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.[1,2] The disease is
characterized by an increase of pulmonary vascular resistance and pulmonary
arterial pressure, leading to right heart insufficiency.[1,2] In later stages
of the disease, the right heart is not able to further increase right
ventricular contractility (cardiac index) during exercise. Within the last
decade, new disease-targeted medical therapies have been approved for treatment
of pulmonary arterial hypertension (PAH).[1-3] Sequential and upfront
combinations of these agents have shown to further improve symptoms, 6-minute
walking distance (6-MWD) and hemodynamics in PAH patients.[1-3]
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.[1] Most
patients die due to chronic right heart insufficiency. Reduced exercise
capacity in PH is associated with depression and anxiety disorders.[4] Thus,
there is a high need of additional therapeutic strategies.
Previous training studies [5-11] have suggested that exercise training as
add-on to medical treatment is highly effective improving exercise capacity,
quality of life and symptoms. Prospective studies with a 24±12 months follow-up
period suggested that exercise training may also improve the rate of clinical
worsening events as the need for hospitalization, additional PH-medication,
lung-transplantation and death.[5-11]
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.[1]
A specialized PH-training program has been performed in Heidelberg since 2003
including >1200 patients with various forms of chronic PH, mostly pulmonary
arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension
(CTEPH). 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. This approach is in line with European
PH-guidelines [12] which classified the exercise training in specialized
centers with a closely monitored program as evidence-level A and recommended
further randomized controlled multicenter trials.

Clinical Setting
This randomized, controlled multicenter trial will investigate the effect of
exercise training on physical exercise capacity, measured by 6-MWD. 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.
European health personnel will be taught the characteristics of the training to
achieve comparable settings and implementation of the program.
All patients have to be on optimized, stable PH-therapy. Medication has to
remain stable throughout the study. About three weeks are based on an
in-hospital stay to adjust and teach the exercise training which will be
continued at home for 12 more weeks. In-hospital stays will be arranged country
specific and hospitalization time may range between 10-30 days.
Patients of the training group will perform an additional routine assessment at
the end of in-hospital rehabilitation to adjust the program and receive advice
for continuation at home.
All patients will visit the clinic at pre-study screening at Day -28 to -1
(Visit [V] 1), at baseline (BL) at Day 1 (V2) and Week 15 (V4). As regular
control visits are usually performed every three months, the visits performed
in this study will comprise of routine visit periods.
Patients will be carefully monitored and treated according to local clinical
practice.

Randomized controlled trial to investigate primary and secondary endpoints in
European centers with patients receiving exercise training compared to patients
who continue their sedentary life-style for a period of 15 weeks.
The clinical investigation is performed as a prospective, randomized,
controlled, investigator-blinded study. Patients will be assessed at baseline
and after 15 weeks. Patients of the training group will also have an
examination at the end of in-hospital rehabilitation.
The rehabilitation program comprises interval ergometer training, dumbbell
training, respiratory therapy, mental training and guided walks for 5-7
times/week.
The clinical investigation across European countries will be initiated by
training of practitioners and health personnel to build up comparable exercise
training programs. The medical personnel will be trained in the low-dose
individually adjusted exercise program. On return to their country, these
trained professionals will establish their own training center and implement PH
rehabilitation therapy in their country.
Reference Treatment
Patients of the control group receive no exercise training and perform their
daily activities at home as usual. Exercise training will be performed after 15
weeks of control intervention. Patients will then be offered to take part in
the three-week training program (waiting-group design). The same measurements
in both groups at each visit will be used to assess changes induced by exercise
training.

Safety variables include and will be determined at each visit:
1. Electrocardiogram (ECG)
2. Vital signs: Blood pressure (BP), heart rate/pulse (HR), oxygen saturation
3. Clinical laboratory investigations
4. Concomitant medication
5. Concomitant diseases
6. Adverse events
A physical examination including vital signs and 12-lead ECG will be performed.
Close in-hospital monitoring within the first 3 weeks, examinations and phone
interviews will be used for assessment during the continuation of exercise
training at home. Safety will be assessed by phone interview until 1 year of
follow-up of the last patient. Patients will also be monitored during their
regular control visits at their PH-center.