Efficacy and Safety of RBCs Derived From Mirasol-treated Whole Blood in Patients Requiring Chronic Transfusion (PRAISE)

• Sponsor: Terumo BCTbio (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT03329404
• Collaborator: United States Department of Defense (U.S. Fed), Joint Warfighter Medical Research Program (Other), U.S. Army Medical Research and Development Command (U.S. Fed)
• Enrollment: 12
• Locations: 9
• Arms: 2
• Actual Duration (Months): 7.9
• Patients Per Site: 1.3
• Patients Per Site Per Month: 0.2

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Transfusion Dependent Thalassemia	Device: Mirasol Red Blood Cells (MIR RBCs); Device: Reference Red Blood Cells (REF RBCs)	N/A

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. 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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 12 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Evaluate the Efficacy and Safety of RBCs Derived From Mirasol-treated Whole Blood Compared With Conventional RBCs in Patients Requiring Chronic Transfusion Support
• Actual Study Start Date: Apr 23, 2018
• Actual Primary Completion Date: Dec 19, 2018
• Actual Study Completion Date: Dec 19, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Mirasol Red Blood Cells (MIR RBCs) MIR RBCs: RBCs will be derived from WB collected in CPD solution, treated with the Mirasol System for WB, LR, and stored in AS-3 for ≤ 21 days at 1-6°C	Device: Mirasol 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.
Active Comparator: Reference Red Blood Cells (REF RBCs) Reference Red Blood Cells (REF RBCs); LR apheresis RBCs or WB-derived RBCs will be per site standard inventory	Device: Reference 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.

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. Hb Increment [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]

   (post-transfusion Hb - pre-transfusion Hb)/Hb transfused]/RBC volume in subject at pre-transfusion

2. 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 Outcome Measures

1. Proportional 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]

   Proportional decline in post-transfusion Hb level

2. 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

3. Incidence of Treatment-emergent Antibody 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]

4. Human Leukocyte Antigen (HLA) Alloimmunization Rates [An average of 15 weeks consisting of the first treatment period including a 50 day wash-in phase followed by 2 transfusion episodes]

5. Treatment Emergent Adverse Events (TEAEs). [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]

6. Transfusion-related Adverse Events (AEs). [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]

7. Serious Adverse Events (SAEs). [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]

8. Unanticipated Adverse Device Effects (UADEs). [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]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 12 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• 1. Transfusion dependent thalassemia patient with mean 2-4 week transfusion intervals for the prior 6 months.

1. Age ≥ 12 years.

2. 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).

3. 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	UCSF Benioff Children's Hospital Oakland	Oakland	California	United States	94609
2	Boston Children's Hospital	Boston	Massachusetts	United States	02116
3	Weill-Cornell Medical College	New York	New York	United States	10065
4	The Children's Hospital of Philadelphia	Philadelphia	Pennsylvania	United States	19104
5	Rambam Health Care Campus	Haifa		Israel	3109601
6	Hadassah Ein Kerem Hospital	Jerusalem		Israel	91120
7	Centro della Microcitemia ed Anemie Congenite Ospedale Gallieria	Genova	Genoa	Italy	16128
8	U.O.C. di Ematologia e Malattie Rare del Sangue e degli Organi Ematopoietici V. Cervello Hospital	Palermo		Italy	90146
9	Ege University Children's Hospital	Bornova	Izmir	Turkey	35040

Sponsors and Collaborators

• Terumo BCTbio
• United States Department of Defense
• Joint Warfighter Medical Research Program
• U.S. Army Medical Research and Development Command

Investigators

• Study Director: Ned Cosgriff, MD, Terumo BCT
• Principal Investigator: Steve Sloan, MD, PhD, Boston Children's Hospital

Study Documents (Full-Text)

• Study Protocol - Feb 15, 2018
• Statistical Analysis Plan - Feb 5, 2018

More Information

Publications

None provided.

• Responsible Party: Terumo BCTbio
• ClinicalTrials.gov Identifier: NCT03329404
• Other Study ID Numbers: CTS-5056
• First Posted: Nov 6, 2017
• Last Update Posted: Apr 28, 2021
• Last Verified: Dec 1, 2019

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: Yes
• Keywords provided by Terumo BCTbio: Thalassemia; pathogen reduction therapy
• Additional relevant MeSH terms: Thalassemia

Study Results

Participant Flow

Recruitment Details

A subject was considered enrolled upon signing the informed consent. The first subject was enrolled on 12 April 2018 and the last subject was enrolled on 26 October 2018.

Pre-assignment Detail

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.

Arm/Group Title	Mirasol Red Blood Cells (MIR RBCs) Followed by Reference RBCs (REF RBCs)	Reference Red Blood Cells (REF RBCs) Followed by Mirasol RBCs (MIR RBCs)
Arm/Group Description	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.	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.
Period Title: Overall Study
STARTED	4	5
COMPLETED	3	1
NOT COMPLETED	1	4

Baseline Characteristics

Arm/Group Title	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
Arm/Group Description	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.	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.	Total of all reporting groups
Overall Participants	4	5	9
Age (Count of Participants)
<=18 years	1 25%	1 20%	2 22.2%
Between 18 and 65 years	3 75%	4 80%	7 77.8%
>=65 years	0 0%	0 0%	0 0%
Sex: Female, Male (Count of Participants)
Female	2 50%	1 20%	3 33.3%
Male	2 50%	4 80%	6 66.7%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	0 0%	0 0%
Not Hispanic or Latino	3 75%	5 100%	8 88.9%
Unknown or Not Reported	1 25%	0 0%	1 11.1%
Region of Enrollment (participants) [Number]
United States	4 100%	5 100%	9 100%

Outcome Measures

1. Primary Outcome

Title	Normalized Hemoglobin (Hb AUC) Calculated From Normalized Hb Between Successive Transfusions as a Measure of Percent Surviving RBCs
Description	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.

Outcome Measure Data

Analysis Population Description

The full Statistical Analysis Plan was not executed for this study because the study was stopped prematurely. 97 subjects were planned to be enrolled however only 12 subjects enrolled and 9 were randomized. Of the 9 randomized, no subjects completed the study due to early termination of the study. The primary outcome measure was not analyzed due to the small sample size and premature termination of the study.

Arm/Group Title	Mirasol Red Blood Cells (MIR RBCs)	Reference Red Blood Cells (REF RBCs)
Arm/Group Description	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.	REF RBCs: Leukoreduced (LR) apheresis RBCs or whole blood (WB)-derived RBCs will be per site standard inventory. MIR RBCs: RBCs will be 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.
Measure Participants	0	0

2. Secondary Outcome

Title	Hb Increment
Description	(post-transfusion Hb - pre-transfusion Hb)/Hb transfused]/RBC volume in subject at pre-transfusion
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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

3. Secondary Outcome

Title	Actual Hb Level Post-transfusion (15 Min)
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

4. Other Pre-specified Outcome

Title	Proportional Decline in Post-transfusion Hb Level
Description	Proportional 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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

5. Other Pre-specified Outcome

Title	RBC Mass Infused
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

6. Other Pre-specified Outcome

Title	Incidence of Treatment-emergent Antibody With Confirmed Specificity to RBCs Derived From Mirasol-treated WB
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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

7. Other Pre-specified Outcome

Title	Human Leukocyte Antigen (HLA) Alloimmunization Rates
Time Frame	An average of 15 weeks consisting of the first treatment period including a 50 day wash-in phase followed by 2 transfusion episodes

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

8. Other Pre-specified Outcome

Title	Treatment Emergent Adverse Events (TEAEs).
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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

9. Other Pre-specified Outcome

Title	Transfusion-related Adverse Events (AEs).
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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

10. Other Pre-specified Outcome

Title	Serious Adverse Events (SAEs).
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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

11. Other Pre-specified Outcome

Title	Unanticipated Adverse Device Effects (UADEs).
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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Time Frame	8 months
Adverse Event Reporting Description	This was a crossover study, therefore adverse events are reported by treatment received, some subjects received both treatments. Of the 9 randomized subjects, 1 subject did not receive any study transfusions, 4 of the 9 subjects received some MIR RBC transfusions and 8 of the 9 subjects received some REF RBC transfusions.
Arm/Group Title	Mirasol Red Blood Cells (MIR RBCs)		Reference Red Blood Cells (REF RBCs)
Arm/Group Description	MIR RBCs: RBCs were derived from whole blood (WB) collected in citrate phosphate dextrose (CPD) solution, treated with the Mirasol System for WB, leukoreduced, and stored in Additive Solution Formula 3 (AS-3) for ≤ 21 days at 1 - 6°C.		REF RBCs: Leukoreduced apheresis RBCs or whole blood-derived RBCs were per site standard inventory.
All Cause Mortality
	Mirasol Red Blood Cells (MIR RBCs)		Reference Red Blood Cells (REF RBCs)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/4 (0%)		0/8 (0%)
Serious Adverse Events
	Mirasol Red Blood Cells (MIR RBCs)		Reference Red Blood Cells (REF RBCs)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/4 (0%)		0/8 (0%)
Other (Not Including Serious) Adverse Events
	Mirasol Red Blood Cells (MIR RBCs)		Reference Red Blood Cells (REF RBCs)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/4 (25%)		4/8 (50%)
Blood and lymphatic system disorders
Thrombocytosis	1/4 (25%)	1	0/8 (0%)	0
Thrombocytopenia	0/4 (0%)	0	1/8 (12.5%)	1
Infections and infestations
Viral upper respiratory tract infection	0/4 (0%)	0	1/8 (12.5%)	1
Investigations
Aspartate aminotransferase increased	0/4 (0%)	0	1/8 (12.5%)	1
Alanine aminotransferase increased	0/4 (0%)	0	1/8 (12.5%)	1
Metabolism and nutrition disorders
Hypoglycemia	1/4 (25%)	1	0/8 (0%)	0
Skin and subcutaneous tissue disorders
Rash	0/4 (0%)	0	1/8 (12.5%)	1

Limitations/Caveats

The primary endpoint was not evaluated due to the early termination of the study and subsequent small sample size with no subjects completing both Period 1 and Period 2 of the study preventing any meaningful results.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.