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Sickle Cell Disease and CardiovAscular Risk - Red Cell Exchange Trial (SCD-CARRE) (SCD-CARRE)

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ClinicalTrials.gov Identifier: NCT04084080
Recruitment Status : Recruiting
First Posted : September 10, 2019
Last Update Posted : February 21, 2023
Sponsor:
Collaborator:
National Heart, Lung, and Blood Institute (NHLBI)
Information provided by (Responsible Party):
Mark Gladwin, University of Maryland, Baltimore

Study Description
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Brief Summary:
The SCD-CARRE trial is a Phase 3, prospective, randomized, multicenter, controlled, parallel two-arm study aimed to determine if automated exchange blood transfusion and standard of care administered to high mortality risk adult SCD patients reduces the total number of episodes of clinical worsening of SCD requiring acute health care encounters (non-elective infusion center/ER/hospital visits) or resulting in death over 12 months as compared with standard of care.

Condition or disease Intervention/treatment Phase
Sickle Cell Disease Biological: Red Blood Cell Other: Standard of care Phase 3

Detailed Description:

As patients with sickle cell disease (SCD) live to adulthood, the chronic impact of sustained hemolytic anemia and episodic vaso-occlusive events take their toll, with the progressive development of cardiopulmonary organ dysfunction. This culminates in the development of pulmonary hypertension, left ventricular diastolic heart disease, dysrhythmia, chronic kidney disease and sudden death, all major cardiovascular complications of SCD for which there are no approved or consensus therapies. The risk of having pulmonary hypertension and diastolic heart disease can be non-invasively assessed by laboratory tests (NT-proBNP) and Doppler-echocardiography (estimated pulmonary artery systolic pressure). A recent meta-analysis of approximately 6000 patients with SCD demonstrated that patients with elevated tricuspid regurgitant jet velocity (TRV), which is an Doppler-echocardiographic measurement that estimates the pulmonary artery systolic pressure, walked an estimated 30.4 meters less in a 6 minute walk test than those without elevated TRV, and elevated TRV was associated with high mortality (hazard ratio of 4.9). In two large registry cohorts of adult patients with SCD, the investigators found that approximately 20% of the adult SCD population have high values for both biomarkers, defined as a TRV ≥ 2.5 meters per second AND a NT-proBNP ≥ 160 pg/mL, and that the 12-month mortality rate is 7.9% in this group as compared to 0.5% in patients with normal TRV or NT-proBNP values, with a risk ratio for hospitalization of 1.6. This suggests that a simple screening profile of TRV and NT-proBNP can identify about 20% of patients with SCD at the highest risk of death and hospitalization.

Given the increased mortality and early loss of functional capacity associated with cardiovascular disease in SCD adults, it is important to test effective therapeutic interventions in such patients. Red blood cell transfusions are administered by either simple or exchange transfusion, the latter removes the patients blood and replaces it with transfused red blood cells. Exchange transfusions have proven effective for acute treatment of almost all SCD complications, including severe acute chest syndrome, stroke, splenic or hepatic sequestration, and multi-organ failure, and are also used chronically for stroke prevention and recurrent acute chest syndrome. In this study the investigators hypothesize that monthly exchange transfusion will limit disease progression, improve exercise capacity, and prevent interval episodes of vaso-occlusive painful crisis and the acute chest syndrome that acutely increases pulmonary pressures and cause right heart failure.

The investigators propose to perform a clinical trial to evaluate the effects of automated exchange blood transfusion on patient morbidity and mortality, compared to standard of care among 150 adult high risk SCD patients. The trial will leverage existing coordinating center infrastructure at the University of Pittsburgh and will involve 22 experienced clinical sites. Despite the safety and wide utilization of erythrocytapheresis in adult patients with SCD, there is no consensus or quality efficacy data on its use to improve outcomes in our aging high-risk SCD patients with progressive end-organ dysfunction.

Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 150 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Sickle Cell Disease and CardiovAscular Risk - Red Cell Exchange Trial (SCD-CARRE)
Actual Study Start Date : February 26, 2020
Estimated Primary Completion Date : December 31, 2025
Estimated Study Completion Date : April 30, 2026

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Experimental: Exchange transfusion plus standard of care
Randomized to standard of care and automated exchange blood transfusion every 3-6 weeks for 12 months.
 Biological: Red Blood Cell
Red blood cell exchange transfusions will be performed every 3-6 weeks to maintain a target post-transfusion hemoglobin S level of <20% and a pre-transfusion hemoglobin S of <30%.
Other Name: Red blood cell (RBC)

Other: Standard of care
NHLBI/ASH/ATS Expert Panel recommended guidelines
Active Comparator: Standard of care
Randomized to standard of care
 Other: Standard of care
NHLBI/ASH/ATS Expert Panel recommended guidelines


Outcome Measures
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Primary Outcome Measures :
  1. Episodes of clinical worsening [ Time Frame: 13 months ]
    The efficacy of the intervention will be measured by comparing the total number of episodes of clinical worsening of SCD requiring acute health care encounters (non-elective infusion center/ER/Hospital visits) or resulting in death over 13 months between groups.


Secondary Outcome Measures :
  1. Acute healthcare event [ Time Frame: 13 months ]
    A 6-level prioritized rank-based outcome: 1.No death or SCD-related acute health care encounters (SCDAcuteE) within (w/in) 13 months (m) of randomization; 2. Had SCDAcuteE but NO major complications (acute kidney injury (AKI), acute chest syndrome (ACS), cor pulmonale, stroke, liver failure) associated with an SCDAcuteE nor death w/in 13 m of randomization; 3. Had 1 major complication (AKI, ACS, cor pulmonale, stroke, or liver failure) associated with an SCDAcuteE but not death w/in 13 m of randomization; 4. Had 2 major complications (AKI, ACS, cor pulmonale, stroke, or liver failure) associated with SCDAcuteE but not death w/in 13 m of randomization; 5. Had ≥ 3 major complications (AKI, ACS, cor pulmonale, stroke, or liver failure) associated with SCDAcuteE but not death w/in 13 m of randomization; 6.Death w/in 13 m of randomization. If the same complication reoccurs, occurrences will be counted as separate complications if the acute health care encounters are separated by ≥7 days.

  2. Twelve-month survival [ Time Frame: 13 months ]
    Survival over thirteen-month period will be analyzed and compared between the group receiving the intervention and the group receiving care routinely provided for sickle cell patients based on the NHLBI guidelines.

  3. Survival free of acute healthcare encounters [ Time Frame: 13 months ]
    Survival free of acute health care encounters over 13 months.

  4. Total number of acute health care encounters [ Time Frame: 13 months ]
    The total number of acute health care encounters (non-elective infusion center/ER/Hospital visits) with evidence of cor pulmonale (physical exam findings, NT-proBNP increase plus echocardiographic evidence of worsening right heart function).

  5. Measures of exercise capacity - 6 minute walk distance [ Time Frame: 4, 8, and 12 months ]
    Measures of exercise capacity assessed at 4, 8 and 12 months by the distance walked in the six minute walk distance assessment

  6. Measures of exercise capacity - outpatient activity [ Time Frame: 4, 8, and 12 months ]
    Measures of exercise capacity assessed at 4, 8 and 12 months by the distance walked in a 7 day in the outpatient setting.

  7. Cardiovascular risk [ Time Frame: 12 months ]
    Established cardiovascular risk biomarkers and indices are combined to help the investigators form an opinion about cardiovascular risks. The following will be measured: NT-proBNP, QT prolongation, systemic pulse pressure, albuminuria, estimated GFR and CKD progression Kidney Disease Improving Global Outcomes (KDIGO) CKD Work Group criteria.

  8. Development of new leg ulcers [ Time Frame: 4, 8 and 12 months ]
    Participants will be assessed for development of new leg ulcers at each physical exam.

  9. Measures of exercise capacity - WHO Classification [ Time Frame: 4, 8 and 12 months ]
    WHO functional status severity will be measured assessing by looking at limitation of usual physical activity from I (no limitation in usual physical activity) to Class IV (inability to perform any physical activity at rest)

  10. Nocturnal desaturation [ Time Frame: 4, 8 and 12 months ]
    Nocturnal desaturation will measured using a wearable device to measure blood oxygen saturation for 7 nights at home.

  11. SCD specific patient reported outcomes - Pain [ Time Frame: 4, 8 and 12 months ]
    SCD specific patient reported outcomes as measured by self-reported pain

  12. SCD specific patient reported outcomes -Quality of Life modified PROMIS scale [ Time Frame: 4, 8 and 12 months ]
    SCD specific patient reported outcomes as measured by a modified version of health related quality of life questionnaire from PROMIS QoL measure

  13. SCD specific patient reported outcomes -Quality of Life modified ASCQ-Me scale [ Time Frame: 4, 8 and 12 months ]
    SCD specific patient reported outcomes as measured by a modified version of health related quality of life questionnaire from ASCQ-Me QoL measure

  14. Cardiovascular function by echocardiography - TRV [ Time Frame: 4, 8 and 12 months ]
    Cardiovascular function measures from echocardiography assessed at 4, 8 and 12 months: echocardiographic measures of tricuspid regurgitant jet velocity in m/s.

  15. Cardiovascular function by echocardiography - diastolic left heart function [ Time Frame: 4, 8 and 12 months ]
    Diastolic left heart function measured by E/A ratio, E/Em ratio, and deceleration times will be assessed by echocardiography.

  16. Cardiovascular function by echocardiography - systolic right heart function [ Time Frame: 4, 8 and 12 months ]
    Systolic right heart health will be measured by assessing tricuspid annular plane systolic excursion (TAPSE), right ventricular size and contractility from echocardiography of the heart.


Eligibility Criteria
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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Age 18 years or older
  • Diagnosis of SCD: homozygous sickle cell disease, hemoglobin-SC, Sβ-thalassemia, hemoglobin-SO or hemoglobin-SD.
  • Patients not on a chronic exchange transfusion program for at least 60 days.
  • If patients are on a SCD drug (e.g. hydroxyurea, glutamine, or P-selectin inhibitors), the doses must be stable for at least 60 days prior to randomization.

  • Any one of the following vasculopathy biomarker clinical results (a, b, c, d or e) measured in the last 24 months before randomization that indicates a high-risk patient:

    1. Both a TRV 2.5- <3.0 m/sec and NT-proBNP plasma level ≥ 160 pg/mL,
    2. TRV ≥ 3.0 m/sec,
    3. Both a mean pulmonary artery pressure (PAP) by right heart catheterization 20-24 mmHg and NT-proBNP plasma level ≥ 160 pg/mL,
    4. Mean PAP by right heart catheterization ≥ 25 mmHg,
    5. Chronic kidney disease (CKD) due to SCD with abnormal measures on 2 separate occasions as defined by: macroalbuminuria (albumin to creatinine ratio (ACR) >300 mg/g) or proteinuria (protein to creatinine ratio >30 mg/mmol), or estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2. (It is recommended that local laboratories use Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] equation without ethnic factors when estimating and reporting GFR).

Clinical results of these biomarkers measured locally at sites within 24 months prior to randomization are acceptable to determine eligibility. TRV, PAP, NT-proBNP, albumin to creatinine ratio, protein to creatinine ratio, or eGFR values must be measured in a steady state (defined as measured ≥ 14 days since an acute care pain event) on different days.

vi. Written informed consent obtained from patient to participate in the trial.

Exclusion Criteria:

  • RBC alloimmunization resulting in inability of blood bank to obtain compatible components for chronic exchange transfusions
  • Previous history of hyper-hemolysis syndrome
  • Previous history of severe transfusion reaction resulting in renal failure or due to serious complications such as hypotension or respiratory distress
  • More than 10 vaso-occlusive episodes in the past 12 months requiring admission to a hospital to receive treatment.
  • Religious objection to receiving blood transfusion
  • Diagnosis of ischemic stroke within the past 6 months
  • Clinical evidence of liver failure or advanced cirrhosis or any co-existing medical condition that in the Investigator's judgement will substantially increase the risk associated with the patient's participation in the trial
  • Women of childbearing potential who have a positive pregnancy test at baseline
Contacts and Locations
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Information from the National Library of Medicine

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): NCT04084080


Contacts
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Contact: Jude Jonassaint, RN 919-219-7481 jonas@pitt.edu
Contact: Nydia Chien, MSN chienn@upmc.edu

Locations
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Sponsors and Collaborators
Gladwin, Mark, MD
National Heart, Lung, and Blood Institute (NHLBI)
Investigators
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Study Chair: Mark Gladwin, MD University of Maryland
Principal Investigator: Darrell Triulzi, MD University of Pittsburgh
Principal Investigator: Maria Brooks, PhD University of Pittsburgh
More Information
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Responsible Party: Mark Gladwin, Vice President for Medical Affairs, University of Maryland and Dean, University of Maryland School of Medicine, University of Maryland, Baltimore
ClinicalTrials.gov Identifier: NCT04084080    
Other Study ID Numbers: STUDY20110362
UG3HL143192 ( U.S. NIH Grant/Contract )
First Posted: September 10, 2019    Key Record Dates
Last Update Posted: February 21, 2023
Last Verified: February 2023
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Results from research conducted under this project will be shared in several ways. Manuscripts will be submitted for publication in high-quality peer-reviewed journals, following the NIH Public Access Policy guidelines. Findings will be presented at relevant national conferences, public lectures, scientific institutions and meetings. The timeline for participant recruitment, data collection and analysis will foster publication, facilitated by the investigators' Publications Committee, of critically important and clinically relevant data throughout the trial. The study datasets will be archived and made available to qualified individuals after a period of exclusive use by the SCD-CARRE trial research team and after publication of the primary manuscripts, following NIH guidelines.
Supporting Materials: Clinical Study Report (CSR)
Time Frame: At the end of the trial, study de-identified datasets will be submitted for permanent archive in the NHLBI BioLINCC repository. The trial will also produce deliverables that will be freely available to the sickle cell community including a description of the protocol for automated red blood cell exchange transfusion.
Access Criteria:

All publications based on the SCD-CARRE trial will adhere to the NIH Public Access Policy (Notice NOT-OD-08-033). All study data will be de-identified. At the end of the trial, study de-identified datasets will be submitted for permanent archive in the NHLBI BioLINCC repository.

The investigators also will work closely with regional and National SCD Foundations to promote recruitment for this study and communicate our results.

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Additional relevant MeSH terms:
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Anemia, Sickle Cell
Anemia, Hemolytic, Congenital
Anemia, Hemolytic
Anemia
 Hematologic Diseases
Hemoglobinopathies
Genetic Diseases, Inborn