Sickle Cell Disease and CardiovAscular Risk - Red Cell Exchange Trial (SCD-CARRE)
Study Details
Study Description
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 |
|---|---|---|
|
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
Arms and Interventions
| 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 Names:
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
Primary Outcome Measures
- Episodes of clinical worsening [12 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 12 months between groups.
Secondary Outcome Measures
- Acute healthcare event [12 months]
A 6-level prioritized rank-based outcome involving death and acute health care encounters with evidence of cor pulmonale, stroke, liver failure, acute kidney injury, or the acute chest syndrome during the 12 months of treatment and follow-up. 1.No death or SCD-related acute health care encounters within 12 months; 2.SCD-related acute health care encounter but NO major complications (acute kidney injury (AKI), acute chest syndrome (ACS), cor pulmonale, stroke, liver failure) or death within 12 months; 3.SCD-related acute health care encounter with 1 major complication (AKI, ACS, cor pulmonale, stroke, or liver failure) but no death within 12 months. 4.SCD-related acute health care encounter with 2 major complications (AKI, ACS, cor pulmonale, stroke, or liver failure) but no death within 12 months; 5.SCD-related acute health care encounter with 3 or more major complications (AKI, ACS, cor pulmonale, stroke, or liver failure) but no death within 12 months; 6.Death within 12 months.
- Twelve-month survival [12 months]
Survival over twelve-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.
- Survival free of acute healthcare encounters [12 months]
Survival free of acute health care encounters over 12 months.
- Total number of acute health care encounters [12 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).
- Measures of exercise capacity - 6 minute walk distance [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
- Measures of exercise capacity - outpatient activity [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.
- Cardiovascular risk [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.
- Development of new leg ulcers [4, 8 and 12 months]
Participants will be assessed for development of new leg ulcers at each physical exam.
- Measures of exercise capacity - WHO Classification [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)
- Nocturnal desaturation [4, 8 and 12 months]
Nocturnal desaturation will measured using a wearable device to measure blood oxygen saturation for 7 nights at home.
- SCD specific patient reported outcomes - Pain [4, 8 and 12 months]
SCD specific patient reported outcomes as measured by self-reported pain
- SCD specific patient reported outcomes -Quality of Life modified PROMIS scale [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
- SCD specific patient reported outcomes -Quality of Life modified ASCQ-Me scale [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
- Cardiovascular function by echocardiography - TRjv [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.
- Cardiovascular function by echocardiography - diastolic left heart function - E/A ratio [4, 8 and 12 months]
Diastolic left heart function measured by E/A ratio will be assessed by echocardiography.
- Cardiovascular function by echocardiography - diastolic left heart function - E/Em ratio [4, 8 and 12 months]
Diastolic left heart function measured by E/Em ratio will be assessed by echocardiography.
- Cardiovascular function by echocardiography - diastolic left heart function - deceleration time [4, 8 and 12 months]
Diastolic left heart function measured by deceleration time will be assessed by echocardiography.
- Cardiovascular function by echocardiography - systolic right heart function -E/Em ratio [4, 8 and 12 months]
Systolic right heart health will be measured by assessing right ventricular size from echocardiography of the heart
- Cardiovascular function by echocardiography - systolic right heart function - ventricular contractility [4, 8 and 12 months]
Systolic right heart health will be measured by assessing right ventricular contractility from echocardiography of the heart
- Cardiovascular function by echocardiography - systolic right heart function - TAPSE [4, 8 and 12 months]
Systolic right heart health will be measured by assessing tricuspid annular plane systolic excursion (TAPSE).
Eligibility Criteria
Criteria
Inclusion Criteria:
-
Age 18 years or older
-
Diagnosis of SCD: homozygous sickle cell disease, hemoglobin-SC, Sβ-thalassemia, hemoglobin-SO or hemoglobin-SD.
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Patients not on a chronic exchange transfusion program for at least 2 months.
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If patients are on hydroxyurea, glutamin, or selectin inhibitors the doses must be stable for at least 2 months prior to randomization.
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Any one of the following vasculopathy biomarker clinical results (a, b, c, d, or e) measured in the 13 months before randomization that indicates a high-risk patient:
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Both a TRV 2.5-2.9 m/sec and NT-proBNP plasma level ≥ 160 pg/mL,
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TRV ≥ 3.0 m/sec,
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Both a mean pulmonary artery pressure (PAP) by right heart catheterization 20-24 mmHg and NT-proBNP plasma level ≥ 160 pg/mL,
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Mean PAP by right heart catheterization ≥ 25 mmHg,
-
Chronic kidney disease (CKD) due to SCD with macroalbuminuria (albumin creatinine ratio (ACR) >300 mg/g) on 2 occasions, or proteinuria (protein creatinine ratio
30 mg/mmol) on 2 occasions, or estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2 calculated on 2 occasions.
- 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
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Previous history of hyper-hemolysis syndrome
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Previous history of severe transfusion reaction resulting in renal failure or due to serious complications such as hypotension or respiratory distress
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More than 10 vaso-occlusive episodes in the past 12 months requiring admission to a hospital to receive treatment.
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Religious objection to receiving blood transfusion
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Diagnosis of ischemic stroke within the past 6 months
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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
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | University of Alabama | Tuscaloosa | Alabama | United States | 35401 |
| 2 | UCSF Benioff Children's Hospital Oakland | Oakland | California | United States | 94609 |
| 3 | Howard University Center for Sickle Cell Disease | Washington | District of Columbia | United States | 20060 |
| 4 | Emory University | Atlanta | Georgia | United States | 30322 |
| 5 | University of Illinois at Chicago | Chicago | Illinois | United States | 60607 |
| 6 | Johns Hopkins University | Baltimore | Maryland | United States | 21206 |
| 7 | Boston Medical Center | Boston | Massachusetts | United States | 02118 |
| 8 | Washington University-St. Louis | Saint Louis | Missouri | United States | 63110 |
| 9 | Icahn School of Medicine at Mount Sinai | New York | New York | United States | 10029 |
| 10 | Montefiore Medical Center | New York | New York | United States | 10461 |
| 11 | University of North Carolina at Chapel Hill | Chapel Hill | North Carolina | United States | 27599 |
| 12 | Atrium Health | Charlotte | North Carolina | United States | 28204 |
| 13 | Duke University | Durham | North Carolina | United States | 27708 |
| 14 | East Carolina University | Greenville | North Carolina | United States | 27834 |
| 15 | Ohio State University | Columbus | Ohio | United States | 43210 |
| 16 | University of Pittsburgh Medical Center | Pittsburgh | Pennsylvania | United States | 15232 |
| 17 | University of Texas Health Science Center at Houston | Houston | Texas | United States | 77030 |
| 18 | Virginia Commonwealth University | Richmond | Virginia | United States | 23284 |
| 19 | Henri Mondor Hopital | Paris | France | ||
| 20 | Imperial College Healthcare NSH Trust-Hammersmith Hospital | London | United Kingdom | W12 0HS |
Sponsors and Collaborators
- Mark Gladwin
- National Heart, Lung, and Blood Institute (NHLBI)
Investigators
- Principal Investigator: Mark Gladwin, MD, University of Pittsburgh
- Principal Investigator: Darrell Triulzi, MD, University of Pittsburgh
- Principal Investigator: Maria Brooks, PhD, University of Pittsburgh
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- PRO19030018
- UG3HL143192