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A Trial to Assess Haploidentical T-depleted Stem Cell Transplantation in Patients With SCD

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04201210
Recruitment Status : Recruiting
First Posted : December 17, 2019
Last Update Posted : May 18, 2022
Sponsor:
Information provided by (Responsible Party):
Prof. Dr. med. Selim Corbacioglu, University of Regensburg

Tracking Information
First Submitted Date  ICMJE December 2, 2019
First Posted Date  ICMJE December 17, 2019
Last Update Posted Date May 18, 2022
Actual Study Start Date  ICMJE June 30, 2021
Estimated Primary Completion Date March 31, 2026   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: December 16, 2019)		 Primary efficacy endpoint: Composite Endpoint: Event free survival (EFS). [ Time Frame: day 0 - day180 ]
Event is defined as incidence of acute GvHD (Grade III - IV), chronic GvHD (moderate/severe), graft failure (GF), or death (from any reason).
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: December 16, 2019)
  • Overall survival [ Time Frame: up to 2 years after transplantation ]
    Overall survival rate (OS) is defined as time from transplantation to death or last follow-up and will be assessed at Day 100 and after 1 year and 2 years.
  • Disease free survival [ Time Frame: up to 2 years after transplantation ]
    • Disease-free survival (DFS) is defined as the minimum time to recurrence, to death or to the last follow-up, from the time of transplantation and will be assessed at Day 100 and after 1 year and 2 years.
  • Graft failure [ Time Frame: up to 2 years after transplantation ]
    defined as initial neutrophil engraftment followed by a decline in ANC <500/µl that is unresponsive to growth factor therapy and/or other intervention
  • Quality of life: EQ-5D [ Time Frame: up to 2 years after transplantation ]
    Adult patients ≥18 years. The European Quality of Life 5 Dimension (EQ-5D) questionnaire has two components: health state description and evaluation. In the description part, health status is measured in terms of five dimensions (5D); mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Mobility dimension asks about the person's walking ability. Self-care dimension asks about the ability to wash or dress by oneself, and usual activities dimension measures performance in "work, study, housework, family or leisure activities". In pain/discomfort dimension, it asks how much pain or discomfort they have, and in anxiety/depression dimension, it asks how anxious or depressed they are.
  • Quality of life: PedsQL [ Time Frame: up to 2 years after transplantation ]
    The Pediatric Quality of Life Inventory (PedsQL) is a 23-item generic health status instrument with parent and child forms that assesses five domains of health (physical functioning, emotional functioning, psychosocial functioning, social functioning, and school functioning) in children and adolescents ages 2 to 18.
  • Quality of life: FACT-BMT [ Time Frame: up to 2 years after transplantation ]
    Functional Assessment of Cancer Therapy-Bone Marrow Transplant (adult patients ≥18 years). FACT-BMT form was designed to measure the QoL in patients undergoing bone marrow transplantation. It combines the FACT-G, an assessment of physical well-being, social/family well-being, emotional well-being and functional well-being, with Bone Marrow Transplantation Sub-scale(BMTS) to measure the QOL of BMT patients.
Original Secondary Outcome Measures  ICMJE
 (submitted: December 16, 2019)
  • Overall survival [ Time Frame: up to 2 years after transplantation ]
    Overall survival rate (OS) is defined as time from transplantation to death or last follow-up and will be assessed at Day 100 and after 1 year and 2 years.
  • Disease free survival [ Time Frame: up to 2 years after transplantation ]
    • Disease-free survival (DFS) is defined as the minimum time to recurrence, to death or to the last follow-up, from the time of transplantation and will be assessed at Day 100 and after 1 year and 2 years.
  • Graft failure [ Time Frame: up to 2 years after transplantation ]
    defined as initial neutrophil engraftment followed by a decline in ANC <500/µl that is unresponsive to growth factor therapy and/or other intervention
  • Quality of life: EQ-5D [ Time Frame: up to 2 years after transplantation ]
    EQ-5D (adult patients ≥18 years),
  • Quality of life: PedsQL [ Time Frame: up to 2 years after transplantation ]
    PedsQL (paediatric patients, age <18 years)
  • Quality of life: FACT-BMT [ Time Frame: up to 2 years after transplantation ]
    FACT-BMT (adult patients ≥18 years)
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Trial to Assess Haploidentical T-depleted Stem Cell Transplantation in Patients With SCD
Official Title  ICMJE A Phase II Stratified Trial to Assess Haploidentical T-depleted Stem Cell Transplantation in Patients With Sickle Cell Disease With no Available Sibling Donor
Brief Summary HSCT is currently the only curative option for SCD but less than 20% of SCD patients have a MD donor available. So far, all curative approaches beyond a MSD HSCT at young age are non-satisfactory. With the lack of a suitable donor for the vast majority of patients, the major question of this trial is, if a haploidentical αß/CD19+ T-cell depleted HSCT can be a valid alternative to a MSD HSCT. The main challenge in non-malignant diseases is to offer a safe and GvHD-free HSCT without rejection.
Detailed Description

Can an α/ß depleted T-Haplo-HSCT with regard to disease free survival, adverse events and safety be considered equivalent to a matched sibling donor transplantation (MSD), in order to offer cure for the majority of patients with sickle cell disease.

The main questions of this trial are:

  • Safety of a α/ß T-depleted haploidentical HSCT
  • Incidence of acute and chronic GvHD
  • Rate of rejection
  • Immune reconstitution
  • Fertility It is expected that the use of TCRαβ+ and CD19+ depleted haploidentical cell grafts in combination with the less aggressive and well tolerated conditioning regimen needed for patient preparation will be associated with a low risk of grade II-IV aGVHD and no extensive cGvHD, no graft failure and increase speed, spectrum and functionality of immune system reconstitution. This is supposed to reduce the incidence of severe infections leading to lower rates of transplantation related mortality (TRM).
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:
Patients who fulfill inclusion criteria will be stratified according to donor availability. Patients with a matched sibling donor (MSD; defined as 8/( or 10/10 allelic match) will be stratified into the control arm.
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • HbS Disease
  • Hemoglobin S Disease
  • Sickle Cell Anemia
  • Sickle Cell Disorders
  • Sickling Disorder Due to Hemoglobin S
  • Sickle Cell Disease
Intervention  ICMJE
  • Other: TCRα/β+ and CD19+ depleted haploidentical stem cell transplantation
    Haploidentical 5+/10 HSCT from a relative, α/β T-depleted
  • Other: Matched sibling donor transplantation
    10/10 HSCT - matched family donor
Study Arms  ICMJE
  • Experimental: Experimental Arm
    Patients with no matched sibling donor (MSD; defined as 8/( or 10/10 allelic match) will be stratified into the experimental arm
    Intervention: Other: TCRα/β+ and CD19+ depleted haploidentical stem cell transplantation
  • Active Comparator: Control Arm
    Patients with a matched sibling donor (MSD; defined as 8/( or 10/10 allelic match) will be stratified into the control arm
    Intervention: Other: Matched sibling donor transplantation
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: December 16, 2019)		 212
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE March 31, 2027
Estimated Primary Completion Date March 31, 2026   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Age 1yr to 35yrs
  • Homozygous hemoglobin S disease or heterozygous hemoglobin SC or S 0/+
  • Study specific consent given

  • Preexisting severe or moderate SCD related complications:

    • Clinically significant neurological event (stroke) or deficit
    • Silent crisis, neurocognitive deficit
    • Pathological angio-MRI with TOF Sequence
    • TCD velocity >200 cm/s at 2 occasions >1 month apart
    • More than 5 vaso-occlusive crises (VOC) in the past 1 year or more than 20 VOC in a lifetime
    • Two or more episodes of acute chest syndrome (ACS) in a lifetime or one episode of ACS in the past 24 months
    • Chronic transfusion requirement or more than 8 transfusions or one exchange transfusion in a lifetime
    • Transfusion-refractory allo-immunization
    • More than five SCD-related hospitalizations in a lifetime
    • Beginning pulmonary hypertension
    • Osteonecrosis at more than 2 sites
    • Beginning SCD Nephropathy
    • Recurrent priapism (>2)

Exclusion Criteria:

  • Karnofsky or Lansky Performance Score < 70%

  • Patients with donor-specific antibodies (DSA) against the potential stem cell donor by either

    • Cell-based crossmatched assays (Complement-dependent cytotoxicity; CDC) or
    • Flow cytometry crossmatch test or
    • Solid-phase immunoassays (SPI) or
    • Modified SPI such as C4d and C1q assays Whichever method the participating center is experienced in.
  • Patients with major AB0 incompatibility defined according to EBMT Handbook, Edition 2019 Tab 23.1.:

ABO incompatibility Recipient Donor Major O A O B O AB A AB B AB

  • Cardiac function:

    • Ejection fraction at rest <45.0% on echocardiography or
    • Shortening fraction of <27.0% by echocardiogram or radionuclide scan (MUGA)
    • Patients with > grade II hypertension by Common Toxicity Criteria (CTC)

  • Renal function:

    • Estimated creatinine clearance (for patients > 12 years) greater than 50.0 mL/minute
    • 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 or
    • Creatinine clearance below threshold defined for stem cell transplantation according to local clinical standard

  • Pulmonary function:

    • DLCO >50% (adjusted for hemoglobin), and FVC and FEV1≥50%; children unable to perform for PFTs, O2 saturation <92% on room air.

  • Liver function:

    • Total bilirubin > 2x the upper limit of normal (unless elevated bilirubin is attributed to Gilbert's Syndrome) and ALT/AST > 2.5x the upper limit of normal.
    • 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 and for at least 12 months thereafter,
  • History of uncontrolled autoimmune disease or on active treatment
  • Patient unable to comply with the treatment protocol
  • Prior autologous or allogeneic hematopoietic stem cell transplant
  • 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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 1 Year to 35 Years   (Child, Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Selim Corbacioglu, MD +49 (0)941 944-2101 Haplo.SCD@ukr.de
Contact: Katharina Kleinschmidt, MD +49 (0)941 944-2101 Haplo.SCD@ukr.de
Listed Location Countries  ICMJE Austria,   Germany
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04201210
Other Study ID Numbers  ICMJE T-Haplo for SCD
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Current Responsible Party Prof. Dr. med. Selim Corbacioglu, University of Regensburg
Original Responsible Party Same as current
Current Study Sponsor  ICMJE University of Regensburg
Original Study Sponsor  ICMJE Same as current
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Selim Corbacioglu, MD University Hospital of Regensburg
PRS Account University of Regensburg
Verification Date May 2022

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP