Exercise, Hypoxia and CPC in TBI Patients

Study Overview
=================
Brief Summary
-----------------
Circulating progenitor cells (CPC) treatments may have great potential for the recovery of neurons and brain function. Our group has reported how exposure to intermittent hypobaric hypoxia with superficial muscle electrostimulation is able to increase the concentration of CPC in peripheral blood in humans. Therefore, we believe that through physical activities and exposure to intermittent hypobaric hypoxia for a period, it will increase CPC in the blood of subjects who have suffered a severe Traumatic Brain Injury (TBI) one or more years ago, promoting regeneration and functional and cognitive recovery. The study primary end-point is to improve physical or psychological functioning of participants with TBI with a program of exercise, muscle electro-stimulation (ME) and/or intermittent-hypobaric-hypoxia (IHH). Secondary end-points are to increase and maintain CPC and also to study their possible relationship with physical or psychological improvement of participants with Traumatic Brain Injury (TBI). In order to achieve these objectives investigators have designed a randomized controlled trial that will include those patients who suffered severe TBI more than one year previously with physical or psychological sequelae. Exercise, muscle electro-stimulation (ME) and/or intermittent hypobaric hypoxia (IHH) programs will be applied during twelve weeks. Psychological and physical stress tests will carry out before and after the program and CPC will measure at the beginning, every two weeks, and at the end of the program.

Detailed Description
-----------------
Clinical, experimental, case control and prospective study. Inclusion criteria are: patients who suffered severe TBI more than one year previously with physical or psychological sequelae, male sex, and age 20-60 years old. Patients with epilepsy are not included. The study was approved by the institution's Research Ethics Committee and informed consent was obtained from the patients. A program of three days per week during twelve weeks will be applied to the active groups: one, exercise and muscle electrical stimulation, and the other, exercise, muscle electrical stimulation and IHH chamber exposure. Control group participants will follow a a day of cognitive activities one day per week during 12 weeks. Psychological and physical stress tests are carried out before and after the program. Psychological tests evaluate features of language and work (verbal memory-RAVLT), Trail Making Test (TMT A and B), Stroop Test, working memory capacity and attention (WAIS III), information processing speed (WAIS III), orientation and verbal fluency (Barcelona test), executive functions (WAIS III and Tower of London tests) and estimated premorbid intelligence index (vocabulary, WAIS III). Reduced Paced Auditory Serial Addition Test (PASAT-G) evaluate work memory components. Physical graded maximum stress tests were performed on a cycle ergometer increasing progressively the workload, in order to evaluate physical capacity and adaptation to different intensities of effort. CPC (CD34+) are measured in peripheral blood according to a previously used method (Viscor et al., 2009), at the beginning, every two weeks, and at the end of the program (blood samples were always obtained before the exercise sessions). Statistical analysis: data will express as mean, median, standard deviation and interquartile range as appropriate. The continuous variables will compare using the Mann-Whitney U test. Wilcoxon signed rank test and Friedman test are used for repeated measures. All tests will perform using Statistical Package for the Social Sciences (SPSS) v.13. Statistical significance was set at P<0.05.

Official Title
-----------------
Exercise, Muscle Electro-stimulation and Intermittent Hypobaric Hypoxia Program and Circulating Progenitor Cells in Traumatic Brain Injured Patients

Conditions
-----------------
Traumatic Brain Injury

Intervention / Treatment
-----------------
* Other: cognitive activities
* Other: Exercise program
* Device: Muscle electro-stimulation
* Other: Intermittent hypobaric hypoxia


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patients who suffered severe TBI more than one year previously with physical or psychological sequelae. Written informed consent from patient Exclusion Criteria: Epilepsy Any medical or psychological contraindications for implementing the program of physical activity or hypobaric chamber. Inclusion in other ongoing study Refuse consent

Ages Eligible for Study
-----------------
Minimum Age: 20 Years
Maximum Age: 60 Years

Sexes Eligible for Study
-----------------
Male

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Supportive Care
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Control group<br>Once a week there will be an attendance cognitive session (specific sessions designed to work on aspects related to body perception, movement, space) and the extraction of blood samples will be carried out to determine the progenitor cells on the same day of the active groups. | Other: cognitive activities<br>* Participants followed a day of cognitive activities 1 day (1 hour/day) per week during 12 weeks.<br>|
| Active Comparator: Exercise group<br>Patients with past history of TBI will perform exercise sessions two hours three days a week during 12 weeks. The sessions will consist of aerobic, strength, flexibility, proprioception and balance activities and muscle electro-stimulation sessions or cycling sessions. | Other: Exercise program<br>* Exercise program of endurance, resistance and proprioception exercises, comprising three sessions per week and muscle electro-stimulation was applied using the Compex Vitality® vascular and capillarization program with electrodes fixed in quadriceps and abdominal muscles or cycling exercise.<br>|
| Active Comparator: Muscle electro-stimulation and IHH<br>Patients with past history of TBI will perform a 12 weeks program: intermittent hypobaric hypoxia (IHH) 2 hours at a simulated altitude of 4500 meters 3 days/week. Muscle electro-stimulation for two periods of 20 minutes during the stay in the hypobaric chamber. | Device: Muscle electro-stimulation<br>* A program of intermittent hypobaric hypoxia and muscle electro-stimulation of 3 days (3 hours/day) per week during 12 weeks<br>Other: Intermittent hypobaric hypoxia<br> <br> |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from initial physical stress test at one week post-intervention | Physical graded maximum stress tests are performed on a cycle ergometer controlling the workload, in order to evaluate physical capacity and adaptation to different intensities of effort.While performance of these tests are conducted, cardiocirculatory (control of heart rate, blood pressure measurement, continuous ECG) and respiratory (breathing gases analysis) are monitored to observe the adaptation to the effort. | One week before and an expected average of one week after the intervention | 
| Change from initial psychological test at one weeks after intervention | Psychological tests evaluated features of language and work (verbal memory-RAVLT), Trail Making Test (TMT A and B), Stroop Test, working memory capacity and attention (WAIS III), information processing speed (WAIS III), orientation and verbal fluency (Barcelona test), executive functions (WAIS III and Tower of London tests) and estimated premorbid intelligence index (vocabulary, WAIS III). Reduced Paced Auditory Serial Addition Test (PASAT-G) | One week before and an average of one week after the intervention | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Circulating progenitor cells increase | Blood CD34 staining and flow cytometry assay in accordance with ISHAGE guidelines (Keeney et al., 1998). CD34 cells/µL. | The day before, every 15 days during the intervention and two weeks after the intervention | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Traumatic brain injury, Progenitor cells, Hypoxia, Exercise, Psychology, Physiology