Sickle Cell Disease Workshop: Clinical Priorities and Clinical Trials

DoubleTree Hotel & Executive Meeting Center
8120 Wisconsin Avenue
Bethesda, Maryland 20814

October 22-24, 2008

Background Document
Working Group on Sickle Cell Disease:
Clinical Priorities/Clinical Trials, Bethesda, Maryland, October 22–24, 2008

Harvey Luksenburg, M.D., NHLBI
Kathryn Hassell, M.D., University of Colorado, NHLBI
Susan B. Shurin, M.D., NHLBI

Sickle Cell Disease (SCD) is an autosomal recessive disorder of the beta globin molecule that causes hemoglobin molecules polymerize in hypoxic areas of microvasculature, distorting the red blood cell. These red blood cells occlude and adhere to the microcirculation, resulting in local injury, which may also stimulate vascular remodeling. Shortened erythrocyte survival causes chronic hemolysis and anemia, and intravascular hemolysis results in depletion of nitric oxide. This results in vascular damage. Beginning in early childhood, these processes result in damage to virtually all organs. Progressive damage with loss of function is seen in the spleen, lung, kidneys and bone, with many patients also experiencing damage to brain. The cardinal symptom of SCD at all ages is severe acute pain (crisis) due largely to chronic cycles of microvascular blockage and reperfusion. The modern era of therapy of SCD, which started in the 1970’s, has led to a prolongation of the median lifespan from less than 10 to 50 years of age or greater in 2008, due largely to prevention of deaths from infection, acute exacerbations of anemia, and selective use of chronic transfusion. The variation in phenotypic expression is striking and is imperfectly understood. Some patients have severe debilitating complications beginning in the first year, while others have few clinical problems, although even patients with moderate disease and relatively little pain may have a reduced lifespan with progressive chronic organ damage.

Broadly speaking, childhood in SCD is dominated by acute syndromes (pain, strokes, splenic events and acute chest syndrome). Stroke occurs in about 11% of subjects before the age 20. SCD is the most common cause of stroke in childhood. A major advance occurred in the 1980s, with the ability to prospectively identify children at high risk of stroke by transcranial Doppler, a non-invasive technique for determining flow velocity in the larger intra-cranial arteries, which is the site of most obstructive lesions in SCD. The development of this technology led to the STOP I and II studies which demonstrated that placing high risk children on a chronic red cell transfusion regimen dramatically decreased the stroke risk. The incidence of overt stroke has decreased significantly.

Adulthood in SCD is characterized by the consequences of the ongoing sequelae of microvascular damage (acute and chronic pain, cardiac, pulmonary, renal, and neurologic disease), and macrovascular damage from the consequences of hemolysis, which appears to factor heavily in the etiology of damage to cerebral and pulmonary vessels. In the last decade a syndrome of pulmonary hypertension, which is often clinically silent, has been discovered to be present in about 30% of adults, and has been shown to be associated with an increased risk of mortality.

SCD is one of the few diseases associated with severe pain that begins in childhood and persists throughout life. Sickle cell painful crisis is the leading cause of emergency department visits and hospitalizations in these patients, but it has been increasingly clear that many adults, up to 50%, suffer from severe chronic pain. In the most severely affected children and adolescents the frequent painful episodes lead to disruption of school attendance, and in adults, to problems with maintaining employment. The management of pain makes use of the entire panoply of narcotics, anti-inflammatory agents and various adjuvant therapies, but pain relief in all clinical syndromes, acute and chronic, is often inadequate.

One drug, hydroxyurea, is FDA-approved for use in SCD. An NHLBI-sponsored Phase III clinical trial conducted in the 1990s, demonstrated a reduction in painful crises in a subgroup of SCD patients who had a baseline rate of greater than three such crises per year. No other Phase III trials have been completed to assess the efficacy of HU in children, adolescents, or adults with less severe disease. No high-quality trials have been completed that demonstrate modification of organ damage by the long-term use of hydroxyurea. NHLBI is currently sponsoring two Phase III trials that may add important new information: BABYHUG, which will assess the efficacy of (liquid) hydroxyurea administered to infants in the modulation of early organ damage to the spleen and kidney; and SWiTCH, where children who have had a stroke and are on transfusion therapy (current standard of practice) will be transitioned to a regimen of hydroxyurea. In February, 2008, the NIH held a Consensus Development Conference on Hydroxyurea in Sickle Cell Disease.http://www.annals.org/cgi/content/full/148/12/932, which confirmed a widespread impression that only a small number of adult patients with SCD who might benefit are actually receiving hydroxyurea.

Hematopoietic stem cell transplantation (HSCT) offers a curative intervention for children with SCD and a matched sibling donor. Reduced intensity conditioning regimens, use of unrelated donors, and HSCT for adults with SCD have not been studied in large multi-center trials.

NHLBI Sponsored Clinical Trials in Sickle Cell Disease

In 1972, Congress passed the National Sickle Cell Anemia Control Act, which mandated federal government programs for diagnosis, control, treatment and research in SCD. The NIH was designated as the lead agency to accomplish these goals. One of the major outcomes of this emphasis were the NIH-funded Cooperative Study of Sickle Cell Disease, (CSSCD), a large-scale, multi-institutional epidemiological study that collected data on subjects from infancy to the sixth decade, which enrolled subjects from 1978-1988, and sustained data collection on some cohorts through 1998.

NHLBI also funded several multi-center studies between the 1980s and 1990s that served as landmarks in the understanding and treatment of SCD:

A second major outcome of the 1972 Act was the creation of the Comprehensive Sickle Cell Centers (CSCC), a group of ten clinical sites that provided multi-disciplinary care of patients as well as support of basic and clinical research. In the 1990s, individual Center principle investigators conducted multi-centers studies of preoperative transfusion and acute chest syndrome. Beginning in 2003, the CSCC formally initiated several phase II multi-center clinical studies and completed a multi-center Phase II clinical trial of arginine supplementation.

In 2005, NHLBI funded the Sickle Cell Disease Clinical Research Network, which was established specifically to carry out Phase III clinical studies. At present, this Network is on track to begin accrual to two such trials. One of these trials will investigate the efficacy of Losartan, an angiotensin II receptor antagonist, to reduce the incidence of microalbuminuria and macroalbuminuria in older children and adults. The other trial (PROACTIVE) is concerned with the preventative therapy of acute chest syndrome, a condition that frequently leads to respiratory and multi-organ failure and is often fatal.

The Rationale for this Working Group

In March 2008, the Director of NHLBI, Elizabeth Nabel, MD, announced a restructuring of the Sickle Cell Program.

http://www.nhlbi.nih.gov/meetings/workshops/Sickle-Cell-Announcement.htm

The recent issuance of the NHLBI Strategic Plan, a blueprint of the Institute’s basic and clinical research priorities for the next five to ten years, and the renewal process for the Sickle Cell Centers Program, provided the opportunity for this re-assessment. The Director first publicly solicited comments from all interested parties (academics, patients, advocacy groups, etc.). A Sub-Committee was formed consisting of distinguished hematologists who are current members of the NHLBI Advisory Council. This Sub-Committee’s report provides the conceptual basis for the restructuring.

(http://www.nhlbi.nih.gov/resources/docs/scd_program.htm)

In response to the recommendations from Council, NHLBI funded the most meritorious components of the submissions to the RFA initially issued for the CSCC program and created two transitional groups: the Basic Translational and Research Program (BTRP), consisting of twelve sites that carry out basic and translational I and II projects; and the Clinical Trials Consortium, which will complete the multi-center Phase II trials that had been initiated under the CSCC. The Sickle Cell Disease Clinical Research Network is in the middle of its five year funding cycle.

Thus, it is now an opportune time to think about the next generation of clinical trials for SCD. A major feature of this Working Group is the participation of relevant specialists who are not primarily SCD investigators.

This Working Group has two objectives:

1. To determine the major clinical priorities of trials in sickle cell disease.
The areas of clinical priority are based on the Advisory Council Sub-Committee’s report, in which eight were identified: Pain, Pulmonary/Cardiac, Renal, Patient Outcomes/Epidemiology, Neurology, Vascular Disease/Pathophysiology, Bone Marrow Transplantation, and Hemoglobin F Modulation. Sub-Committees for all of these high priority areas are being convened, and they will be asked to propose Phase II and III clinical trials that will address the most urgent clinical questions in each field.

2. To form a clinical trials framework that will allow maximal accessibility to patients and qualified investigators.
The second objective of this Working Group is the determination of the optimal organizational structure for the implementation of these trials. NHLBI is seeking expertise from clinical trialists in diseases that have faced similar challenges: HIV, asthma, pediatric and adult oncology. NHLBI is eager to leverage investments in other clinical trial infrastructure, and to create a highly flexible and nimble approach accessible to interested investigators and patient participants, as well as to reach deeply into communities in which they live.

Obstacles in Clinical Trials in Sickle Cell Disease

Sickle cell patients are predominantly African American. Many are of low socioeconomic status with a high burden of disease. All struggle with a condition which requires lifelong attention, acute and chronic pain relief, episodic exacerbations which make it difficult for them to stay in school and hold stable employment. Few adult patients are covered by Medicaid, and often do not have a medical home or access to medical caregivers with expertise in SCD.

Some of the major obstacles to the implementation of clinical trials in SCD:

  • Fragmentation of care: Most clinical trials are conducted on the backbone of a system which provides access to medical care. Children with SCD are more likely to receive integrated care than adults, but their care is highly dependent on the availability of local expertise. For most patients older than 18, access to specialist care is fragmentary, with a dearth of qualified hematologists with an interest in SCD. Patients with painful crises and acute complications seek care in emergency departments or urgent care settings, rather than in a stable system which might facilitate access to and participation in research protocols.
  • Lack of outside sources of funding: Most successful specialty networks leverage research dollars with support from patient care, philanthropy and pharmaceutical industry sources. To date, new agents for SCD likely to attract the interest and support of the pharmaceutical industry have not appeared.
  • Disease-specific: Patients with SCD have a chronic disease marked by recurrent pain. Many patients have cognitive dysfunction as a result of repeated vascular damage to their brains over the course of a lifetime.
  • Patients with SCD have difficulty completing their education due to their repeated medical problems, and often have difficulty serving as their own advocates.
  • It is frequently difficult to identify eligible subjects with SCD and to enroll them into clinical trials. Most studies have enrolled subjects from urban areas predominantly, and many patients are not seen consistently in academic centers. Many trials require a series of baseline clinical and laboratory assessments. The occurrence of acute events that disrupt this baseline status, such as crises and infections, is a frequent obstacle to accrual.
  • It is difficult for a small number of research sites, even those with large potential subject populations, to complete successful multi-center studies in sickle cell disease due to the heterogeneity of the disease and its manifestations, and the increasing use of disease modifying therapies. Experience suggests at least 20 sites are necessary to successfully enroll subjects in sickle cell disease trials.
  • Interventions demonstrated to be effective are often poorly implemented in the population which may benefit. This is true for use of hydroxyurea and TCD. Little research emphasis has been placed on effectiveness, such that advances in the management of the disease do not appear to be realized by a significant portion of the affected population.

Goals of a Clinical Trial Framework:

Optimally, a new clinical trial framework should incorporate the following goals:

  • Maximum access to care to the majority of the US SCD population. The current NHLBI Sickle Cell Disease institutions care for fewer than 9% of the estimated population of SCD patients.
  • Opportunity for all qualified investigators to participate. There are numerous medical centers both with and without academic affiliations that have access to patients, are staffed by investigators with expertise and enthusiasm, and have the infrastructure necessary to conduct clinical research. Many of these institutions have not been part of previous NHLBI sponsored SCD studies.
  • A level playing field for investigators. Any participating investigator, or group of investigators, should have an opportunity to propose, develop and lead a given protocol as principal investigator, if the study is adopted by the clinical trial framework.
  • Utilize existing infrastructure to the extent possible so that the framework retains a high degree of flexibility and responds to, rather than determines, the scientific agenda. Use of the CTSA and other infrastructure should be considered to provide mutual benefit to the SCD communities and existing infrastructures, enable studies to be started and completed quickly, ensure access to subjects in community settings, and exploit support systems for investigators for training, coordinator and data support, and bioinformatics.