Stem Cell Transplant in Patients With Severe Sickle Cell Disease
|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: NCT03421756|
Recruitment Status : Recruiting
First Posted : February 5, 2018
Last Update Posted : May 14, 2018
|Condition or disease||Intervention/treatment||Phase|
|Sickle Cell Disease||Drug: Alemtuzumab Radiation: Total Body Irradiation Drug: Sirolimus||Early Phase 1|
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||12 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||A Pilot Study Evaluating the Efficacy of Non-Myeloablative Matched Related Donor Peripheral Blood Stem Cell Transplant in Patients With Severe Sickle Cell Disease|
|Actual Study Start Date :||March 29, 2018|
|Estimated Primary Completion Date :||February 15, 2022|
|Estimated Study Completion Date :||February 15, 2023|
Experimental: Non Myeloablative regimen (Alemtuzumab)
Sickle cell patient receives sibling donor peripheral blood stem cell transplant with non-myeloablative pre-transplant conditioning.
Alemtuzumab is a non-myeloablative pre-transplant conditioning regimen. Non-myeloablative therapy uses doses of chemotherapy and radiation to weaken (but not destroy) the patients bone marrow and immune system, while still allowing their body will accept the donor's stem cells. Alemtuzumab will be given 7 days prior to stem cell infusion at 0.03 mg/kg IV, 6 days prior to stem cell infusion at 0.1 mg/kg IV, and 5 thru 3 days prior to stem cell infusion at 0.3 mg/kg IV.
Radiation: Total Body Irradiation
300 cGy will be administered in a single fraction on Day - 2. TBI is used commonly as part of pre-transplant conditioning in a variety of settings.
Other Name: TBI
Sirolimus will be used for the prevention of graft-verus-host disease and will begin on Day - 1.
Other Name: Rapammune
- Treatment Success [ Time Frame: up to 1 year after HSCT ]by evaluating reversal of Hb S % to that of the donor's phenotype, in recipients of HLA matched-sibling peripheral blood - hematopoietic stem cell transplantation (HSCT) with NMA conditioning regimen. Testing for treatment success will include Hb Electrophoresis. Recipients with donors AA should have nearly 0% Hb S. Recipients with donors AS should have similar Hb S % (approximately < 60%) as the donor. The proportion of patients experiencing treatment success, will be calculated with a 90% exact confidence interval.
- Engraftment [ Time Frame: up to 1 year after HSCT ]To estimate the probability of engraftment, using absolute neutrophil count and platelets along with chimerism analysis after HSCT. This will by evaluated by: 1) Time to ANC of >500/uL on the first of three consecutive days. 2) Time to platelet count >50,000/µL for 3 days without transfusion. 3) Peripheral blood chimerism analysis of whole blood and CD3-lineage will be performed on or around day +30, +90, +180, and +360. 4) Additional peripheral blood chimerism studies may be performed as clinically indicated. The statistical analysis plan will be calculated with a 90% exact confidence interval.
- Probability of developing acute GVHD after HSCT. [ Time Frame: up to 100 days after HSCT ]Acute GVHD will be diagnosed and graded using the clinical and laboratory criteria in Appendix A of the protocol. During the inpatient stay, clinical evaluations will occur daily. During the outpatient stay, each patient should be evaluated at least every other week until they are discharged from the transplant clinic. Subsequent evaluations will occur at roughly Days +30, +60, +90 and until +100 days. Clinical evaluations will be performed and grade will be assigned at the time of diagnosis by an attending physician. The decision to initiate GVHD therapy will be made by the attending physician. The statistical analysis plan will be calculated with a 90% exact confidence interval.
- Probability of developing chronic GVHD after HSCT. [ Time Frame: up to 2 years after HSCT ]Chronic GVHD will be diagnosed using NIH criteria outlined in Appendix B of the protocol. b. Evaluation will be conducted by BMT team at day +100, +360 and yearly up to 2 years after HCT. The patient's sickle cell physician will conduct clinical assessments between these time points as required per institutional guidelines. This will be evaluate by: 1) The occurrence of chronic GHVD meeting NIH criteria and requiring systemic pharmacological immunosuppression 2) The use of additional immune suppressive agents other than first line therapy 3) Time to completion of prednisone, if required for treatment of acute GVHD 4) Time to completion of all immunosuppression 5) Requirement for immunosuppression at 1 year and 2 years after transplant. The statistical analysis plan will be calculated with a 90% exact confidence interval.
- Graft failure or Relapse [ Time Frame: up to 2 years after HSCT ]Relapse is defined by the presence of recipient's Hb SS on electrophoresis. Testing for recurrent disease will include Hb electrophoresis to determine recipient vs. donor Hb-type and peripheral blood chimerism to document loss of donor cell engraftment. Endpoints will include: time to relapse and status of compliance with immunosuppressive therapy. Primary graft failure defined as the absence of donor cells assessed by peripheral blood chimerism assays, by any lineage, on or after day +30. Secondary graft failure defined as the presence of < 20% donor cells by peripheral blood chimerism assays in a patient with prior evidence of ≥ 20% of donor cells. The analysis plan for graft failure or relapse will be calculated with a 90% exact confidence interval.
- Discontinuation of Immunosuppressive therapy [ Time Frame: up to 2 years after HSCT ]The time (in days) it takes to taper immunosuppressive therapy will be measured. Tapering will begin once 50% donor CD3 chimerism is achieved. To estimate the time to discontinuation of immunosuppressive therapy. The product-limit (Kaplan-Meier) estimate of the distribution of time to discontinuation will be calculated with a 90% confidence region. In an exploratory analysis, proportional hazards (Cox) regression will be applied to identify potential predictors of time to discontinuation.
- Sickle cell disease related organ damage [ Time Frame: up to 2 years after HSCT ]Cardiac function, pulmonary function, renal function, cerebrovascular function will be measured. We will measure and record BNP, left atrial diameter and the tricuspid regurgitant velocity, noted on transthoracic echocardiogram, (TTE) as a marker of improvement at an outpatient cardiology follow-up visit. We will measure and record a 6-minute walking distance test and pulmonary function test variables to include: FEV1, FVC, TLC, RV, DLCO, and O2 saturation at an outpatient pulmonology follow-up visit.We will measure and record the urine-albumin creatinine ratio as a measure of micro-/macro-albuminuria and 24-hr urine proteinat an outpatient nephrology follow-up visit.We will obtain a brain MRI at an outpatient neurology follow-up visit. All evaluations will take place at baseline, Day +365, and Day +720.
- Lymphocyte subsets [ Time Frame: up to 2 years after HSCT ]To evaluate lymphocyte subsets. This analysis will be descriptive.
- Changes in monthly transfusions after HSCT [ Time Frame: up to 2 years after HSCT ]We will monitor the number of transfusions required on a monthly basis pre- and post-HSCT Patient's monthly transfusions will be recorded starting 3 months pre-HSCT. Patient's monthly transfusions will be recorded post-HSCT at the following time points: Days +30, +60, +90, +180, +365, +720. To evaluate changes in monthly transfusion dependence after HSCT in patients, will be modeled using mixed effects regression.
- Changes in the annual frequency of SCD-related hospitalization after [ Time Frame: up to 2 years after HSCT ]The patients frequency of hospital stays will be measured compared to prior HSCT. Number of hospitalizations per year post-HSCT will be recorded at Days 0, +365 and +720. A mixed effects Poisson regression model will compare the patients' frequency of hospitalization three years pre-transplant to post-transplant.
- Quality of life measures [ Time Frame: up to 2 years after HSCT ]Quality of life will be measured utilizing validated tools as well as new tools specific for sickle cell disease including the questionnaires: SF-36, Adult Sickle Cell Quality of life Measurement Information System (ASCQ-Me), Pittsburgh Sleep Quality Index, Generalized Anxiety Disorder-7, Brief Pain Inventory, and Painimation. To evaluate improvement in quality of life measures after HSCT. The recommended summary indices for the quality of life instruments will be calculated and their change over time by mixed effects linear models.
- Transplant-related mortality [ Time Frame: up to 2 years after HSCT ]TRM is defined as mortality in any patient for whom there has not been a diagnosis of relapse.To estimate transplant-related mortality: The product-limit (Kaplan-Meier) estimate of the distribution of time to discontinuation will be calculated with a 90% confidence region. In an exploratory analysis, proportional hazards (Cox) regression will be applied to identify potential predictors of time to discontinuation.
- Opioid independence [ Time Frame: up to 2 years after HSCT ]We will monitor the narcotic use in all recipients. Opioid adjustments are made by our SCD physicians who will be caring for these patients both pre- and post-transplant. Information on weekly narcotic use will be obtained and will be converted to the intravenous morphine equivalent dose for data collection. This will be done for the one week duration immediately prior to the following time points: Days 0, +30, +60, +90, +180, +365, +720. To evaluate changes in weekly narcotic use after HSCT. Weekly narcotic use, converted to the intravenous morphine equivalent dose, will be modeled using mixed effects regression.
- MDC, whole blood and CD3 Lineage [ Time Frame: up to 1 year after HSCT ]To estimate the probability of MDC, whole blood and CD3-lineage at 1 year.The statistical analysis plan will be calculated with a 90% exact confidence interval.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03421756
|Contact: Rita Johnson, RN||(412) firstname.lastname@example.org|
|United States, Pennsylvania|
|UPMC Hillman Cancer Center||Recruiting|
|Pittsburgh, Pennsylvania, United States, 15232|
|Contact: Rita Johnson, RN 412-647-8571 email@example.com|
|Principal Investigator:||Kathleen Dorritie, MD||UPMC Hillman Cancer Center|