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

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

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.

Study Overview

• Status: Completed
• Conditions: Hemoglobin S Disease; Sickle Cell Hemoglobin C Disease
• Intervention / Treatment: Other: Training Program

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 Type: Interventional
• Enrollment (Actual): 40
• Phase: Not Applicable

Contacts and Locations

Study Locations

• France
  • Bobigny, France, 93000
    • Hôpital Avicenne
  • Corbeil-essonnes, France, 91100
    • Centre Hospitalier Sud Francilien
  • Creteil, France, 94010
    • CHU Henri Mondor
  • Le Kremlin Bicetre, France, 93270
    • CHU Kremlin-Bicêtre
  • Paris, France, 75015
    • Hopital Europeen Georges Pompidou
  • Paris, France, 75020
    • Hôpital Tenon
  • Paris, France, 75015
    • Hopital Necker
  • Saint-denis, France, 93200
    • Centre Hospitalier de Saint-Denis
  • Saint-etienne, France, 42000
    • CHU de SAINT-ETIENNE

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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,

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Power output (W) associated with the 4 mmol/L blood lactate concentration	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	8 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Muscle fiber types distribution (%)	Patients will be subjected to a biopsy of the vastus lateralis muscle (≈ 200 mg).	8 weeks
perimeter (µm) of muscle fiber	Patients will be subjected to a biopsy of the vastus lateralis muscle (≈ 200 mg).	8 weeks
surface area (µm2) of muscle fiber	Patients will be subjected to a biopsy of the vastus lateralis muscle (≈ 200 mg).	8 weeks
satellite cell account	Patients will be subjected to a biopsy of the vastus lateralis muscle (≈ 200 mg).	8 weeks
Creatine Kinase (CK) of muscle	Patients will be subjected to a biopsy of the vastus lateralis muscle (≈ 200 mg).	8 weeks
Phosphofructokinase (PFK) of muscle	Patients will be subjected to a biopsy of the vastus lateralis muscle (≈ 200 mg).	8 weeks
Citrate Synthetase (CS) of muscle	Patients will be subjected to a biopsy of the vastus lateralis muscle (≈ 200 mg).	8 weeks
HAD (µmol/min/g dry muscle) of muscle	Patients will be subjected to a biopsy of the vastus lateralis muscle (≈ 200 mg).	8 weeks
COx (arbitrary unit, a.u.) of muscle	Patients will be subjected to a biopsy of the vastus lateralis muscle (≈ 200 mg).	8 weeks
Lactate Dehydrogenase (LDH) of muscle	Patients will be subjected to a biopsy of the vastus lateralis muscle (≈ 200 mg).	8 weeks
isoforms (%) of muscle	Patients will be subjected to a biopsy of the vastus lateralis muscle (≈ 200 mg).	8 weeks
Number of capillaries per mm2 (capillary density) and in contact with a muscle fiber	Patients will be subjected to a biopsy of the vastus lateralis muscle (≈ 200 mg).	8 weeks
surface area of microvessels (µm2)	Patients will be subjected to a biopsy of the vastus lateralis muscle (≈ 200 mg).	8 weeks
diameter of microvessels (µm)	Patients will be subjected to a biopsy of the vastus lateralis muscle (≈ 200 mg).	8 weeks
capillary tortuosity (quotient)	Patients will be subjected to a biopsy of the vastus lateralis muscle (≈ 200 mg).	8 weeks
expired volume (VE)	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.	8 weeks
oxygen consumption (VO2)	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.	8 weeks
carbon dioxide production (VCO2) (L/min)	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.	8 weeks
respiratory quotient (QR)	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.	8 weeks
Heart Rate (HR) (min-1)	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.	8 weeks
lactate level (mmol/l) at the end of submaximal incremental exercise	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.	8 weeks
Pulmonary volumes (L)	The volumes are measured by plethysmography	8 weeks
Performance to the six minute walk test (m)		8 weeks
Index of muscular blood flow and tissular oxygenation at rest (%)	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.	8 weeks
Index of exercise using Near-infrared reflectance spectroscopy (NIRS) (%)	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.	8 weeks
Maximal voluntary contraction (N)	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.	8 weeks
Neuromuscular fatigability (%)	It is measured in the same time that MVC	8 weeks
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)	Patients will be subjected to blood samplings	8 weeks
Blood and plasma viscosity (centipoise)	Patients will be subjected to blood samplings	8 weeks
Erythrocyte deformability (%)	Patients will be subjected to blood samplings	8 weeks
aggregation properties (a.u.)	Patients will be subjected to blood samplings	8 weeks
dense red blood cells (%)	Patients will be subjected to blood samplings	8 weeks
Plasma analyses of adhesion molecules and markers of inflammation	Patients will be subjected to blood samplings	8 weeks
oxidative stress	Patients will be subjected to blood samplings	8 weeks
NO metabolism (µmol/L)	Patients will be subjected to blood samplings	8 weeks
Activity of antioxidant enzymes (µmol/L/min)	Patients will be subjected to blood samplings	8 weeks
Expression of erythrocytes membrane proteins (u.a.)	Patients will be subjected to blood samplings	8 weeks
Red blood cell (RBC) adhesion to endothelial cells (count of adhering RBC /mm²)	Patients will be subjected to blood samplings	8 weeks
Various hemodynamic criteria using echocardiography at rest and exercise		8 weeks
vaso-occlusive crises and acute chest syndrome	During the 8 weeks, all vaso-occlusive crises and acute chest syndrome will be collected	8 weeks

Collaborators and Investigators

• Sponsor: Centre Hospitalier Universitaire de Saint Etienne
• Collaborators: Claude Bernard University; Laboratoire de Physiologie de l'Exercice; Centre de Référence des Syndromes Drépanocytaires Majeurs
• Investigators: Study Director: Laurent MESSONIER, PhD, Université de Savoie

Publications and helpful links

General Publications

• Merlet AN, Feasson L, Bartolucci P, Hourde C, Schwalm C, Gellen B, Galacteros 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 Nov;95(11):1257-1268. doi: 10.1002/ajh.25936. Epub 2020 Aug 1.
• Merlet AN, Messonnier LA, Coudy-Gandilhon C, Bechet D, Gellen B, Rupp T, Galacteros F, Bartolucci P, Feasson 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, Galacteros F, Audureau E, Merlet AN, Rupp T, Peyrot S, Martin C, Feasson 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.

Study record dates

Study Major Dates

• Study Start: September 1, 2014
• Primary Completion (ACTUAL): April 1, 2016
• Study Completion (ACTUAL): April 1, 2016

Study Registration Dates

• First Submitted: August 25, 2015
• First Submitted That Met QC Criteria: October 7, 2015
• First Posted (ESTIMATE): October 8, 2015

Study Record Updates

• Last Update Posted (ACTUAL): September 13, 2021
• Last Update Submitted That Met QC Criteria: September 6, 2021
• Last Verified: September 1, 2021

More Information

Terms related to this study

• Keywords: Lactate; Hemoglobin S Disease; Sickle Cell Hemoglobin C Disease; Sports Training
• Additional Relevant MeSH Terms: Hematologic Diseases; Genetic Diseases, Inborn; Anemia; Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Hemoglobinopathies; Anemia, Sickle Cell; Hemoglobin SC Disease; Sickle Cell Trait; Hemoglobin C Disease
• Other Study ID Numbers: 1408030; 2014-A00334-43 (OTHER: ANSM)