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

• ClinicalTrials.gov Identifier: NCT02571088
• Recruitment Status: Completed
• First Posted: October 8, 2015
• Last Update Posted: April 11, 2016
• Sponsor: Centre Hospitalier Universitaire de Saint Etienne
• Collaborators: Centre de Référence des Syndromes Drépanocytaires Majeurs; Laboratoire de Physiologie de l’Exercice; Claude Bernard University
• Information provided by (Responsible Party): Centre Hospitalier Universitaire de Saint Etienne

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	Not Applicable

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 (Clinical Trial)
• 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: September 2014
• Actual Primary Completion Date: April 2016
• Actual Study Completion Date: April 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

Outcome Measures

Primary Outcome Measures :

1. Power output (W) associated with the 4 mmol/L blood lactate concentration [ Time Frame: 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 :

1. Muscle fiber types distribution (%) [ Time Frame: 8 weeks ]
   Patients will be subjected to a biopsy of the vastus lateralis muscle (≈ 200 mg).
2. perimeter (µm) of muscle fiber [ Time Frame: 8 weeks ]
   Patients will be subjected to a biopsy of the vastus lateralis muscle (≈ 200 mg).
3. surface area (µm2) of muscle fiber [ Time Frame: 8 weeks ]
   Patients will be subjected to a biopsy of the vastus lateralis muscle (≈ 200 mg).
4. satellite cell account [ Time Frame: 8 weeks ]
   Patients will be subjected to a biopsy of the vastus lateralis muscle (≈ 200 mg).
5. Creatine Kinase (CK) of muscle [ Time Frame: 8 weeks ]
   Patients will be subjected to a biopsy of the vastus lateralis muscle (≈ 200 mg).
6. Phosphofructokinase (PFK) of muscle [ Time Frame: 8 weeks ]
   Patients will be subjected to a biopsy of the vastus lateralis muscle (≈ 200 mg).
7. Citrate Synthetase (CS) of muscle [ Time Frame: 8 weeks ]
   Patients will be subjected to a biopsy of the vastus lateralis muscle (≈ 200 mg).
8. HAD (µmol/min/g dry muscle) of muscle [ Time Frame: 8 weeks ]
   Patients will be subjected to a biopsy of the vastus lateralis muscle (≈ 200 mg).
9. COx (arbitrary unit, a.u.) of muscle [ Time Frame: 8 weeks ]
   Patients will be subjected to a biopsy of the vastus lateralis muscle (≈ 200 mg).
10. Lactate Dehydrogenase (LDH) of muscle [ Time Frame: 8 weeks ]
    Patients will be subjected to a biopsy of the vastus lateralis muscle (≈ 200 mg).
11. isoforms (%) of muscle [ Time Frame: 8 weeks ]
    Patients will be subjected to a biopsy of the vastus lateralis muscle (≈ 200 mg).
12. Number of capillaries per mm2 (capillary density) and in contact with a muscle fiber [ Time Frame: 8 weeks ]
    Patients will be subjected to a biopsy of the vastus lateralis muscle (≈ 200 mg).
13. surface area of microvessels (µm2) [ Time Frame: 8 weeks ]
    Patients will be subjected to a biopsy of the vastus lateralis muscle (≈ 200 mg).
14. diameter of microvessels (µm) [ Time Frame: 8 weeks ]
    Patients will be subjected to a biopsy of the vastus lateralis muscle (≈ 200 mg).
15. capillary tortuosity (quotient) [ Time Frame: 8 weeks ]
    Patients will be subjected to a biopsy of the vastus lateralis muscle (≈ 200 mg).
16. expired volume (VE) [ Time Frame: 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.
17. oxygen consumption (VO2) [ Time Frame: 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.
18. carbon dioxide production (VCO2) (L/min) [ Time Frame: 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.
19. respiratory quotient (QR) [ Time Frame: 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.
20. Heart Rate (HR) (min-1) [ Time Frame: 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.
21. lactate level (mmol/l) at the end of submaximal incremental exercise [ Time Frame: 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.
22. Pulmonary volumes (L) [ Time Frame: 8 weeks ]
    The volumes are measured by plethysmography
23. Performance to the six minute walk test (m) [ Time Frame: 8 weeks ]
24. Index of muscular blood flow and tissular oxygenation at rest (%) [ Time Frame: 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.
25. Index of exercise using Near-infrared reflectance spectroscopy (NIRS) (%) [ Time Frame: 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.
26. Maximal voluntary contraction (N) [ Time Frame: 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.
27. Neuromuscular fatigability (%) [ Time Frame: 8 weeks ]
    It is measured in the same time that MVC
28. Quality of life : Scores to the Short Form 36 (SF-36) [ Time Frame: 8 weeks ]
29. Quality of life : Functional Assessment of Cancer Therapy (FACT Fatigue Part) [ Time Frame: 8 weeks ]
30. Quality of life : State-Trait Anxiety Scale (STAI Y-A) [ Time Frame: 8 weeks ]
31. Quality of life : Physical Self-Description Questionnaire( PSDQ) [ Time Frame: 8 weeks ]
32. Complete blood count and biochemical analyses (ionogram, urea, creatinine, LDH, creatine phosphokinase (CPK), aspartate aminotransferase ; usual units) [ Time Frame: 8 weeks ]
    Patients will be subjected to blood samplings
33. Blood and plasma viscosity (centipoise) [ Time Frame: 8 weeks ]
    Patients will be subjected to blood samplings
34. Erythrocyte deformability (%) [ Time Frame: 8 weeks ]
    Patients will be subjected to blood samplings
35. aggregation properties (a.u.) [ Time Frame: 8 weeks ]
    Patients will be subjected to blood samplings
36. dense red blood cells (%) [ Time Frame: 8 weeks ]
    Patients will be subjected to blood samplings
37. Plasma analyses of adhesion molecules and markers of inflammation [ Time Frame: 8 weeks ]
    Patients will be subjected to blood samplings
38. oxidative stress [ Time Frame: 8 weeks ]
    Patients will be subjected to blood samplings
39. NO metabolism (µmol/L) [ Time Frame: 8 weeks ]
    Patients will be subjected to blood samplings
40. Activity of antioxidant enzymes (µmol/L/min) [ Time Frame: 8 weeks ]
    Patients will be subjected to blood samplings
41. Expression of erythrocytes membrane proteins (u.a.) [ Time Frame: 8 weeks ]
    Patients will be subjected to blood samplings
42. Red blood cell (RBC) adhesion to endothelial cells (count of adhering RBC /mm²) [ Time Frame: 8 weeks ]
    Patients will be subjected to blood samplings
43. Various hemodynamic criteria using echocardiography at rest and exercise [ Time Frame: 8 weeks ]
44. vaso-occlusive crises and acute chest syndrome [ Time Frame: 8 weeks ]
    During the 8 weeks, all vaso-occlusive crises and acute chest syndrome will be collected

Eligibility Criteria

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

Criteria

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

France

Hopital Avicenne

Bobigny, France, 93000

Centre hospitalier sud francilien

Corbeil-essonnes, France, 91100

CHU Henri MONDOR

Creteil, France, 94010

CHU Kremlin-Bicêtre

Le Kremlin Bicetre, France, 93270

Hopital Europeen Georges POMPIDOU

Paris, France, 75015

Hopital Necker

Paris, France, 75015

Hopital Tenon

Paris, France, 75020

Centre hospitalier de Saint-Denis

Saint-denis, France, 93200

CHU de SAINT-ETIENNE

Saint-etienne, France, 42000

Sponsors and Collaborators

Centre Hospitalier Universitaire de Saint Etienne

Centre de Référence des Syndromes Drépanocytaires Majeurs

Laboratoire de Physiologie de l’Exercice

Claude Bernard University

Investigators

• Principal Investigator: Leonard FEASSON, MD; CHU de SAINT-ETIENNE
• Study Director: Laurent MESSONIER, PhD; Université de Savoie

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Merlet AN, Féasson L, Bartolucci P, Hourdé C, Schwalm C, Gellen B, Galactéros F, Deldicque L, Francaux M, Messonnier LA; EXDRE collaborative study group. Muscle structural, energetic and functional benefits of endurance exercise training in sickle cell disease. Am J Hematol. 2020 Jul 18. doi: 10.1002/ajh.25936. [Epub ahead of print]

Merlet AN, Messonnier LA, Coudy-Gandilhon C, Béchet D, Gellen B, Rupp T, Galactéros F, Bartolucci P, Féasson L. Beneficial effects of endurance exercise training on skeletal muscle microvasculature in sickle cell disease patients. Blood. 2019 Dec 19;134(25):2233-2241. doi: 10.1182/blood.2019001055.

Gellen B, Messonnier LA, Galactéros F, Audureau E, Merlet AN, Rupp T, Peyrot S, Martin C, Féasson L, Bartolucci P; EXDRE collaborative study group. Moderate-intensity endurance-exercise training in patients with sickle-cell disease without severe chronic complications (EXDRE): an open-label randomised controlled trial. Lancet Haematol. 2018 Nov;5(11):e554-e562. doi: 10.1016/S2352-3026(18)30163-7.

• Responsible Party: Centre Hospitalier Universitaire de Saint Etienne
• ClinicalTrials.gov Identifier: NCT02571088
• Other Study ID Numbers: 1408030; 2014-A00334-43 ( Other Identifier: ANSM )
• First Posted: October 8, 2015
• Last Update Posted: April 11, 2016
• Last Verified: April 2016

Keywords provided by Centre Hospitalier Universitaire de Saint Etienne:

Sickle Cell Hemoglobin C Disease; Sports Training; Hemoglobin S Disease; Lactate

Additional relevant MeSH terms:

Anemia, Sickle Cell; Sickle Cell Trait; Hemoglobin C Disease; Hemoglobin SC Disease; Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Anemia; Hematologic Diseases; Hemoglobinopathies; Genetic Diseases, Inborn