EXDRE: Evaluation of a Training Program for Homozygous Sickle Cell Disease Patients

Sponsor

Centre Hospitalier Universitaire de Saint Etienne (Other)

Overall Status

Completed

CT.gov ID

NCT02571088

Collaborator

Centre de Référence des Syndromes Drépanocytaires Majeurs (Other), Laboratoire de Physiologie de l'Exercice (Other), Claude Bernard University (Other)

Enrollment

Locations

Arms

Duration (Months)

4.4

Patients Per Site

0.2

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Sickle cell disease (SCD) is the most frequent inherited disease in the world. Literature reports that SCD patients display intolerance to exercise, important muscle weakness and profound remodeling of skeletal muscle including amyotrophy and rarefied microvascular network.

Because strenuous exercise induces acidosis, hemorheological alterations, endothelial activation and oxidative stress, it constitutes a potential triggering factor of sickling and vaso-occlusive crisis. As a consequence, physical activity is usually discouraged in patients with SCD. However, moderate and regular physical activity seems to be not only safe but also beneficial for SCD patients.

Condition or Disease	Intervention/Treatment	Phase
Sickle Cell Hemoglobin C Disease Hemoglobin S Disease	Other: Training Program	N/A

Detailed Description

Besides, endurance training is known to induce moderate muscle hypertrophy and increase microvascular network. Therefore, adapted, moderate and regular physical activity appears as a potential strategy able to improve muscle function, decrease symptoms of the disease and improve autonomy and quality of life of patients with SCD. However, it remains necessary to define the modalities of exercise therapy in SCD and to objectively evaluate the risks, limitations and gains on physical ability, muscle function and quality of life in patients with SCD.

Study Design

Study Type:

Interventional

Actual Enrollment :

40 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Evaluation of a Training Program for Homozygous Sickle Cell Disease Patients: Benefits on Physical Ability and Skeletal Muscle. An Interventional Pilot, Multicentric, Prospective, Longitudinal Study

Study Start Date :

Sep 1, 2014

Actual Primary Completion Date :

Apr 1, 2016

Actual Study Completion Date :

Apr 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Training Program The treatment will consist in an endurance training program. Only patients of the trained group will be subjected to this training program which will typically consist in 3 training sessions per week during 8 weeks i.e., 24 training sessions. Each training session will last 45 min. All training sessions will take place at the hospital and will be under medical supervision.	Other: Training Program Each training session will last 45 min. Exercise will start by a 5-min warm-up cycling period, followed by 30 min of cycling at the power output (W) individually determined before and corresponding to the first lactate threshold corresponding approximately to 2.5 mmol/l . Then patients will cool down for 5 min. Finally, the training sessions will end by 5 min of light stretching. All training sessions will take place at the hospital and will be under the supervision of a physician. Heart rate, oxygen saturation and blood lactate concentrations will be regularly measured. Work rate will be adjusted according to the obtained results. As a safety procedure, blood lactate concentration must not exceed 4 mmol/L during the training sessions. A particular attention will be paid to the hydration of patients. Pain and fatigue will be evaluated everyday by the patients using (100 mm) visual analog scales.
No Intervention: No Training Program It will be asked to the control patients to not change their habitual physical activity during the entire period of observation

Arm

Intervention/Treatment

Experimental: Training Program

The treatment will consist in an endurance training program. Only patients of the trained group will be subjected to this training program which will typically consist in 3 training sessions per week during 8 weeks i.e., 24 training sessions. Each training session will last 45 min. All training sessions will take place at the hospital and will be under medical supervision.

Other: Training Program

Each training session will last 45 min. Exercise will start by a 5-min warm-up cycling period, followed by 30 min of cycling at the power output (W) individually determined before and corresponding to the first lactate threshold corresponding approximately to 2.5 mmol/l . Then patients will cool down for 5 min. Finally, the training sessions will end by 5 min of light stretching. All training sessions will take place at the hospital and will be under the supervision of a physician. Heart rate, oxygen saturation and blood lactate concentrations will be regularly measured. Work rate will be adjusted according to the obtained results. As a safety procedure, blood lactate concentration must not exceed 4 mmol/L during the training sessions. A particular attention will be paid to the hydration of patients. Pain and fatigue will be evaluated everyday by the patients using (100 mm) visual analog scales.

No Intervention: No Training Program

It will be asked to the control patients to not change their habitual physical activity during the entire period of observation

Outcome Measures

Primary Outcome Measures

Power output (W) associated with the 4 mmol/L blood lactate concentration [8 weeks]
The blood lactate concentration curve in response to incremental exercise depends on the physical ability of patients. Endurance training is known to increase the power output (W) associated with a given blood lactate concentration. For the present study, we used the 4 mmol/L blood lactate concentration as a remarkable/singular point of the curve

Secondary Outcome Measures

Muscle fiber types distribution (%) [8 weeks]
Patients will be subjected to a biopsy of the vastus lateralis muscle (≈ 200 mg).
perimeter (µm) of muscle fiber [8 weeks]
Patients will be subjected to a biopsy of the vastus lateralis muscle (≈ 200 mg).
surface area (µm2) of muscle fiber [8 weeks]
Patients will be subjected to a biopsy of the vastus lateralis muscle (≈ 200 mg).
satellite cell account [8 weeks]
Patients will be subjected to a biopsy of the vastus lateralis muscle (≈ 200 mg).
Creatine Kinase (CK) of muscle [8 weeks]
Patients will be subjected to a biopsy of the vastus lateralis muscle (≈ 200 mg).
Phosphofructokinase (PFK) of muscle [8 weeks]
Patients will be subjected to a biopsy of the vastus lateralis muscle (≈ 200 mg).
Citrate Synthetase (CS) of muscle [8 weeks]
Patients will be subjected to a biopsy of the vastus lateralis muscle (≈ 200 mg).
HAD (µmol/min/g dry muscle) of muscle [8 weeks]
Patients will be subjected to a biopsy of the vastus lateralis muscle (≈ 200 mg).
COx (arbitrary unit, a.u.) of muscle [8 weeks]
Patients will be subjected to a biopsy of the vastus lateralis muscle (≈ 200 mg).
Lactate Dehydrogenase (LDH) of muscle [8 weeks]
Patients will be subjected to a biopsy of the vastus lateralis muscle (≈ 200 mg).
isoforms (%) of muscle [8 weeks]
Patients will be subjected to a biopsy of the vastus lateralis muscle (≈ 200 mg).
Number of capillaries per mm2 (capillary density) and in contact with a muscle fiber [8 weeks]
Patients will be subjected to a biopsy of the vastus lateralis muscle (≈ 200 mg).
surface area of microvessels (µm2) [8 weeks]
Patients will be subjected to a biopsy of the vastus lateralis muscle (≈ 200 mg).
diameter of microvessels (µm) [8 weeks]
Patients will be subjected to a biopsy of the vastus lateralis muscle (≈ 200 mg).
capillary tortuosity (quotient) [8 weeks]
Patients will be subjected to a biopsy of the vastus lateralis muscle (≈ 200 mg).
expired volume (VE) [8 weeks]
Patients will perform a submaximal incremental exercise on a cycle ergometer. Exercise will start at 20 W and 30 W for females and males, respectively. After 2 minutes at this load, and every 2 minutes thereafter, work rate will increase by 10 W and 15 W for females and males, respectively. Total exercise duration is expected to be within 8 to 14 minutes.
oxygen consumption (VO2) [8 weeks]
Patients will perform a submaximal incremental exercise on a cycle ergometer. Exercise will start at 20 W and 30 W for females and males, respectively. After 2 minutes at this load, and every 2 minutes thereafter, work rate will increase by 10 W and 15 W for females and males, respectively. Total exercise duration is expected to be within 8 to 14 minutes.
carbon dioxide production (VCO2) (L/min) [8 weeks]
Patients will perform a submaximal incremental exercise on a cycle ergometer. Exercise will start at 20 W and 30 W for females and males, respectively. After 2 minutes at this load, and every 2 minutes thereafter, work rate will increase by 10 W and 15 W for females and males, respectively. Total exercise duration is expected to be within 8 to 14 minutes.
respiratory quotient (QR) [8 weeks]
Patients will perform a submaximal incremental exercise on a cycle ergometer. Exercise will start at 20 W and 30 W for females and males, respectively. After 2 minutes at this load, and every 2 minutes thereafter, work rate will increase by 10 W and 15 W for females and males, respectively. Total exercise duration is expected to be within 8 to 14 minutes.
Heart Rate (HR) (min-1) [8 weeks]
Patients will perform a submaximal incremental exercise on a cycle ergometer. Exercise will start at 20 W and 30 W for females and males, respectively. After 2 minutes at this load, and every 2 minutes thereafter, work rate will increase by 10 W and 15 W for females and males, respectively. Total exercise duration is expected to be within 8 to 14 minutes.
lactate level (mmol/l) at the end of submaximal incremental exercise [8 weeks]
Patients will perform a submaximal incremental exercise on a cycle ergometer. Exercise will start at 20 W and 30 W for females and males, respectively. After 2 minutes at this load, and every 2 minutes thereafter, work rate will increase by 10 W and 15 W for females and males, respectively. Total exercise duration is expected to be within 8 to 14 minutes.
Pulmonary volumes (L) [8 weeks]
The volumes are measured by plethysmography
Performance to the six minute walk test (m) [8 weeks]
Index of muscular blood flow and tissular oxygenation at rest (%) [8 weeks]
Patients will perform a submaximal incremental exercise on a cycle ergometer. Exercise will start at 20 W and 30 W for females and males, respectively. After 2 minutes at this load, and every 2 minutes thereafter, work rate will increase by 10 W and 15 W for females and males, respectively. Total exercise duration is expected to be within 8 to 14 minutes.
Index of exercise using Near-infrared reflectance spectroscopy (NIRS) (%) [8 weeks]
Patients will perform a submaximal incremental exercise on a cycle ergometer. Exercise will start at 20 W and 30 W for females and males, respectively. After 2 minutes at this load, and every 2 minutes thereafter, work rate will increase by 10 W and 15 W for females and males, respectively. Total exercise duration is expected to be within 8 to 14 minutes.
Maximal voluntary contraction (N) [8 weeks]
Maximal Voluntary Contraction (MVC) will be measured 3 times 1 min apart to determine an initial MVC. After 10 min of rest following the MVC trials, neuromuscular fatigability will be assess by repetition of series of 10 submaximal contractions (of 4 s separated by 5 s) followed by a MVC trial until a decrease of 25% of the initial MVC is observed. No more than 7 series will be performed, even if the 25% decrease of initial MVC is not observed.
Neuromuscular fatigability (%) [8 weeks]
It is measured in the same time that MVC
Quality of life : Scores to the Short Form 36 (SF-36) [8 weeks]
Quality of life : Functional Assessment of Cancer Therapy (FACT Fatigue Part) [8 weeks]
Quality of life : State-Trait Anxiety Scale (STAI Y-A) [8 weeks]
Quality of life : Physical Self-Description Questionnaire( PSDQ) [8 weeks]
Complete blood count and biochemical analyses (ionogram, urea, creatinine, LDH, creatine phosphokinase (CPK), aspartate aminotransferase ; usual units) [8 weeks]
Patients will be subjected to blood samplings
Blood and plasma viscosity (centipoise) [8 weeks]
Patients will be subjected to blood samplings
Erythrocyte deformability (%) [8 weeks]
Patients will be subjected to blood samplings
aggregation properties (a.u.) [8 weeks]
Patients will be subjected to blood samplings
dense red blood cells (%) [8 weeks]
Patients will be subjected to blood samplings
Plasma analyses of adhesion molecules and markers of inflammation [8 weeks]
Patients will be subjected to blood samplings
oxidative stress [8 weeks]
Patients will be subjected to blood samplings
NO metabolism (µmol/L) [8 weeks]
Patients will be subjected to blood samplings
Activity of antioxidant enzymes (µmol/L/min) [8 weeks]
Patients will be subjected to blood samplings
Expression of erythrocytes membrane proteins (u.a.) [8 weeks]
Patients will be subjected to blood samplings
Red blood cell (RBC) adhesion to endothelial cells (count of adhering RBC /mm²) [8 weeks]
Patients will be subjected to blood samplings
Various hemodynamic criteria using echocardiography at rest and exercise [8 weeks]
vaso-occlusive crises and acute chest syndrome [8 weeks]
During the 8 weeks, all vaso-occlusive crises and acute chest syndrome will be collected

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Sickle cell disease patient (HbSS or HbS-βthal0),
Affiliated to a Health Security program,
Consent form signed,
Patients in stabilized state at the onset of the experiment: at least one month after an acute adverse event and at least 3 months after a blood transfusion.

Exclusion Criteria:

Patients whom adhesion/compliance to the protocol appears uncertain,
Patient involved in another clinical trial or within the exclusion period of a previous clinical trial,
Patients known to be affected by a chronic inflammatory or infectious pathology,
Patients having an intercurrent infection, especially inflammatory, unsolved since less than one month,
Patients with clinical signs of heart failure or hospitalized for cardiac decompensation during the past 12 months,
Patients with left ventricular ejection fraction < 50%, pulmonary arterial hypertension with tricuspid regurgitation velocity > 2.5 m/s, atrial fibrillation, ventricular rhythm disorders during exercise, left ventricular hypertrophy (septal to lateral wall thickness ≥ 10 mm), significant valvulopathy, established coronary disease, uncontrolled hypertension,
Patients with a treatment against cardiac arrhythmia or altering sino-atrial node activity (beta-blockers, atropine, sympathomimetic agents…),
Patients under anti-coagulant treatment,
Patients with pacemaker or defibrillator,
Body Mass Index (BMI) > 35,
Patients with hip osteonecrosis,
Patients with cerebral vasculopathy or history of stroke (cerebrovascular attack) with epilepsy,
Pregnant or lactating patients,
Homeless patients,
Patients with the inability to understand the aims,

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	Hopital Avicenne	Bobigny	France	93000
2	Centre hospitalier sud francilien	Corbeil-essonnes	France	91100
3	CHU Henri MONDOR	Creteil	France	94010
4	CHU Kremlin-Bicêtre	Le Kremlin Bicetre	France	93270
5	Hopital Europeen Georges POMPIDOU	Paris	France	75015
6	Hopital Necker	Paris	France	75015
7	Hopital Tenon	Paris	France	75020
8	Centre hospitalier de Saint-Denis	Saint-denis	France	93200
9	CHU de SAINT-ETIENNE	Saint-etienne	France	42000