Transfusion Dependent Thalassemia
Conditions
Keywords
Thalassemia, pathogen reduction therapy
Brief summary
This is a prospective, multi-center, randomized, crossover trial to evaluate the clinical effectiveness of red blood cells (RBCs) derived from Mirasol-treated whole blood (WB) versus conventional RBCs in transfusion dependent thalassemia patients. Throughout the clinical study, RBC transfusion volume and frequency will be determined by each subject's treating physician.
Detailed description
Patients will be randomized 1:1 to receive either Mirasol-treated RBCs followed by conventional RBCs, or to receive conventional RBCs followed by Mirasol-treated RBCs. The blood centers will collect the donor RBCs and supply the Mirasol-treated RBCs to the hospital sites for transfusion into patients. Hospital sites will order conventional RBCs as per their normal process, from their standard vendor. Blood transfusion is the mainstay of care for individuals with thalassemia major. The purpose of transfusion is twofold: to improve the anemia and to suppress the ineffective erythropoiesis. A transfusion episode for these thalassemia patients are the routine transfusions administered on a regular schedule for the life of the patient. The crossover trial design will consist of 2 treatment periods: Period 1 = Mirasol-treated RBCs followed by conventional (reference) RBCs; Period 2 = Reference RBCs followed by Mirasol-treated RBCs. Each period will include a 50 day wash-in phase (Day 0 of the wash-in = Day 0 of the treatment period) followed by 2 transfusion episodes. An end of study treatment follow-up visit will occur 2-4 weeks after the last per protocol transfusion, prior to the next standard of care transfusion. A final study visit will occur at least 60 days after the last per protocol transfusion. The primary objective of the PRAISE study is to determine if percent survival of RBCs derived from Mirasol-treated WB is non-inferior to conventional RBCs when transfused into patients requiring chronic RBC transfusion support. The secondary objectives include comparing other efficacy and safety endpoints between treatment groups.
Interventions
DEVICEMirasol Red Blood Cells (MIR RBCs)
Mirasol Red Blood Cells (MIR RBCs) derived from Mirasol-treated WB; WB will be Mirasol treated, centfifuged and leukoreduced and the derived RBCs will be stored before transfusion for up to 21 days and transfused according to the patient's transfusion schedule.
DEVICEReference Red Blood Cells (REF RBCs)
Reference Red Blood Cells (REF RBCs) will be acquired from routine use inventory and transfused according to the patient's transfusion schedule.
Sponsors
United States Department of Defense
Joint Warfighter Medical Research Program
U.S. Army Medical Research and Development Command
Terumo BCTbio
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
12 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* 1\. Transfusion dependent thalassemia patient with mean 2-4 week transfusion intervals for the prior 6 months. 2\. Age ≥ 12 years. 3\. Negative pregnancy test for women of childbearing potential and agreement to practice a medically acceptable contraception regimen throughout the participation in the clinical trial. Not required if female subjects are not of child-bearing potential (ie, prior to menses onset, surgically sterilized, 1-year postmenopausal). 4\. Signed informed consent from the patient, or if the patient is \< 18 years of age, signed assent from patient and consent from parent/guardian, according to local Institutional Review Board/Ethics Committee (IRB/EC) requirements.
Exclusion criteria
1. Historical RBC transfusion requirement of more than 250 mL/kg/year. 2. Presence of RBC antibodies that make procurement of compatible RBC units not feasible per the treating physician's clinical judgment for reasonable execution of the study. 3. Prior treatment with pathogen-reduced RBCs with subsequent development of known antibodies to the associated RBCs. 4. Planned treatment requirement of frozen RBC products. 5. Treatment requirements for any medication that is known to cause hemolysis. 6. Receiving cardiac medications for heart failure. 7. Patients anticipated to receive massive transfusion, per the treating physician's clinical judgment. 8. Known HIV infection (defined as HIV RNA positive) with changes to antiviral regimen within the 12 months prior to screening. 9. Acute or chronic medical disorder that, in the opinion of the Investigator, would impair the ability of the patient to receive study treatment. 10. Participation in another clinical study, either concurrently or within the previous 28 days, in which the study drug or device may influence study endpoints or patient safety, according to Investigator discretion. 11. Participation in another clinical study within the past 3 months if investigational RBCs or treatment or drugs were received that are likely to have long term effect on RBCs function. 12. Pregnant or breastfeeding. 13. Planned concurrent treatment with other pathogen reduction treated blood products during participation in this study. 14. Patients who received prior treatment with pathogen-reduced RBCs within the past 120 days. 15. Inability to comply with study procedures and/or follow-up.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Normalized Hemoglobin (Hb AUC) Calculated From Normalized Hb Between Successive Transfusions as a Measure of Percent Surviving RBCs | Crossover design with 2 treatment periods. Each period included a 50-day wash-in followed by 2 transfusion episodes for primary endpoint assessment. Expected participation was approximately 7-10 months, depending on the subject's transfusion schedule. | The Hb AUC is calculated using the trapezoidal method on normalized Hb. The normalization is accomplished by dividing all posttransfusion Hb values by the 15-minute posttransfusion Hb level. The ratio is expressed as a percentage. A natural log-transform of the observed normalized Hb AUC will be utilized. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Hb Increment | Endpoint assessments was evaluated at 15 min Post Transfusion, 1 Day Post Transfusion, 7 Day Post Transfusion, and End of Transfusion Episode. | (post-transfusion Hb - pre-transfusion Hb)/Hb transfused\]/RBC volume in subject at pre-transfusion |
| Actual Hb Level Post-transfusion (15 Min) | An average of 30 weeks consisting of 2 crossover treatment periods with each period including a 50 day wash-in phase followed by 2 transfusion episodes for endpoint assessment | Actual Hb level post-transfusion (15 min) |
Other
| Measure | Time frame | Description |
|---|---|---|
| Percentage Decline in Post-transfusion Hb Level | An average of 30 weeks consisting of 2 crossover treatment periods with each period including a 50 day wash-in phase followed by 2 transfusion episodes for endpoint assessment. | Percentage decline in post-transfusion Hb level |
| Number of Participants With Human Leukocyte Antigen (HLA) Alloimmunization Post Transfusion | Up to 40 weeks consisting of 2 crossover treatment periods with each period including a 50 day wash-in phase followed by 2 transfusion episodes for endpoint assessment and a final study visit 60 days after last study. | The highest of three different normalized background ratio (NBG) cut-offs was used to quantify positivity for Class I HLA antibodies prior to transfusion as it was used to identify conversion from HLA antibody negative prior to transfusion to positivity after transfusion(s) within the applicable treatment group. |
| RBC Mass Infused | An average of 30 weeks consisting of 2 crossover treatment periods with each period including a 50 day wash-in phase followed by 2 transfusion episodes for endpoint assessment | volume x Hb/unit |
| Number of Antibody Screening Test With Confirmed Specificity to RBCs Derived From Mirasol-treated WB | Up to 40 weeks consisting of 2 crossover treatment periods with each period including a 50 day wash-in phase followed by 2 transfusion episodes for endpoint assessment and a final study visit 60 days after last study transfusion | Antibody screening was performed in a total of 8 (100%) subjects in the SS at a total of 97 intervals (Pre-Transfusion, 7 Days Post-Transfusion or End of Study Treatment Follow-up Visit). |
Countries
Israel, Italy, Turkey (Türkiye), United States
Participant flow
Recruitment details
Nine subjects were enrolled and assigned into treatment arms. The first subject signed consent on 12 April 2018 and the last subject signed consent on 03 October 2018.
Pre-assignment details
This was a crossover study, all 9 randomized subjects were to receive both Mirasol and Reference RBCs in either period 1 or 2. 4 subjects were randomized to the MIR/REF RBC treatment sequence and 5 subjects were randomized to the REF/MIR RBC sequence. 4 subjects completed period 1, no subjects completed period 2 due to study suspension. Because no subjects completed the study, the primary endpoint was not evaluated and results are summarized by treatment type rather than treatment sequence.
Participants by arm
| Arm | Count |
|---|---|
| Mirasol Red Blood Cells (MIR RBCs)/Reference Red Blood Cells (REF RBCs) Treatment Sequence MIR RBCs: RBCs were derived from whole blood (WB) collected in citrate phosphate dextrose (CPD) solution, treated with the Mirasol System for WB, Leukoreduced (LR), and stored in Additive Solution Formula 3 (AS-3) for ≤ 21 days at 1 - 6°C.
REF RBCs: LR apheresis RBCs or WB-derived RBCs were per site standard inventory. | 4 |
| Reference Red Blood Cells (REF RBCs)/Mirasol Red Blood Cells (MIR RBCs) Treatment Sequence REF RBCs: Leukoreduced (LR) apheresis RBCs or whole blood (WB)-derived RBCs were per site standard inventory.
MIR RBCs: RBCs were derived from WB collected in citrate phosphate dextrose (CPD) solution, treated with the Mirasol System for WB, LR, and stored in Additive Solution Formula 3 (AS-3) for ≤ 21 days at 1 - 6°C. | 5 |
| Total | 9 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | The study was suspended. | 1 | 4 |
Baseline characteristics
| Characteristic | Mirasol Red Blood Cells (MIR RBCs)/Reference Red Blood Cells (REF RBCs) Treatment Sequence | Reference Red Blood Cells (REF RBCs)/Mirasol Red Blood Cells (MIR RBCs) Treatment Sequence | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 1 Participants | 1 Participants | 2 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 3 Participants | 4 Participants | 7 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 3 Participants | 5 Participants | 8 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 1 Participants |
| Region of Enrollment United States | 4 participants | 5 participants | 9 participants |
| Sex: Female, Male Female | 2 Participants | 1 Participants | 3 Participants |
| Sex: Female, Male Male | 2 Participants | 4 Participants | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 4 | 0 / 8 |
| other Total, other adverse events | 1 / 4 | 4 / 8 |
| serious Total, serious adverse events | 0 / 4 | 0 / 8 |
Outcome results
Primary
Normalized Hemoglobin (Hb AUC) Calculated From Normalized Hb Between Successive Transfusions as a Measure of Percent Surviving RBCs
The Hb AUC is calculated using the trapezoidal method on normalized Hb. The normalization is accomplished by dividing all posttransfusion Hb values by the 15-minute posttransfusion Hb level. The ratio is expressed as a percentage. A natural log-transform of the observed normalized Hb AUC will be utilized.
Time frame: Crossover design with 2 treatment periods. Each period included a 50-day wash-in followed by 2 transfusion episodes for primary endpoint assessment. Expected participation was approximately 7-10 months, depending on the subject's transfusion schedule.
Population: The Statistical Analysis Plan was not executed for this study because the study was stopped prematurely. Ninety-seven subjects were planned to be enrolled however 9 were randomized. None of the 9 randomized subjects completed the sequence arms and met the per protocol criteria and as such the primary endpoint was not collected.
Secondary
Actual Hb Level Post-transfusion (15 Min)
Actual Hb level post-transfusion (15 min)
Time frame: An average of 30 weeks consisting of 2 crossover treatment periods with each period including a 50 day wash-in phase followed by 2 transfusion episodes for endpoint assessment
Population: The SAP was not executed for this study as the study was stopped prematurely. None of the 9 randomized subjects completed the sequence arms and met the per protocol criteria. Post-hoc analysis was performed by intervention, not by the randomized sequence arm. Of the 9 randomized subjects, 1 subject did not enter either treatment period.There were 4 MIR treatment periods and 8 REF treatment periods.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Mirasol Red Blood Cells (MIR RBCs) | Actual Hb Level Post-transfusion (15 Min) | 11.19 grams/dL | Standard Deviation 1.44 |
| Reference Red Blood Cells (REF RBCs) | Actual Hb Level Post-transfusion (15 Min) | 11.49 grams/dL | Standard Deviation 0.65 |
Secondary
Hb Increment
(post-transfusion Hb - pre-transfusion Hb)/Hb transfused\]/RBC volume in subject at pre-transfusion
Time frame: Endpoint assessments was evaluated at 15 min Post Transfusion, 1 Day Post Transfusion, 7 Day Post Transfusion, and End of Transfusion Episode.
Population: The Statistical Analysis Plan was not executed for this study because the study was stopped prematurely. Ninety-seven subjects were planned to be enrolled however 9 were randomized. None of the 9 randomized subjects completed the sequence arms and met the per protocol criteria and as such the secondary endpoint was not analyzed as planned in the Statistical Analysis Plan.~The limited data collected was analyzed per intervention, not by sequence.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Mirasol Red Blood Cells (MIR RBCs) | Hb Increment | 15 minute Post-Transfusion | 0.000299 delta g/dl per mL RBC transfused | Standard Deviation 0.000422 |
| Mirasol Red Blood Cells (MIR RBCs) | Hb Increment | 1 Day Post-Transfusion | 0.000297 delta g/dl per mL RBC transfused | Standard Deviation 0.000486 |
| Mirasol Red Blood Cells (MIR RBCs) | Hb Increment | 7 Day Post-Transfusion | 0.000173 delta g/dl per mL RBC transfused | Standard Deviation 0.000287 |
| Mirasol Red Blood Cells (MIR RBCs) | Hb Increment | End of Transfusion Interval | 0.000014 delta g/dl per mL RBC transfused | Standard Deviation 0.000159 |
| Reference Red Blood Cells (REF RBCs) | Hb Increment | End of Transfusion Interval | -0.000041 delta g/dl per mL RBC transfused | Standard Deviation 0.0000999 |
| Reference Red Blood Cells (REF RBCs) | Hb Increment | 15 minute Post-Transfusion | 0.000288 delta g/dl per mL RBC transfused | Standard Deviation 0.0004 |
| Reference Red Blood Cells (REF RBCs) | Hb Increment | 7 Day Post-Transfusion | 0.000149 delta g/dl per mL RBC transfused | Standard Deviation 0.000181 |
| Reference Red Blood Cells (REF RBCs) | Hb Increment | 1 Day Post-Transfusion | 0.000362 delta g/dl per mL RBC transfused | Standard Deviation 0.00033 |
Other Pre-specified
Number of Antibody Screening Test With Confirmed Specificity to RBCs Derived From Mirasol-treated WB
Antibody screening was performed in a total of 8 (100%) subjects in the SS at a total of 97 intervals (Pre-Transfusion, 7 Days Post-Transfusion or End of Study Treatment Follow-up Visit).
Time frame: Up to 40 weeks consisting of 2 crossover treatment periods with each period including a 50 day wash-in phase followed by 2 transfusion episodes for endpoint assessment and a final study visit 60 days after last study transfusion
Population: Safety Set. The Statistical Analysis Plan was not executed for this study because the study was stopped prematurely. Of the 97 subjects planned to be enrolled, only 9 subjects were randomized and none completed the sequence arms. Of the 9 subjects, one did not enter either treatment period. The limited data collected was analyzed per intervention, not by sequence.
| Arm | Measure | Value (COUNT_OF_UNITS) |
|---|---|---|
| Mirasol Red Blood Cells (MIR RBCs) | Number of Antibody Screening Test With Confirmed Specificity to RBCs Derived From Mirasol-treated WB | 0 antibody screen test |
| Reference Red Blood Cells (REF RBCs) | Number of Antibody Screening Test With Confirmed Specificity to RBCs Derived From Mirasol-treated WB | 3 antibody screen test |
Other Pre-specified
Number of Participants With Human Leukocyte Antigen (HLA) Alloimmunization Post Transfusion
The highest of three different normalized background ratio (NBG) cut-offs was used to quantify positivity for Class I HLA antibodies prior to transfusion as it was used to identify conversion from HLA antibody negative prior to transfusion to positivity after transfusion(s) within the applicable treatment group.
Time frame: Up to 40 weeks consisting of 2 crossover treatment periods with each period including a 50 day wash-in phase followed by 2 transfusion episodes for endpoint assessment and a final study visit 60 days after last study.
Population: Safety Set. The Statistical Analysis Plan was not executed for this study because the study was stopped prematurely. Of the 97 subjects planned to be enrolled, only 9 subjects were randomized and none completed the sequence arms. Of the 9 subjects, one did not enter either treatment period. The limited data collected was analyzed by sequence.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Mirasol Red Blood Cells (MIR RBCs) | Number of Participants With Human Leukocyte Antigen (HLA) Alloimmunization Post Transfusion | 1 Participants |
| Reference Red Blood Cells (REF RBCs) | Number of Participants With Human Leukocyte Antigen (HLA) Alloimmunization Post Transfusion | 0 Participants |
Other Pre-specified
Percentage Decline in Post-transfusion Hb Level
Percentage decline in post-transfusion Hb level
Time frame: An average of 30 weeks consisting of 2 crossover treatment periods with each period including a 50 day wash-in phase followed by 2 transfusion episodes for endpoint assessment.
Population: The Statistical Analysis Plan was not executed for this study because the study was stopped prematurely. Ninety-seven subjects were planned to be enrolled however 9 were randomized. None of the 9 randomized subjects completed the sequence arms and met the per protocol criteria and as such the secondary endpoint was not analyzed according to the Statistical Analysis Plan. The limited data collected was analyzed per intervention, not by sequence.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Mirasol Red Blood Cells (MIR RBCs) | Percentage Decline in Post-transfusion Hb Level | -4.256 percent change | Standard Deviation 5.367 |
| Reference Red Blood Cells (REF RBCs) | Percentage Decline in Post-transfusion Hb Level | -3.249 percent change | Standard Deviation 5.568 |
Other Pre-specified
RBC Mass Infused
volume x Hb/unit
Time frame: An average of 30 weeks consisting of 2 crossover treatment periods with each period including a 50 day wash-in phase followed by 2 transfusion episodes for endpoint assessment
Population: The Statistical Analysis Plan was not executed for this study because the study was stopped prematurely. Ninety-seven subjects were planned to be enrolled however 9 were randomized. None of the 9 randomized subjects completed the sequence arms and met the per protocol criteria and as such the secondary endpoint was not analyzed as planned in the Statistical Analysis Plan. The limited data collected was analyzed per intervention, not by sequence.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Mirasol Red Blood Cells (MIR RBCs) | RBC Mass Infused | 1445.796 grams | Standard Deviation 33.622 |
| Reference Red Blood Cells (REF RBCs) | RBC Mass Infused | 107.039 grams | Standard Deviation 29.583 |