RElated Haplo-DonoR Haematopoietic stEm Cell Transplantation for Adults With Severe Sickle Cell Disease

Study Overview
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Brief Summary
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The purpose of this clinical trial is to evaluate the clinical and cost effectiveness of Haploidentical Stem Cell Transplantation (SCT) for adults with severe sickle cell disease (SCD), who have failed other therapies or are intolerant of existing therapies or require chronic transfusions to prevent on-going complications of SCD.

Official Title
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A Multi-centre Open Randomised Controlled Trial to Assess the Effect of Related Haplo-donor Haematopoietic Stem Cell Transplantation Versus Standard of Care (no Transplant) on Treatment Failure at 24 Month in Adults With Severe Sickle Cell Disease

Conditions
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Sickle Cell Disease

Intervention / Treatment
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* Procedure: Haploidentical stem cell transplantation
* Other: Standard medical care


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult patients age ≥ 18 years Confirmed haploidentical donor Severe SCD phenotype who are at high risk for morbidity and mortality. Severe SCD is defined by at least one of the following: i. Clinically significant neurologic event (stroke) or deficit lasting > 24 hours. ii. History of ≥2 acute chest syndromes in a 2-year period preceding enrolment despite optimum treatment, e.g. with hydroxycarbamide (HC). iii. History of ≥3 severe pain crises per year in a 2-year period preceding enrolment despite the institution of supportive care measures (e.g. optimum treatment with HC). iv. Administration of regular transfusion therapy (=8 packed red blood transfusions per year for 1 year to prevent vaso-occlusive complications). v. Patients assessed as requiring transfusion but with red cell allo-antibodies/very rare blood type, rendering it difficult to continue/commence chronic transfusion. vi. Patients requiring HC/transfusion for treatment of SCD complications who cannot tolerate either therapy due to significant adverse reactions. vii. Established end organ damage relating to SCD, including but not limited to progressive sickle vasculopathy and hepatopathy. End-organ sufficient for entry to this trial shall be ratified at the UK NHP. d) Patients must be fit to proceed to Haploidentical SCT as defined below: i. Karnofsky score ≥60 ii. Cardiac function: LVEF ≥45% or shortening fraction ≥25% iii. Lung Function: FEV1, FVC and TLCO ≥50% iv. Renal function: EDTA GFR ≥40 ml/min/1.73m2 v. Hepatic function: ALT <x3 ULN and bilirubin <x2 the upper limit of normal, those with hyperbilirubinemia due to sickle related haemolysis will not be excluded. No radiological evidence of cirrhosis. e) Written informed consent. Exclusion Criteria: Fully matched sibling donor. Previous bone marrow transplant. Pregnancy or breast feeding. Participants able to conceive a child that are unprepared to use effective contraception. Clinically significant donor specific HLA antibodies. HIV infection or active Hepatitis B or C. Uncontrolled infection including bacterial, fungal and viral. Participation in another interventional trial in the last three months. Pre-existing condition deemed to significantly increase the risk of Haploidentical SCT by the local Principal Investigator.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Standard of care<br>The comparator arm is standard medical care for this patient population. Standard medical care may include all currently available non-trial therapies for SCD. | Other: Standard medical care<br>* Standard medical care may include any currently available therapies for SCD patients. These may or may not include regular elective transfusion therapy or medications such as hydroxycarbamide.<br>|
| Experimental: Haploidentical stem cell transplantation<br>Participants receiving Haploidentical Stem Cell Transplantation will receive the transplant conditioning regimen as per the standard transplant protocol. Stem cells from a haploidentical donor will be infused on Day 0 according to standard institutional practices. Bone marrow is the preferred stem cell source however peripheral blood may be used as an alternative where required due to donor reasons. | Procedure: Haploidentical stem cell transplantation<br>* Stem cell transplant from bone marrow or peripheral blood from haploidentical donor using standard nationally approved transplant procedure.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Treatment failure or mortality | Treatment failure is defined as occurrence of vaso-occlusive crisis, or transfusion from 6 months post-randomisation. | 24 months post-randomisation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Health related quality of life | Quality of life as measured by EQ-5D-5L | At 3, 6, 9, 12, 15, 18, 21 and 24 months post-randomisation | 
| All cause mortality | Death by any cause | 24 months post-randomisation | 
| Sickle Cell Disease-related mortality (excluding transplant related complications) | Death due to any sickle cell disease related cause | 24 months post-randomisation | 
| Sickle type haemoglobin percentage (HbS%) | Sickle type haemoglobin as measured by haemoglobin electrophoresis | At 6, 12 and 24 months post-randomisation | 
| Sickle cell disease related complications | Defined as transfusion requirement, painful VOC, stroke, pulmonary hypertension | 24 months post-randomisation | 
| Haemoglobin levels, Reticulocyte count, LDH, Bilirubin |  | At 6, 12 and 24 months post-randomisation | 
| Pulmonary Function | As measured by FEV1 %, FEV1/FVC ratio, TLCO % | At 12 months and 24 months post-randomisation | 
| Renal Function | As measured by urea, creatinine and eGFR | At 6, 12 and 24 months post-randomisation | 
| Iron overload | As measured by Ferritin and FerriScan (R2-MRI) | 24 months post-randomisation | 
| Cardiac function and pulmonary hypertension | As measured by echocardiogram/TRV | At 12 and 24 months post-randomisation | 
| Cerebrovascular progression | As measured by clinical stroke or evidence of progression on MRI/MRA | 24 months post-randomisation | 
| Evidence of hepatic progression | As measured by liver function (ALT, AST, ALP, GGT, Bilirubin) and FibroScan | 24 months post-randomisation | 
| Percentage of participants requiring opioid use for pain related to vaso-occlusive sickle related crisis |  | At 12 and 24 months post-randomisation | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Sickle, Haploidentical, Stem cell, Transplant