Standard of Care Comparative Arm of Phase 1/2 Gene Therapy Trial DREPAMIR" in Severe Sickle Cell Disease Patients

Обзор

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).

Подробное описание

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)

Вмешательства

• Препарат standard 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

Первичные конечные точки

• Disease-related mortality [Срок оценки: Up to the 24 months follow-up]
• All-cause mortality [Срок оценки: Up to the 24 months follow-up]
• Occurrence of vaso-occlusive events [Срок оценки: between 3 and 15 months following IV infusion of DREAM01 of the corresponding matched DREPAMIR patient]

Вторичные конечные точки (12)

• Percentage of HbS [Срок оценки: Up to the 24 months follow-up]
• Percentage of HbF [Срок оценки: Up to the 24 months follow-up]
• Rate of Hemolysis [Срок оценки: Up to the 24 months follow-up]
• Rate of Anemia [Срок оценки: Up to the 24 months follow-up]
• Transfusion requirement [Срок оценки: Up to the 24 months follow-up]
• Change in number of units of RBCs transfused [Срок оценки: Up to the 24 months follow-up]
• Changes in brain function [Срок оценки: Up to the 24 months follow-up]
• Changes in brain function [Срок оценки: Up to the 24 months follow-up]
• Changes in ocular function [Срок оценки: Up to the 24 months follow-up]
• Changes in ocular function [Срок оценки: Up to the 24 months follow-up]
• Changes in cardiac function [Срок оценки: Up to the 24 months follow-up]
• Changes in the occurrence of left ventricular ejection fraction [LVEF] right and left atrial [Срок оценки: Up to the 24 months follow-up]

Критерии участия

Критерии включения

• 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

Критерии исключения

• 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.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Не применимо

Модель

Одна группа

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

Франция · 1 центр

• Necker-Enfants Malades Hospital, Apheresis Unit — Paris

Публикации

• Magrin E, Semeraro M, Hebert N, Joseph L, Magnani A, Chalumeau A, Gabrion A, Roudaut C, Marouene J, Lefrere F, Diana JS, Denis A, Neven B, Funck-Brentano I, Negre O, Renolleau S, Brousse V, Kiger L, Touzot F, Poirot C, Bourget P, El Nemer W, Blanche S, Treluyer JM, Asmal M, Walls C, Beuzard Y, Schmidt M, Hacein-Bey-Abina S, Asnafi V, Guichard I, Poiree M, Monpoux F, Touraine P, Brouzes C, de Monta PMID 35075288
• Brusson M, Chalumeau A, Martinucci P, Romano O, Felix T, Poletti V, Scaramuzza S, Ramadier S, Masson C, Ferrari G, Mavilio F, Cavazzana M, Amendola M, Miccio A. Novel lentiviral vectors for gene therapy of sickle cell disease combining gene addition and gene silencing strategies. Mol Ther Nucleic Acids. 2023 Mar 22;32:229-246. doi: 10.1016/j.omtn.2023.03.012. eCollection 2023 Jun 13. PMID 37090420
• Sobrino S, Joseph L, Magrin E, Chalumeau A, Hebert N, Corsia A, Denis A, Roudaut C, Aussel C, Leblanc O, Brusson M, Felix T, Diana JS, Petrichenko A, El Etri J, Godard A, Tibi E, Manceau S, Treluyer JM, Mavilio F, Bushman FD, Marcais A, Castelle M, Neven B, Hermine O, Renolleau S, Magnani A, Asnafi V, El Nemer W, Bartolucci P, Six E, Semeraro M, Miccio A, Cavazzana M. Severe inflammation and linea PMID 40169559

Идентификаторы

NCT: NCT07752043 · APHP260040 · ID-RCB Number

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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