    Safety parameter

  44. Change in blood pressure [ Time Frame: 15 weeks ]
    Safety parameter

  45. frequency of pathological findings in long-term ECG [ Time Frame: 15 weeks ]
    Safety parameter

  46. Qualitative Review of electrocardiogram (ECG) [ Time Frame: 15 weeks ]
    Safety Parameter; pathological findings

  47. Assessment of survival [ Time Frame: 1 year ]
    Training and control Group; transplant-free and Overall survival

  48. Change of the right ventricular size [ Time Frame: 15 weeks ]
    Optional: Changes in MRI parameters

  49. Change of the right ventricular pump function [ Time Frame: 15 weeks ]
    Optional: Changes in MRI parameters

  50. Change of the left ventricular size [ Time Frame: 15 weeks ]
    Optional: Changes in MRI parameters

  51. Change of the left ventricular pump function [ Time Frame: 15 weeks ]
    Optional: Changes in MRI parameters

  52. Change in microRNA expression [ Time Frame: 15 weeks ]
    Optional: Epigenetic changes

  53. Change in DNA-methylation [ Time Frame: 15 weeks ]
    Optional: Epigenetic changes

  54. Assessment of relationship of DNA mutations and disease progression [ Time Frame: 15 weeks ]
    Optional: Investigation of DNA mutations relationship to disease progression

  55. Assessment of relationship of DNA mutations and training effects [ Time Frame: 15 weeks ]
    Optional: Investigation of DNA mutations



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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 (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

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03345212


Contacts
Contact: Ekkehard Grünig, MD +4962213968053 ekkehard.gruenig@med.uni-heidelberg.de

Locations
Germany
Centre for pulmonary hypertension of the Thoraxclinic at the University Hospital Heidelberg Recruiting
Heidelberg, Germany, 69126
Contact: Ekkehard Grünig, MD    +4962213968053    ekkehard.gruenig@med.uni-heidelberg.de   
Principal Investigator: Ekkehard Grünig, MD         
Sponsors and Collaborators
Heidelberg University
Investigators
Principal Investigator: Ekkehard Grünig, MD Centre for pulmonary hypertension of the Thoraxclinic at the University Hospital Heidelberg

Publications:

Responsible Party: Prof. Dr. med. Ekkehard Gruenig, Prof. Dr. med., Heidelberg University
ClinicalTrials.gov Identifier: NCT03345212     History of Changes
Other Study ID Numbers: EU-TRAIN-01
First Posted: November 17, 2017    Key Record Dates
Last Update Posted: November 27, 2017
Last Verified: November 2017

Additional relevant MeSH terms:
Hypertension
Hypertension, Pulmonary
Vascular Diseases
Cardiovascular Diseases
Lung Diseases
Respiratory Tract Diseases