Clinical trial NCT04084080: Sickle Cell Disease and CardiovAscular Risk - Red Cell Exchange Trial (SCD-CARRE)
Official title: Sickle Cell Disease and CardiovAscular Risk - Red Cell Exchange Trial (SCD-CARRE)
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Sickle Cell Disease
Lead sponsor: University of Pittsburgh
Sponsor class: OTHER
Collaborators: name: National Heart, Lung, and Blood Institute (NHLBI)
First posted: 2019-09-10
Enrollment: 173
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Eligibility 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. At the time of randomization, participants must be off Oxbryta for at least 30 days.
* 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

Primary outcomes:
measure: Episodes of clinical worsening
timeFrame: 13 months
Secondary outcomes:
measure: Acute healthcare event
timeFrame: 13 months
measure: Twelve-month survival
timeFrame: 13 months
measure: Survival free of acute healthcare encounters
timeFrame: 13 months
measure: Total number of acute health care encounters
timeFrame: 13 months
measure: Measures of exercise capacity - 6 minute walk distance
timeFrame: 4, 8, and 12 months
measure: Measures of exercise capacity - outpatient activity
timeFrame: 4, 8, and 12 months
measure: Cardiovascular risk
timeFrame: 12 months
measure: Development of new leg ulcers
timeFrame: 4, 8 and 12 months
measure: Measures of exercise capacity - WHO Classification
timeFrame: 4, 8 and 12 months
measure: Nocturnal desaturation
timeFrame: 4, 8 and 12 months
measure: SCD specific patient reported outcomes - Pain
timeFrame: 4, 8 and 12 months
measure: SCD specific patient reported outcomes -Quality of Life modified PROMIS scale
timeFrame: 4, 8 and 12 months
measure: SCD specific patient reported outcomes -Quality of Life modified ASCQ-Me scale
timeFrame: 4, 8 and 12 months
measure: Cardiovascular function by echocardiography - TRV
timeFrame: 4, 8 and 12 months
measure: Cardiovascular function by echocardiography - diastolic left heart function
timeFrame: 4, 8 and 12 months
measure: Cardiovascular function by echocardiography - systolic right heart function
timeFrame: 4, 8 and 12 months
measure: Total number of acute health care encounters
timeFrame: 13 months
Other outcomes:
Locations:
city: Tuscaloosa
country: United States
facility: University of Alabama
state: Alabama
city: Oakland
country: United States
facility: UCSF Benioff Children's Hospital Oakland
state: California
city: Washington
country: United States
facility: Howard University Center for Sickle Cell Disease
state: District of Columbia
city: Atlanta
country: United States
facility: Emory University
state: Georgia
city: Chicago
country: United States
facility: University of Illinois at Chicago
state: Illinois
city: Baltimore
country: United States
facility: University of Maryland
state: Maryland
city: Baltimore
country: United States
facility: Johns Hopkins University
state: Maryland
city: Boston
country: United States
facility: Boston Medical Center
state: Massachusetts
city: St. Louis
country: United States
facility: Washington University-St. Louis
state: Missouri
city: New York
country: United States
facility: Icahn School of Medicine at Mount Sinai
state: New York
city: New York
country: United States
facility: Montefiore Medical Center
state: New York
city: Chapel Hill
country: United States
facility: University of North Carolina at Chapel Hill
state: North Carolina
city: Charlotte
country: United States
facility: Atrium Health
state: North Carolina
city: Durham
country: United States
facility: Duke University
state: North Carolina
city: Greenville
country: United States
facility: East Carolina University
state: North Carolina
city: Cleveland
country: United States
facility: University Hospitals Cleveland Medical Center
state: Ohio
city: Columbus
country: United States
facility: Ohio State University
state: Ohio
city: Pittsburgh
country: United States
facility: University of Pittsburgh Medical Center
state: Pennsylvania
city: Houston
country: United States
facility: University of Texas Health Science Center at Houston
state: Texas
city: Richmond
country: United States
facility: Virginia Commonwealth University
state: Virginia
city: Rio De Janeiro
country: Brazil
facility: Hemorio
city: Créteil
country: France
facility: Kremlin-Bicêtre
city: Paris
country: France
facility: Henri Mondor Hopital
Study officials:
affiliation: University of Maryland
name: Mark Gladwin, MD
role: STUDY_CHAIR
affiliation: University of Pittsburgh
name: Darrell Triulzi, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Pittsburgh
name: Maria Brooks, PhD
role: PRINCIPAL_INVESTIGATOR
References: