| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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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 | 21.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10040644 |
| E.1.2 | Term | Sickle cell disease |
| E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders |
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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 |
| The objective of this phase II trial is to prove that EFS following T-Haplo-SCT (experimental group E) is non-inferior to matched sibling donor (MSD) HSCT (reference group R) as well as evaluation of safety/tolerability and feasibility of haploidentical PBSC grafts depleted of TCR α/β+ and CD19+ cells using the CliniMACS TCR α/β/CD19 System in adult and paediatric patients with sickle cell disease: Incidence of disease free survival and grade III–IV acute graft-versus-host disease (GVHD) until Day 100 post-transplantation |
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| E.2.2 | Secondary objectives of the trial |
- Incidence of grade I-II acute GVHD until Day 100 post-transplantation
- Incidence and severity of chronic GVHD 1 year after omission of immunosuppression
- Incidence of TRM at all visits throughout the study
- Incidence and severity of acute infusional toxicities
- Graft failure from Day 0 to Day 28
- Neutrophil and platelet engraftment Day 0 to Day 28
- OS at Day 100 and after 1 year
- Disease-free survival Day 100 and after 1 year
- Transfusion requirement from Day 0 to Day 100
- QoL at baseline, Day 100 + after 1 year
- Donor chimerism
- Split chimerism
- Reconstitution of T, B, NK, T regulatory (Treg) cell subsets by immune cell phenotyping
- Infections: Incidence of CMV, ADV, EBV and aspergillus, as well as other viral, bacterial and fungal infections
- Incidence, severity and type of AEs/SAEs
- Vital signs + physical examination
- Safety laboratory (blood count, blood chemistry)
- Fertility
- Incidence and severity of transplant-related neurotoxicity and PRES |
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| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Analyses of splitchimerism and immune reconstitution after stem cell transplantation in patients with sickle cell disease
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| E.3 | Principal inclusion criteria |
Inclusion criteria*
(for the experimental arms)
* The transplant indication for patients with a MSD follows the respective local and national guidelines
• Age 2 yrs to 35yrs
• Homozygous hemoglobin S disease or heterozygous hemoglobin SC or S 0/+
• Study specific consent given
• Preexisting severe or moderate SCD related complications (at least one):
o Clinically significant neurological event (stroke) or deficit
o Silent crisis, neurocognitive deficit
o Pathological angio-MRI with TOF Sequence
o TCD velocity >200 cm/s at 2 occasions >1 month apart
o More than 5 vaso-occlusive crises (VOC) in the past 1 year or more than 20 VOC in a lifetime
o Two or more episodes of acute chest syndrome (ACS) in a lifetime or one episode of ACS in the past 24 months
o Chronic transfusion requirement or more than 8 transfusions or one exchange transfusion in a lifetime
o Transfusion-refractory allo-immunization
o More than five SCD-related hospitalizations in a lifetime
o Beginning pulmonary hypertension
o Osteonecrosis at more than 2 sites
o Beginning SCD Nephropathy
o Recurrent priapism (>2)
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| E.4 | Principal exclusion criteria |
Exclusion criteria (for both arms)
• Karnofsky or Lansky Performance Score < 70%
• Patients with donor-specific antibodies (DSA) against the potential stem cell donor by either
o Cell-based crossmatched assays (Complement-dependent cytotoxicity; CDC) or
o Flow cytometry crossmatch test or
o Solid-phase immunoassays (SPI) or
o Modified SPI such as C4d and C1q assays
Whichever method the participating center is experienced in.
• Patients with a haploidentical donor with major AB0 incompatibility defined according to EBMT Handbook, Edition 2019 Tab 23.1.:
ABO incompatibility Recipient Donor
Major 0 A
0 B
0 AB
A AB
B AB
• Cardiac function:
o Ejection fraction at rest <45.0% on echocardiography or
o Shortening fraction of <27.0% by echocardiogram or radionuclide scan (MUGA)
o Patients with > grade II hypertension by Common Toxicity Criteria (CTC)
• Renal function:
o Estimated creatinine clearance (for patients > 12 years) lower than 50.0 mL/minute
o for pediatric patients (> 1 year to 12 years), GFR estimated by the updated Schwartz formula < 90.0 mL/min/1.73 m2. If < 90 mL/min/1.73 m2, renal function must be measured by 24-hour creatinine clearance or nuclear GFR and must be > 70.0 mL/min/1.73 m2 for inclusion or
o Creatinine clearance below threshold defined for stem cell transplantation according to local clinical standard
• Pulmonary function:
o DLCO <50% (adjusted for hemoglobin), and FVC and FEV1<50%; children unable to perform for PFTs, O2 saturation <92% on room air.
• Liver function:
o Direct bilirubin > 3 x the upper limit of normal (ULN) (unless elevated bilirubin is attributed to Gilbert’s Syndrome) and ALT/AST > 2.5x the ULN.
o Chronic active viral hepatitis
• Women who are pregnant (positive serum or urine βHCG) or breastfeeding.
Note: Women of childbearing potential must have a negative serum pregnancy test at study entry.
• Adults of reproductive potential not willing to use an effective method of birth control during study treatment up to the end of follow-up >24 months after HSCT)
• History of uncontrolled autoimmune disease or on active treatment
• Patient unable to comply with the treatment protocol
• Prior autologous or allogeneic HSCT
• Vaccination with a live virus vaccine during the trial
• HIV infection
• Patients with a history of psychiatric illness or a condition which could interfere with their ability to understand the requirements of the study (this includes alcoholism/drug addiction)
• Patients unwilling or unable to comply with the protocol or unable to give informed consent.
• Concurrent severe or uncontrolled medical disease (e.g. uncontrolled diabetes, congestive heart failure, myocardial infarction within 6 months prior to the study, unstable and uncontrolled hypertension, chronic renal disease, or active uncontrolled infection) which by assessment of the treating physician could compromise participation in the study.
• Patients with prior malignancies, except resected non-melanoma or treated cervical carcinoma in situ. Cancer treated with curative intent >5 years previously will be allowed. Cancer treated with curative intent < 5 years previously will not be allowed unless approved by the Protocol Officer or one of the Protocol Chairs.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Primary efficacy endpoint: Composite Endpoint: Event free survival (EFS). Event is defined as incidence of acute GvHD (Grade III – IV), chronic GvHD (moderate/severe), graft failure (GF), or death (from any reason). |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| before HSCT, Day+100, +180, +240, 1 year 1,5 years and 2 years after HSCT |
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| E.5.2 | Secondary end point(s) |
| Key secondary endpoint(s): (i) Overall survival (OS); (ii) Disease-free survival (DFS); (iii) Graft failure (GF); (iv) Immune-reconstitution; (v) Quality of life (QOL); (vi) Fertility |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
before HSCT, Day+100, +180, +240, 1 year 1,5 years and 2 years after HSCT
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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 | Yes |
| 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) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| 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 | Yes |
| 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 | Yes |
| 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 | Yes |
| E.8.2.3.1 | Comparator description |
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| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 10 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 11 |
| 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 | Yes |
| 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 |
| Austria |
| Finland |
| Sweden |
| Spain |
| Switzerland |
| Germany |
| Italy |
| Belgium |
| United Kingdom |
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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 | 6 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 6 |
| 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 |
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