Sickle Cell Disease (SCD), Vaso-occlusive Events
Conditions
Keywords
Sickle cell disease, Vaso-occlusive events
Brief summary
The purpose of this study is to compare the efficacy and safety of transplantation of gene modified autologous CD34+ cells in SCD patients within a therapeutic strategy that may include anti-inflammatory treatment as a pre-transplant treatment in case of severe inflammation detected at the inclusion analysis; the autologous CD34+ cell will be transduced by the bifunctional βAS3m/miR7m lentiviral vector expressing the therapeutical beta-globin, βAS3m, and the miRNA anti-HbS vs Standard Of Care (SOC).
Detailed description
Sickle cell disease is a severe hemoglobinopathy characterized by anemia, chronic hemolysis, and vaso-occlusive crises, leading to high morbidity and mortality. Medical management options or Standard Of Care (SOC) currently available for SCD include supportive management of VOC, long-term RBC transfusions, and foetal haemoglobin (HbF) induction with hydroxyurea (HU). Hematopoietic stem cell transplantation is curative but available only for a minority of patients. Gene therapy approaches (gene addition or gene editing) have shown significant reductions in vaso-occlusive events, but residual hemolysis persists and their truly curative potential remains uncertain. In France, the absence of a control arm in clinical trials has limited regulatory approval, supporting the development of the DREPAMIR protocol, which incorporates a Standard Of Care control group to better assess the efficacy clinical value and cost effectiveness of gene therapy in severe sickle cell disease. The aim of this study is to compare the efficacy and safety of transplantation of gene modified autologous CD34+ cells in SCD patients within a therapeutic strategy that may include anti-inflammatory treatment as a pre-transplant treatment in case of severe inflammation detected at the inclusion analysis; the autologous CD34+ cell will be transduced by the bifunctional βAS3m/miR7m lentiviral vector expressing the therapeutical beta-globin, βAS3m, and the miRNA anti-HbS vs Standard Of Care (SOC). Drepamir-SOC is the control arm of the main study DREPAMIR (NCT07432867)
Interventions
DRUGstandard of care
Supportive management of VOC, long-term RBC transfusions, and foetal haemoglobin (HbF) induction with hydroxyurea (HU) Myocardic MRI (evaluation of function and fibrosis) + hematocrit measurement QoL questionnaires Imaging (brain MRI, transcranial and cervical ultrasound) Cardiac US, ECG Cardiac and Liver MRI (Fe assessment) Physical ability assessments Neuropsychological assessments Fertility
Sponsors
Assistance Publique - Hôpitaux de Paris
URC-CIC Paris Descartes Necker Cochin
Imagine Institute
Association Française contre les Myopathies (AFM), Paris
Marie Lannelongue Hospital
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
12 Years to 35 Years
Healthy volunteers
No
Inclusion criteria
* Age 12 - 35 years * Diagnosis of HbSS by Hb electrophoresis and genetic analysis to analyse the alpha locus * Clinical history or ongoing evidence of severe sickle cell anemia with one OR more of the following clinical complications demonstrating disease severity: At least 3 vaso-occlusive crises requiring hospitalization, under hydroxyurea or transfusion, within 2 years prior to enrollment One severe acute chest syndrome (ACS) hospitalized in the intensive care unit At least 2 episodes of ACS, including one under HU. Acute priapism (at least 2 episodes \>3h in the preceding year or in the year prior to the start of a regular transfusion program), OR stuttering priapism ≥ 1 by week under sickle cell treatment (HU, transfusion or phlebotomy). Tricuspid regurgitation velocity \>2.8m/s on cardiac echocardiograph without pulmonary hypertension confirmed by right heart catheterization (mPAP\>\<25mmHg) * Failed hydroxyurea (HU) therapy, were unable to tolerate HU therapy, OR inadequate clinical response to HU, defined as any one of the following outcomes, while on HU for at least 3 months: 2 or more acute sickle pain crisis requiring hospitalization, requirement of transfusion to maintain Hb \>6.0g/dL, an episode of ACS despite adequate supportive care measures * Karnovsky/Lansky performance score ≥ 60% * Sexually active patients must be willing to use an acceptable method of double-barrier contraception for at least 12 months post-infusion (beyond 12 months at the discretion of the investigator) * Procedure for obtaining consent (adults, dependent minors, to give their consent) * Affiliation to social security
Exclusion criteria
: * Existence of a matched sibling donor * Based on myelogram, the presence of chromosomal (detected by karyotyping) or molecular abnormalities (detected by NGS) and retained dangerous by the Hemato-Oncology referent and validated during a specific multidisciplinary concerted meeting * Patients who have already been treated with gene therapy or BMT * Hematologic evaluation: Leukopenia (WBC \<3,000/µL) or neutropenia (ANC \<1,000/µL) or thrombocytopenia (platelet count \<100,000/µL) within 90 days prior to mobilization or harvest (not due to an erytrapheresis procedure or possible acute viral infection) * PT/INR or PTT \>1.5 times the upper limit of normal (ULN) or clinically significant bleeding disorder * Two alpha deletions (risk of alpha-thalassemia after gene therapy) Evaluations within 6 months prior to screening visit: * ALT or AST \>3 times ULN * Severe liver iron overload evaluated by MRI (\>15mg Fe/g dry weight or \>270umol Fe/g dry weight) or liver cirrhosis suspicion on echography or elastometry or CT scan or MRI AND confirmed by histology * Measured GFR \<60ml/min/1.73 m² * Cardiac evaluation: LVEF \<40% by cardiac echocardiogram or by MUGA scan or clinically significant ECG abnormalities * Stroke with significant CNS sequelae i.e., Rankin \>2 * Specific sickle cell disease cerebral vasculopathy confirmed by MRA (magnetic resonance angiography) OR transcranial doppler ultrasound with or without Moya-moya WITH an indication of chronic transfusion program (target HbS\<30%) * Lung interstitial infiltrate AND Forced Vital Capacity less than 70% AND DLCO less than 60% at steady state * Confirmed pulmonary hypertension defined by a right heart catheterization (PAPm \>25 mmHg). Right heart catheterization is required if tricuspid regurgitation velocity \>2.8m/s on cardiac echocardiograph OR \>2.5m/s with an abnormal Brain Natriuretic Peptide dosage or an important decrease in transcutaneous Hb O2 saturation during the 6 minutes' walk test. * Seropositivity for HIV (Human Immunodeficiency Virus), HCV (Hepatitis C Virus), HTLV-1 (Human T-Lymphotropic Virus), or active Hepatitis B Virus, or active infection by CMV or parvovirus B19, based on positive blood PCR. * Pregnancy or breastfeeding in a postpartum female * Any current cancer or prior history of a malignant disease, with the exception of curatively treated non-melanoma skin cancer * Immediate family member with an established or suspected Familial Cancer Syndrome * Diagnosis of significant psychiatric disorder of the subject that could seriously impede the ability to participate in the study * Patients who failed previous HSCT * Any clinically significant active infection * Participation in another clinical study with an investigational drug within 30 days of screening * Any condition, based on perspective of the medical monitor and treating investigator, which may lead to increased safety risk or inability to comply with the protocol.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Disease-related mortality | Up to the 24 months follow-up |
| All-cause mortality | Up to the 24 months follow-up |
| Occurrence of vaso-occlusive events | between 3 and 15 months following IV infusion of DREAM01 of the corresponding matched DREPAMIR patient |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of HbS | Up to the 24 months follow-up | Measure of HbS |
| Percentage of HbF | Up to the 24 months follow-up | Measure of HbF |
| Rate of Hemolysis | Up to the 24 months follow-up | Biological parameters that reflect hemolysis : Total hemoglobin, Reticulocytes, lactate dehydrogenase LDH, circulating erythroblasts, haptoglobin, free plasmatic heme, no conjugated bilirubin, erythropoietin EPO |
| Rate of Anemia | Up to the 24 months follow-up | Biological parameters that reflect anemia : Total hemoglobin, Reticulocytes, lactate dehydrogenase LDH, circulating erythroblasts, haptoglobin, free plasmatic heme, no conjugated bilirubin, erythropoietin EPO |
| Transfusion requirement | Up to the 24 months follow-up | absence of vaso-occlusive events (VOE) in patients who have discontinued the transfusion program or/and hydroxyurea |
| Change in number of units of RBCs transfused | Up to the 24 months follow-up | — |
| Changes in brain function | Up to the 24 months follow-up | Occurrence of ischemic lesions, vascular stenosis, aneurysm assessed using cervical doppler ultrasound and cerebral MRI |
| Changes in ocular function | Up to the 24 months follow-up | Assessed Using Fundus examination |
| Changes in cardiac function | Up to the 24 months follow-up | Evaluated through electrocardiographic (ECG) assessment : overall interpretation with 3 categories such as Normal/ Abnormal, not clinically significant/ Abnormal, clinically significant |
| Changes in the occurrence of left ventricular ejection fraction [LVEF] right and left atrial | Up to the 24 months follow-up | Occurrence of left ventricular ejection fraction \[LVEF\], right and left atrial, left assessed using cardiac ultrasound. |
| Changes in left ventricular size | Up to the 24 months follow-up | Changes in left ventricular size assessed using cardiac ultrasound. |
| Changes in left ventricular wall thickness | Up to the 24 months follow-up | Changes in the left ventricular wall thickness assessed using cardiac ultrasound. |
| Changes in systolic pulmonary artery pressure [sPAP ] | Up to the 24 months follow-up | Changes in systolic pulmonary artery pressure \[sPAP\], assessed using cardiac ultrasound. |
| Changes in tricuspid regurgitation velocity [TRV ] | Up to the 24 months follow-up | Changes in tricuspid regurgitation velocity \[TRV\] assessed using cardiac ultrasound |
| Title : Changes in tricuspid regurgitation velocity [TRV] | Up to the 24 months follow-up | Changes in tricuspid regurgitation velocity \[TRV\] assessed using Doppler echocardiography |
| Changes in E/A ratio | Up to the 24 months follow-up | Changes in of E/A ratio assessed using cardiac ultrasound, cardiac MRI (including myocardial imaging), Doppler echocardiography and transthoracic echocardiography |
| Change in serum electrolyte panel | Up to the 24 months follow-up | — |
| Change in serum creatinine | Up to the 24 months follow-up | — |
| Change in estimated glomerular filtration rate (eGFR ) | Up to the 24 months follow-up | Renal function assessed through estimated glomerular filtration rate (eGFR) calculated using CKD-EPI equation |
| Change in urinary microalbumin | Up to the 24 months follow-up | — |
| Change in protein excretion | Up to the 24 months follow-up | — |
| Change in urinary creatinine | Up to the 24 months follow-up | — |
| Changes in creatinine clearence | Up to the 24 months follow-up | — |
| Change in liver enzyme AST | Up to the 24 months follow-up | — |
| Change in liver enzyme ALT | Up to the 24 months follow-up | — |
| Change in liver enzyme GGT | Up to the 24 months follow-up | — |
| Changes in in liver enzyme ALP | Up to the 24 months follow-up | — |
| Change in total bilirubin | Up to the 24 months follow-up | — |
| Change in unconjugated (free) bilirubin | Up to the 24 months follow-up | — |
| Changes in hepatic function | Up to the 24 months follow-up | overall interpretation with 3 categories such as Normal/ Abnormal, not clinically significant/ Abnormal, clinically significant |
| Change in diffusing capacity for carbon monoxide (DLCO ) | Up to the 24 months follow-up | — |
| Change in vital capacity (VC ) | Up to the 24 months follow-up | — |
| Change in residual volume (RV ) | Up to the 24 months follow-up | — |
| Change in FEV1/FVC ratio (Tiffeneau index ) | Up to the 24 months follow-up | — |
| Changes in bone metabolism | Up to the 24 months follow-up | Assessed through osteodensitometry |
| Changes in muscular function | Up to the 24 months follow-up | Overall interpretation with 3 categories such as Normal/ Abnormal, not clinically significant/ Abnormal, clinically significant |
| Occurrence of iron overload | Up to the 24 months follow-up | — |
| Fertility evaluation | Up to the 24 months follow-up | Assessed through hormonal testing |
| Quality of life Evaluation: patient health | Up to the 24 months follow-up | Medical Outcomes Study Short Form 36 SF-36 The Short Form (36) Health Survey is a 36-item, patient-reported survey of patient health. 0-100 scale so that a higher score indicates a better outcome. |
| Quality of life Evaluation : fatigue | Up to the 24 months follow-up | FACIT-Fatigue (Functional Assessment of Chronic Illness Therapy-Fatigue Scale) FACIT-Fatigue is a 13-item self-report scale that assesses fatigue and its effect on daily activities and function. 0-52 scale so that a higher score indicates a better outcome. |
| Quality of life Evaluation: physical , mental, and social health | Up to the 24 months follow-up | PROMIS® (Patient-Reported Outcomes Measurement Information System) is a set of person-centered measures that evaluates and monitors physical, mental, and social health in adults and children. PROMIS domain scores are reported as T-scores, with a mean of 50 and a standard deviation of 10 in the reference population. Higher scores indicate better health for physical function and ability to participate in social roles and activities, whereas higher scores indicate worse health for fatigue, pain interference, depressive symptoms, anxiety, and sleep disturbance. |
| Health-realted Quality of life Evaluation | Up to the 24 months follow-up | Pediatric Quality of Life Inventory (PedsQL ) Generic Core Scales PedsQL is a modular system that assesses health-related quality of life in healthy and ill children and adolescents. It combines generic core scales and disease-specific modules into one measurement system. 0-100 scale, so that higher scores indicate better outcome. |
| Walk ability | Up to the 24 months follow-up | 6-minute walk-test |
| jump | Up to the 24 months follow-up | Vertical jump test : The jump height will be recorded using video analysis software. The average height of the 3 jumps will be calculated |
| Physical ability | Up to the 24 months follow-up | physical ability questionnaire, using the Global physical activity questionnaire (GPAQ) (16 items) developed by WHO. Minimum value is 0 with no theoretical maximum value. Higher scores indicate better outcome. |
| Cardiopulmonary capacity | Up to the 24 months follow-up | Cardiopulmonary exercise test, using the Cardio Pulmonary Exercise Test |
| Costs | Up to the 24 months follow-up | Costs of treatment calculated yearly and cost per event (VOC and ATS) |
| Cost effectiveness | Up to the 24 months follow-up | Model-based incremental cost effectiveness ratio of gene therapy with inputs for SoC |
| Changes in cardiac global function | Up to the 24 months follow-up | Assessed through cardiac magnetic resonance imaging, using ventricular function - Overall interpretation with 3 categories such as Normal/ Abnormal, not clinically significant/ Abnormal, clinically significant |
| Changes in myocardial tissular | Up to the 24 months follow-up | Using late gadolinium myocardial enhancement |
Countries
France
Contacts
CONTACTJoseph LAURE, MD, PhD
CONTACTNelly BRIAND, PHD
STUDY_DIRECTORMarina CAVAZZANA, MD, PhD
Department of Biotherapy, Necker-Enfants Malades Hospital
Outcome results
None listed