E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Hemoglobinopathies |
hémoglobinopathies |
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E.1.1.1 | Medical condition in easily understood language |
a kind of genetic defect that results in abnormal structure of one of the globin chains of the hemoglobin molecule |
défaut génétique qui entraîne une structure anormale de l'une des chaînes de globine de la molécule d'hémoglobine |
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E.1.1.2 | Therapeutic area | Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 18.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10054658 |
E.1.2 | Term | Thalassemia |
E.1.2 | System Organ Class | 100000004850 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 18.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10040645 |
E.1.2 | Term | Sickle cell disease NOS |
E.1.2 | System Organ Class | 100000004850 |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
Assess the acute toxicities associated with the infusion of CordIn, within 24 hours post-infusion
Assess the proportion of patients with donor-derived engraftment at 42 days following transplantation
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Évaluer les toxicités aiguës associées à l'injection de CordIn™, dans les 24 heures suivant l'injection
Évaluer la proportion de patients obtenant une prise de greffe des cellules du donneur 42 jours post-greffe
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E.2.2 | Secondary objectives of the trial |
Cumulative incidence of transplant-related mortality at day 100 after transplantation
Event-free survival at day 100 and 1 year after transplantation (patient’s death, autologous recovery, primary or secondary graft failure will be considered events for this endpoint)
Overall survival at 1 year after transplantation (patient’s death will be considered the relevant event)
RBC transfusion-free survival at 1 year in thalassemia patients
Proportion of treatment free HbS ≤ 30% at 1 year in SCD patients
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Incidence cumulée de mortalité liée à la greffe au jour 100 post-greffe
Survie sans événement au jour 100 et un an après la greffe (le décès du patient, la récupération autologue, et l'échec de greffe primaire ou secondaire seront considérés comme des événements pour ce critère)
Survie globale un an après la greffe (le décès du patient sera considéré comme l'événement pertinent)
Survie sans transfusion de globules rouges à un an, chez les patients atteints de thalassémie
Proportion d'HbS sans traitement ≤30% à un an chez les patients atteints de drépanocytose
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1.Patients must be 2–25 years of age and at least 10kg
2.Patient is a candidate for allogeneic SCT for treatment of SCD or thalassemia:
a.Patient must have clinically severe SCD(eg. SS, SC or SBeta0 Thal) with at least one of the following clinical complications:
Recurrent painful events(at least 3 in the 2 years prior to enrollment) that cannot be explained by other causes. Pain may occur in typical sites associated with vaso-occlusive painful events and cannot be explained by causes other than sickle cell disease. Pain lasts at least 4 hours and requires parenteral narcotic treatment,equianalgesic dose of oral narcotics or parenteral nonsteroidal anti-inflamrnatory drugs. These painful events may be treated in any setting,but events managed at home will be considered only if there is documentation of the event in a clinical record that may be reviewed by an investigator. These events must occur despite adequate supportive care measures.
Acute chest syndrome with at least two episodes with the development of a new infiltrate on chest radiograph and/or having a perfusion defect demonstrable on a lung radioisotope scan within the past two years that required hospitalization, oxygen therapy, and RBC transfusion. These episodes must occur despite adequate supportive care measures.
Any combination of painful events and acute chest syndrome episodes that total three events within the two years before transplantation.
Any clinically significant neurologic event (stroke or hemorrhage) or any neurologic defect lasting more than 24 hours.
Patients on chronic PRBC transfusion therapy, defined as receiving 8 or more transfusions per year for > 1 year to prevent vaso-occlusive clinical complications (e.g. pain, stroke, and acute chest syndrome)
Abnormal cerebral MRI and abnormal cerebral MRA.
Abnormal Transcranial Doppler (TCD), as defined by a TCD velocity that exceeds 200 cm/sec by the non-imaging technique (or TCD measurement of >185 cm/sec by the imaging technique) measured at a minimum of two separate occasions one month or more apart
OR;
b.Patient must have thalassemia major requiring regular RBC transfusions
3.Patients must have a partially HLA-matched CBU. The unit must be HLA-matched at 4-6/6 HLA class I (HLA-A & HLA-B, low resolution) and II (HLA-DRB1, high resolution) loci with the subject. For patients weighing ≥ 25 kg, the CBU must have a pre-cryopreserved, total CD34+ cell dose of ≥10x10^6 as well as a pre-cryopreserved total nucleated cell dose of ≥1.8x10^9. For patients weighing < 25 kg, the CBU must have a pre-cryopreserved, total CD34+ cell dose of ≥7x10^6 as well as a pre-cryopreserved total nucleated cell dose of ≥1.6x10^9.
4.The CBU will have undergone volume reduction (both plasma and red blood cell depletion) prior to cryopreservation.
5.Patients must have autologous stem cells harvested from bone marrow as a backup in case of graft failure.
6.Patients’ Performance score ≥70% by Lansky or Karnofsky performance status scale
7.Patient has sufficient physiologic reserves including:
Cardiac: Left ventricular ejection fraction (LVEF) > 50% by echocardiogram radionuclide scan or cardiac MRI; or LV shortening fraction > 26%.
Pulmonary: Pulse oximetry with a baseline O2 saturation of ≥ 85% is required for all patients, DLCO > 60% of predicted for age (corrected for hemoglobin) for patients in whom pulmonary function testing can be performed.
Renal: Serum creatinine ≤ 1.5 x upper limit of normal for age and GFR > 70 mL/min/1.73 m2.
Hepatic: Serum conjugated (direct) bilirubin < 2 x upper limit of normal for age as per local laboratory in the absence of gall bladder disease or prior cholecystectomy; Hepatic transaminases (ALT and AST) < 5 x upper limit of normal range
8.In SCD patients, HbS should be ≤ 45%, as measured in non-chronically RBC transfused patients, within 7 days prior to initiation of conditioning regimen. If the HbS level is >45% then the patient must receive RBC transfusions or erythrocyte exchange prior to conditioning regimen initiation.
9.Females of childbearing potential, defined as any female who has experienced menarche and is not postmenopausal or permanently sterilized (e.g. tubal occlusion, hysterectomy, bilateral salpingectomy), agree to use an appropriate method of contraception from at least 7 days prior to preparative therapy until completion of follow-up procedures. An appropriate method of contraception is defined as one that results in a low failure rate (i.e., less than 1 percent per year) when used consistently and correctly, such as implants, injectables, combined oral contraceptives, some intrauterine contraceptive devices (IUDs), sexual abstinence, or a vasectomized partner.
10.Patient and/or legal guardian signs the written informed consent after being made aware of the nature of the patient’s disease and willingly consents to the treatment program after being informed of alternative treatments, potential risks, benefits, and discomforts
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E.4 | Principal exclusion criteria |
1.Evidence of uncontrolled bacterial, viral or fungal infections or severe concomitant diseases, which in the judgment of the Principal Investigator, indicate that the patient could not tolerate transplantation
2.Evidence of HIV infection or HIV positive serology
3.Evidence of active Hepatitis B, Hepatitis C or EBV as determined by serology or PCR
4.Pregnancy, as indicated by a positive serum human chorionic gonadotrophin (HCG) test, or lactation
5.Patients with 10/10 or 9/10 HLA-matched related family donor or unrelated donor able to donate
6.Severe alloimmunization with inability to guarantee a supply of adequate PRBC donors
7.Evidence of anti-HLA antibodies to the selected CordIn™ CBU (MFI>1000)
8.Prior allogeneic hematopoietic stem cell transplant within last 12 months .
9.Allergy to bovine, Gentamicin, or to any product which may interfere with the treatment
10.Psychologically incapable of undergoing bone marrow transplant (BMT) with associated strict isolation or documented history of medical non-compliance and/or psychiatric illness and/or social situations that would limit compliance with study requirements
11.Enrolled in another clinical trial or received an investigational treatment during the last 30 days, unless approved by Sponsor
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E.5 End points |
E.5.1 | Primary end point(s) |
1. acute toxicities associated with the infusion of CordIn™, within 24 hours post-infusion
2. proportion of patients with donor-derived engraftment at 42 days following transplantation |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
1. Cumulative incidence of transplant-related mortality at day 100 after transplantation
2. Event-free survival at day 100 and 1 year after transplantation (patient’s death, autologous recovery, primary or secondary graft failure will be considered events for this endpoint)
3. Overall survival at 1 year after transplantation (patient’s death will be considered the relevant event)
4. RBC transfusion-free survival at 1 year in thalassemia patients
5. Proportion of treatment free HbS ≤ 30% at 1 year in SCD patients
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. day 100
2. day 100 and 1 year
3. 1 year
4. 1 year
5. 1 year |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | Yes |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | Yes |
E.7.1.3.1 | Other trial type description |
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E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 2 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 5 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |