Bethesda, Maryland

November 6, 2006


Dr. F. Daniel Armstrong (chair), University of Miami, Dr. Frans Kuypers, Children’s Hospital of Oakland Research Institute, Dr. Russell Ware, St. Jude Children’s Hospital, Ms. Shirley Miller, Southwestern Comprehensive Sickle Cell Center, Dallas, Dr. Johnson Haynes, University of South Alabama, Dr. Dorothy Moore, Boonton New Jersey, Dr. Eugene Orringer, University of North Carolina, Chapel Hill, Dr. Michael Bender, Fred Hutchinson Cancer Research Institute, Dr. Punam Malik, Children’s Hospital of Los Angeles


Dr. Michael DeBaun, Washington University of Saint Louis, Dr. Kim Smith-Whitley, Children’s Hospital of Philadelphia


Ms. Tracy Becker, American Society of Hematology, Dr. Marie Mann, HRSA, Ms. Judy Hagopian, HRSA, Ms. Lorraine Brown, HRSA, Dr. Joseph DeSimone, Veterans Administration (Illinois, Chicago), Dr. Roshni Kulkarni, Center for Disease Control, Dr. Marie Early, CDC, Dr. Willarda Edwards, Sickle Cell Disease Association of America (SCDAA), Ms. Sonja Ross, SCDAA, Dr. William Winter, Howard University


Dr. Greg Evans, NHLBI, Dr. Ellen Werner, NHLBI, Dr. Harvey Luksenburg, NHLBI, Dr. Kathryn Hassell, NHLBI, Dr. Pankaj Qasba. NHLBI, Dr. Chuck Peterson, NHLBI, Dr. Susan Shurin, NHLBI, Dr. Terry Bishop, NIDDK

Executive Secretary: Dr. Blaine Moore with the assistance of Ms. Petronella Barrow.


    Dr. Blaine Moore called the meeting to order at 8:30 am, welcomed everyone to the meeting and provided brief remarks regarding the agenda. Dr. Moore turned the meeting over to Dr. Armstrong, the chair of the committee.

    Dr. Armstrong requested an approval to the minutes which had been distributed to them previously. The minutes were approved. Next, Dr. Armstrong introduced Dr. Susan Shurin, the Deputy Director of the National Heart, Lung and Blood Institute and invited her to share perspectives from the Institute.

    Dr. Shurin greeted everyone and expressed the interest of the Institute in sickle cell disease. She acknowledged that the budget, at this time, is decreasing at a time when the number of investigators and the number of applications submitted to the NIH are increasing. This is a challenge not only for NHLBI but for all of the institutes at NIH. She mentioned that this funding limitation may ease up over the next few years as large grant programs within the Institute come to a close. Dr. Shurin also stated that the Institute was developing a strategic plan for the Institute and that phase II has been completed. A final draft of the plan is expected in the winter/spring of 2007. The first CTSA programs are now beginning and three of them are with investigators who are funded by the Institute. There may be more sites funded as this program continues over the next couple of years. It is hoped that surrounding institutions will take advantage of these clinical resources.


    The first presenter was Dr. Ramesh Pandey from Xechem Co. . Support personnel included Dr. Renuka Misra, Dr. Peter Gillette, and Dr. Don Abraham. Dr. Pandey presented new information on two anti-sickling drugs that have great potential, NICOSAN and 5-HMF (5-hydroxy methyl-2-furfural). 5-HMF is a water-soluble aldehyde that is easily absorbed, slowly metabolized and free of any significant side effects. It is a strong anti-sickling agent by virtue of its ability to shift the oxygen saturation curve of hemoglobin to the left, thereby making it more difficult to polymerize. In the sickle mouse model, 5-HMF significantly extends the survival time following episodes of hypoxia. Concentrations up to 3 mM effecting 95% of the available hemoglobin have been obtained. NICOSAN is an herbal extract from four separate plants. In addition to its anti-hemoglobin S polymerization properties it acts to hydrate the cells. This counteracts the dehydration of cells that often occurs during reversible sickling. Dehydration concentrates the hemoglobin and makes it more susceptible to polymerization.

    The second presenter was Dr. Knox Todd, Professor at Albert Einstein College of Medicine and Director of the Pain and Emergency Medicine Institute at the Beth Israel Medical Institute. The title of his talk was, “Strategic Partnering for Sickle Cell Research: Emergency Medicine Opportunities. Dr. Todd indicated that there is a consortium of physicians in the United States and Canada who are interested in the treatment of Sickle Cell Patients for Pain in Emergency Rooms. They are collecting data on treatment of SCD patients with drugs such as meperidine, morphine, dilaudid, ketorolac and Oxycodone in both adults and children. The route of giving pain medicines, e.g. intramuscularly, IV (bolus or slow drip), orally, is of interest to determine the most effective treatment. The tests that accompany pain therapy has been surveyed, in particular, CBC, reticulocyte counts, blood cultures, urinalyses, chest X-rays and pulse oxymetries. Questionnaires have been distributed to assess ER physicians and hematologists about their viewpoints on pain medicine use in this cohort of patients. Finally the consortium has prepared a manual for the treatment of pain in sickle cell patients and submitted it to the American Pain Society Guidelines.


    Dr. Armstrong indicated that this is his first meeting as the chair and that he was honored to be selected for this position. He stated that he would like to develop action items from the recommendations of the minutes today and evaluate them for progress at future meetings. Dr. Moore indicated that this might be useful to do for past meetings as well.


    Health Resources and Services Administration: Dr. Marie Mann, Ms. Judy Hagopian and Ms. Lorraine Brown were present at the meeting. Dr. Mann provided the report to the Advisory Committee. She stated that HRSA’s Maternal and Child Health Bureau (MCHB) has two sickle cell disease (SCD) initiatives. One initiative, the SCD and newborn screening program (SCD-NS), funds 17 sites across the nation and a national coordinating center. The current grantee for the coordinating center is the Sickle Cell Disease Association of America (SCDAA). The SCD-NS grantees are focusing on educational and counseling activities for affected children and SCD carriers and their families. A major activity is the development of a minimum dataset that may serve as a model for other SCD projects. The second initiative is the Sickle Cell Disease Treatment Demonstration program, which was authorized by the Talent legislation. This demonstration program was appropriated $2 million dollars in fiscal year 2006 with the goal of increasing access to comprehensive quality care for individuals with SCD. Four sites located in Alabama, Illinois, North Carolina, and Ohio received funding to establish networks made up of comprehensive sickle cell centers, community-based SCD support organizations and ambulatory primary care delivery entities, specifically Federally-qualified community health centers. These networks will seek to coordinate efforts around education and training, up-to date treatments, and continuity of care and services for individuals with SCD. RTI in North Carolina received a contract to serve as the national coordinating center for the program with a focus on collection and dissemination of data, best practices and findings related to the program. Finally, MCHB funds seven regional collaborative sites (RC) across the nation under the Heritable Disorders Program (HDP). The RC’s work to provide coordination of regional genetic programs to enhance equitable access to genetic services; and to address related genetics and newborn screening issues such as best practice models for transitioning from pediatric to adult care. A federal advisory committee, the Advisory Committee on Heritable Disorders and Genetic Diseases in Newborns and Children, provides advice and recommendations to the HHS Secretary in matters related to heritable disorders and the HDP.

    Veterans Administration: Dr. Joseph DeSimone reported that the VA is experiencing the funding shortfall as are all agencies within the government at this time. During these times of limited funds, the VA shows less interest in Sickle Cell Disease, particularly in gene regulation studies.

    Sickle Cell Disease Association of America: Dr. Willarda Edwards, the COO and President of SCDAA reported on the very successful convention that their association had in Dallas in September 2006. She also informed the group that they are pleased to work with the National Heart Lung and Blood Institute to arrange a combined Sickle Cell meeting in Washington DC in September 2007.

    Center for Disease Control: Dr. Roshni Kulkarni and Dr. Marie Early attended the meeting on behalf of the CDC. Dr. Kulkarni acknowledged that the CDC is supporting efforts in hemophilia, thalassemia and Diamond Blackfan Anemia. She expressed an interest in developing a program at CDC that would involve patients with sickle cell disease. She was appreciative of being invited to the Advisory Committee meeting.


    Dr. Charles Peterson gave a presentation of some of the changes taking place at NHLBI and what programs are being considered for the future. First, the NHLBI logo has changed and there have been some changes to the infrastructure of the Heart and Epidemiology Divisions. The Blood Division has 3 branches, the Blood Diseases Branch, the Transfusion Medicine and Cell Therapies Branch and the Thrombosis and Hemostasis Branch. Currently, the Division is recruiting for three positions, the Deputy Director of the Division, a Medical Officer for the Hemostasis and Thrombosis Branch and a Medical officer for the Blood Diseases Branch.

    Sickle Cell Disease is a major focus of research effort for the Blood Diseases Branch and for the Division as a whole. Since 1972, over 1 billion dollars has been put in to studying sickle cell disease. There have been a number of successful programs and clinical trials that include: the comprehensive sickle cell centers; the Cooperative Study for Sickle Cell Disease, the PROPS studies to prevent septicemia in young children with SCD,; the STOP studies and the SWiTCH trial to identify and manage SCD patients who are at risk of having a stroke or who have had a stroke; the hydroxyurea trials such as MSH, HUG Kids and Baby HUG testing the therapeutic benefits of this drug for adults, children and infants; and now the Sickle Cell Disease Clinical Research Network to perform phase III clinical trials. As a result of these efforts, sickle cell patients are now living longer with an improved quality of life. One of our new challenges is the care of adult patients who have chronic disease.

    One of NHLBI’s new approaches is to break down existing silos and to develop partnerships among our clinical studies, our networks, our agencies and our global community. In a time of constricting resources it is necessary to create synergistic relationships. Even now, we have contacts with the Food and Drug Administration, the Health Resources and Services Administration, the Center for Disease Control, the Veterans Administration, the Fogarty International Center, the Sickle Cell Disease Association of America and other institutes within NIH. However, we can extend this list to include epidemiological groups (e.g. NHANES etc.), industry and small businesses. Leveraging big programs such as genomics and proteomics and stem cell facilities will be advantageous.


    Comprehensive Sickle Cell Centers: There are 10 centers that are currently funded each of which conduct clinical and basic research. Several also perform education and community outreach. The program has developed a Clinical Trials Consortium (CTC), the purpose of which is to carry out multi-center phase I/II studies on sickle cell disease. At present, there are eight projects that are underway and a ninth that is to be put before the CSCC PRC in early 2007. A list of the projects was handed to the committee and there was brief discussion about some of the projects.

    The open renewal competition for CSCC grant applications will occur during 2007. The receipt date for the applications is January 23, 2007 and the review date will occur sometime between May and July of 2007.

    SCD CRN: The members of the Protocol Review Committee and the DSMB have been selected and approved. The rosters are now near completion. There are three protocols that are currently in development:

    • Preventing Acute Chest Syndrome by Transfusion Trial - “PROACTIVE.
    • Renoprotective Effect of Angiotensin II Blockade with Losartan in Albuminuric Patients with Sickle Cell Nephropathy.
    • Genetic Basis of Variability of Opioid Response in Sickle Cell Pain

    Each of these protocols has had a protocol sub-committee that consists of the author of the study, plus three or four members of the Steering Committee. Each of these three sub-committees is currently working on various logistical and statistical problems in the protocols. It is anticipated that at least two of these protocols should be ready to accrue patients in late spring or early summer 2007.

    SWiTCH Clinical Trial: The purpose of the multi-centered trial is to determine if sickle cell children who have already experience a stroke can switch therapy from transfusion plus iron chelation to oral hydroxyurea plus phlebotomy. The trial involves 22 clinical sites, of which 16 have been activated (72%). The protocol has been open to enroll subjects for 3 weeks, and 5 subjects have been enrolled thus far. The primary site is St. Jude Children’s Hospital and Research Institute and Dr. Russell Ware is the principal investigator. The Data Coordinating Cite for the trial is Rho Inc. and the principal investigator is Dr. Ron Helms. The Data and Safety Monitoring Board for the SWiTCH trial has met and approved the final version of the protocol.

    Sickle Cell Health Related Quality of Life: This NHLBI-funded contract completed year 1 of this 3-year project. The contractor is the American Institutes for Research (AIR), under the direction of Dr. San Keller, the co-developer of the SF-36 (to assess generic health-related quality of life). During the first year, a comprehensive literature search was conducted on health-related quality of life issues related to sickle cell disease, draft taxonomy was created of issues (“domains”), patients and providers were interviewed to revise and validate the taxonomy, and critical incidents were coded from those interviews to identify important events that impact patients’ quality of life. The AC asked if NHLBI will require all investigators to use this SCHRe-QoL questionnaire. Dr. Werner replied that we will not require that, but if investigators plan to compare SCD patients to each other (e.g., in a clinical trial) or to themselves (e.g., in a cohort study), then it would not make sense for them to use a generic instrument. A study section should be able to recognize the mismatch between investigators’ hypotheses and measurement tool. On the other hand, if investigators plan to compare SCD patients to another patient population, such as asthma, then the SF-36 or similar generic tool, is appropriate.

    Working Group on Health Objectives in Sickle Cell Disease: The NHLBI held a Working Group on Health Objectives in SCD on September 15-16, 2006. A draft report has been written that is under review by participants. The report will be posted on the NHLBI website.

    Best Practices in Pain Management: The Development of Best Practices for the Management of Acute and Chronic Pain in Adults with Sickle Cell Disease was held on September 25-27, 2006 in Dallas, in conjunction with the National Annual SCDAA Meeting. This activity was supported by an R-13 Conference Grant from the Office of Rare Diseases and the Office of Dietary Supplements, awarded to Dr. Kathy Hassell. A multidisciplinary expert panel led by the Dr. Jim Eckman addressed the development of best practices for pain management in the areas of Emergency Medicine, Acute/Inpatient Services, Chronic Pain, and Implementation. The results of the conference were presented and open to commentary in a public forum during the SCDAA meeting. A preliminary report has been submitted to the Office of Rare Diseases, and a full proceedings of the meeting should be available by February, 2007.

    Baby HUG Phase III Clinical Trial: The primary objectives of this multi-center trial are to determine if hydroxyurea can prevent damage to kidneys and spleens of infants with sickle cell disease. The trial consists of 14 clinical centers headed up by Dr. Winfred Wang of St. Jude Children’s Hospital and a Data Coordinating Center headed up by Dr. Bruce Thompson of C-TASC. The target enrollment is 200 patients. Currently, the trial has screened 174 patients and randomized132. The trial was temporarily placed on hold for two months between April and June of this year to correct the labels on the containers.

    MSH Patients Follow-up Cohort Trial: The multi-center study for hydroxyurea (MSH) occurred in the 1990’s to determine if this drug would be beneficial to adult patients with sickle cell disease. Following the trial a patient follow-up contract was established over a 10 year period beginning in 1997. This contract was established in two parts, an initial follow-up period in the first five years and an extension of this follow-up in the second five years. At present the contract is ending year 4 of the extension or year 9 of the entire follow-up phase. The purpose of the follow-up extension has been to assess any changes in morbidity or mortality as a consequence of taking the drug as well as any adverse events, particularly cytogenetic changes and occurrences of any malignancies in the cohort. It is believed that many of these questions are now able to be answered from the currently obtained data and the plan is to halt patient visits as of December 31, 2006. Year 10 of the follow-up will focus on completing any final analyses which need to be performed on samples already taken and to prepare and submit final publications associated with the trial and the follow-up.

    Pulmonary Complications of Sickle Cell Disease: The Pulmonary Complications of Sickle Cell Disease RFA was funded in July 2005. This initiative encourages collaborative research between investigators in hematology and pulmonary science that combines basic and clinical approaches. The funded program (five grants) includes multidisciplinary basic and clinical research on all the important (known) pulmonary complications of sickle cell disease- vasculopathy due to hemoglobin desaturation, asthma, pulmonary hypertension, and acute chest syndrome. A significant amount of human genetics work is also included. The second PI meeting took place in August 2006 as part of the annual Fall Sickle Cell Clinical Meetings that DBDR organizes every year at NIH. Since the initiative was funded, all five projects have submitted at least one clinical protocol to the DSMB and all five of these protocols are now active.

    Sildenafil Trial: Treatment of Pulmonary Hypertension in SCD: This trial was funded in September 2006. Its purpose is to evaluate the use of sildenafil (Viagra) to improve exercise capacity and health-related quality of life for adult patients with sickle cell disease-associated pulmonary hypertension. This condition is very serious in adults as it comes with a 50% mortality risk only two years after diagnosis. The funded program includes nine contracts plus the intramural NHLBI. DSMB review of this protocol has begun, and enrollment is expected to begin in the Spring of 2007.

    The following is a comment from a member of the Advisory Committee regarding the Sildenafil Trial: All patients enrolled into this trial with a Tricuspid valve regurgitation jet (TRJ) velocity of 2.5 m/sec should be randomized and/or included in patients to have right heart catheterization. Patients who undergo right heart catheterization (RHC) with a mean pulmonary artery pressure less than 25 at rest should be considered a false positive and not receive life-long sildenafil. The cost of RHC as compared with the cost of life-long sildenafil is probably less. There is no difference in risk reported based on the TRJ velocity. It is important for the study to determine if the intent is to investigate sildenafil as a therapeutic option for pulmonary hypertension or for a TRJ velocity above 2.5 m/sec.


    The Sickle Cell Disease Advisory Committee recognizes the recent restriction in government funds for research, however, the committee is disappointed by the decreased interest expressed by the Veterans Administration in sponsoring research for sickle cell disease. Previously sponsored research into novel therapies to increase hemoglobin F levels in patients with sickle cell disease to reduce or prevent sickling have been promising and it is hoped that the VA will renew its interest as soon as funds allow.

    The SCDAC would like to be sent a copy of the NHLBI Strategic Plan draft when it becomes available in the New Year.

    The SCDAC will be reviewing past recommendations to assess if there are any action items that have not been achieved.



    June 4, 2007

    Novermber 5, 2007

    ___________________________                                    _____________
    Dr. F. Daniel Armstrong                                                   Date
    Sickle Cell Disease Advisory Committee

    ___________________________                                     ______________
    R. Blaine Moore PhD                                                        Date
    Executive Secretary
    Sickle Cell Disease Advisory Committee

    Last updated: October 28, 2007

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