Full Text HL-97-013
 
CLINICAL RESEARCH ON COOLEY'S ANEMIA
 
NIH GUIDE, Volume 26, Number 25, August 1, 1997
 
RFA NUMBER:  HL-97-013
 
P.T.


Keywords: 

 
National Heart, Lung, and Blood Institute
National Institute of Diabetes and Digestive and Kidney Diseases
 
Letter of Intent Receipt Date: October 15, 1997
Application Receipt Date:  January 8, 1998
 
PURPOSE
 
The Blood Diseases Program of the Division of Blood Diseases and
Resources, National Heart, Lung, and Blood Institute (NHLBI), and the
Hematology Program of the Division of Kidney, Urologic and
Hematologic Diseases, National Institute of Diabetes and Digestive
and Kidney Diseases (NIDDK), invite grant applications for support of
research efforts to improve the clinical management of patients with
Cooley's anemia (beta-thalassemia).  The focus of this initiative is
to support clinically-related or translational research.  Areas of
particular importance include studies on improved methods for the
non-invasive measurement of tissue iron burden, alternative
approaches to iron chelation therapy, and pharmacologic enhancement
of fetal hemoglobin.
 
HEALTHY PEOPLE 2000
 
The Public Health Service (PHS) is committed to achieving the health
promotion and disease prevention objectives of Healthy People 2000, a
PHS-led national activity for setting priority areas.  This request
for applications (RFA), Clinical Research on Cooley's Anemia, is
related to the priority area of maternal and infant health, and
diabetes and chronic disabling diseases.  Potential applicants may
obtain a copy of "Healthy People 2000" (Full Report:  Stock
No.017-001-00474-0 or Summary Report: Stock No. 017-001-00473-1)
through the Superintendent of Documents, Government Printing Office,
Washington, DC 20402-9325 (telephone 202-512-1800).
 
ELIGIBILITY REQUIREMENTS
 
Applications may be submitted by domestic and foreign, for-profit and
nonprofit organizations, public and private, such as universities,
colleges, hospitals, laboratories, units of State or local
governments, and eligible agencies of the Federal government.
Racial/ethnic minority individuals, women, and persons with
disabilities are encouraged to apply as Principal Investigators.
Domestic applications may include foreign components. FOREIGN
INSTITUTIONS: Awards under this announcement may be made to foreign
institutions provided the application (1) is of high scientific merit
and (2) offers a special opportunity for furthering research programs
through the use of unusual talents, resources, populations, or
conditions in other countries which are not readily available in the
United States or which augment existing U.S. resources.
 
All current policies and requirements that govern the research grant
programs of the NIH will apply to grants awarded under this RFA.
 
MECHANISM OF SUPPORT
 
This RFA will use the NIH Research Project grant (R01) mechanism of
support. Responsibility for the planning, direction, and execution of
the proposed project will be solely that of the applicant.
Applicants, including those from foreign institutions, may request up
to five years of support.
 
It is anticipated that support for this program will begin in July
1998.  Administrative adjustments in project period and/or amount may
be required at the time of the award.
 
This RFA is a one-time solicitation.  Successful applicants, upon
completion of their entire project period (up to five years) may
submit an unsolicited competing renewal application which will
compete with all investigator-initiated applications and be reviewed
according to the customary peer review procedures.
 
FUNDS AVAILABLE
 
Awarding of grants pursuant to this RFA is contingent upon receipt of
funds for this purpose.  Approximately seven awards will be made.
The NHLBI is planning for five grants at a total cost of $2,000,000
for the first year of support for this initiative.  The NIDDK will
award approximately two grants and has budgeted $800,000 for the
first year of support. The specific number of grants to be funded
will depend on the merit and scope of the applications received and
on the availability of funds. Applicants may request up to a 3
percent inflationary increase per year.  Increases above this amount
must be specifically justified.
 
CONSORTIUM ARRANGEMENTS
 
If a grant application includes research activities that involve
institutions other than the grantee institution, the program is
considered a consortium effort.  A consortium application should be
prepared so that the scientific, fiscal, and administrative
considerations are explained fully. The published policy governing
consortia is available in the business offices of institutions that
are eligible for Federal grants-in-aid. Consult the latest published
policy governing consortia before developing the application.  If
clarification of the policy is needed, please contact Ms. Jane R.
Davis (see below).
 
RESEARCH OBJECTIVES
 
Background
 
Cooley's anemia (also called beta-thalassemia major or thalassemia
major) and its clinical management has been the subject of an
extensive review (1).  Cooley's anemia is a genetic blood disease
that results in an inadequate production of hemoglobin, the essential
oxygen-carrying substance in blood.  This causes severe anemia that
begins shortly after birth.  As a group, thalassemic disorders are
one of the most common single-gene genetic diseases worldwide.  In
the United States, thalassemia mainly affects specific ethnic groups,
including people of Mediterranean, Middle Eastern, African, Southeast
Asian, Chinese, and Asiatic Indian origin.  Individuals affected with
Cooley's anemia require frequent and lifelong blood transfusions to
sustain life.  Because there are no natural means for the body to
eliminate iron, the iron contained in the transfused red blood cells
builds up over many years and eventually becomes toxic to tissues and
organ systems.  This excess iron must be removed from Cooley's anemia
patients or they may not survive beyond the second decade of life.
To accomplish this, patients must use the iron-binding or chelating
drug, deferoxamine, that is administered for about 10 hours every day
by pumping it through a needle inserted either under the skin or
intravenously.
 
Before the introduction of transfusion and chelation therapy, life
expectancy for patients with Cooley's anemia was two or three years.
Today, the picture is considerably brighter with some patients living
into their thirties and beyond.  Survival and quality of life depend
upon the absence or control of transfusion complications such as
infectious diseases (mainly hepatitis and AIDS) and the adequate
removal of excess iron.
 
In spite of the increased survival and quality of life, the current
treatment modalities are inadequate. Iron-chelation therapy is
extremely demanding, and many patients experience considerable
discomfort from administration of the drug.  In fact, the therapy is
so burdensome that many adolescents and teenagers have refused to
continue.  The prognosis for these noncompliant patients is quite
poor.  In addition to the physical and psychological burden of
therapy, the financial burden on the family is substantial.  The cost
of transfusions and iron-chelation therapy amounts to about $30,000
per year per patient, and it has been estimated that the total annual
Cooley's anemia-related costs may be as much as $100,000 per year per
patient.
 
The search for an improved chelator continues.  A variety of
compounds have been produced and examined as potential oral iron-
chelating agents.  One of these, deferiprone (1,2-dimethyl-3-
hydroxypyridin-4-one, also known as L1, CP20, and DMHP) has been
administered to patients in other countries, but some patients have
developed neutropenia or agranulocytosis.  The magnitude of the risk
of agranulocytosis is being evaluated in a multicenter clinical trial
in the U.S. and other countries.  No published data, however, are
available on the long-term efficacy of deferiprone.  A recent
prospective evaluation of this orally active chelator (2) has
suggested that deferiprone may induce decreases in hepatic iron, but
continued use does not result in sufficiently diminished levels of
hepatic iron, despite the continued urinary excretion of iron in
these patients.  This implies that deferiprone may be chelating a
pool of iron that may not be readily accessible to deferoxamine and
that perhaps therapy utilizing a combination of these two chelators
may be clinically superior to a single agent.  Experts would still
argue that deferiprone alone may be quite efficacious in the
prevention, rather than the reversal, of iron overload in young
children.  There is an urgent need to undertake further studies to
firmly establish whether this promising oral iron chelator has a role
in the management of iron overload in transfusion-dependent anemias.
 
Other iron chelators are being investigated.  A single bolus
injection of a long-acting form of deferoxamine linked to a polymeric
backbone of hydroxyethyl starch has been reported to induce a urinary
iron excretion equal to that excreted after several days of
deferoxamine infusions.  This approach should be investigated
further. Results of animal studies have shown that a new, water
soluble, synthetic hexadentate chelator (IRC11) having a higher
affinity for iron(III) than deferoxamine, but much less toxic, may be
useful in the treatment of transfusional iron overload (4).
 
Progress in our ability to reverse the ontogenic switch from fetal to
adult hemoglobin, thereby reactivating the expression of the dormant
gamma-globin gene, has increased in the past decade.  This holds
promise that a new, effective form of therapy for thalassemic
patients may soon be available.  Three classes of drugs, (a)
cytotoxic drugs, (b) hematopoietic growth factors and cytokines, and
(c) fatty acids, have been shown to enhance fetal hemoglobin
production, but their effects have been minimal.  However, there are
encouraging suggestions that the effects of these drugs may be
additive (5).  Clinical studies are needed to test the effectiveness
and safety of combinations of these drugs and other new hemoglobin
switching agents as they are identified.
 
The importance of the accurate assessment of body iron in patients
with thalassemia major has been emphasized by advances in
understanding the quantitative relationship between iron burden and
clinical outcome.  The current gold standard for quantifying tissue
iron burden still relies on the chemical analysis of liver biopsy
specimens. None of the less invasive clinically available methods of
evaluating body iron (serum ferritin concentration, transferrin
saturation, or urinary iron excretion after administration of a
chelating agent) is sufficiently accurate to permit optimal
management of iron-chelation therapy.  Magnetic susceptometry
measurement of hepatic iron using the Superconducting Quantum
Interference Device (SQUID) can provide accurate measurements.
However, perhaps due to the liquid helium operating temperature and
the large size, only two such instruments are available worldwide.
 
Potential approaches to improving the measurement of body iron
include refinements in the assay of serum ferritin (such as the
measurement of ferritin iron, glycosylated ferritin, H- or L-
subunits, and other methods), advances in the quantitative use of
magnetic resonance imaging (MRI), and improvement in the availability
of magnetic susceptibility by development of instruments utilizing
"high-temperature" (liquid nitrogen) superconducting materials.
Approaches that would be useful for measuring cardiac iron levels are
of particular importance.
 
Transfusion therapy continues to be the centerpiece of the management
of thalassemia.  The advantages of regular transfusion of red cells
are well established and include improved growth and development,
decreased enlargement of the liver and spleen, increased longevity
and a vastly improved overall well-being.  At the same time,
transfusions continue to be the source of toxic iron deposits in
vital organs.  In addition, patients with thalassemia major are at a
particularly high risk of contracting transfusion-transmitted
diseases because of their lifelong dependence on blood transfusions.
The optimal hemoglobin level at which to maintain patients with
thalassemia remains uncertain, and new methods for determining the
relationship between hemoglobin level and suppression of bone marrow
erythropoietic activity may help clinicians adjust the hemoglobin
level to achieve the desired results of transfusion therapy while
limiting the number of donor exposures and the amount of newly
accumulated iron.  Alternative approaches to conventional transfusion
therapy, including erythrocytapheresis, have been suggested as
methods for decreasing the amount of transfusional iron accumulation
but currently remain unproven.  Clinical studies are needed to
improve the safety and effectiveness of transfusion therapy and to
develop alternative methods of blood transfusion to reduce the degree
of iron loading.
 
This initiative is intended to stimulate the submission of grant
applications which address important clinical issues in the
management of Cooley's anemia.  GRANT APPLICATIONS MUST INCLUDE
STUDIES DIRECTLY INVOLVING PATIENTS, either for an intervention
protocol or for the development and testing of diagnostic
technologies such as noninvasive measurement of tissue iron
concentration.  Areas of particular importance include, but are not
limited to, the following:
 
1) Clinical studies of more effective iron chelators, new modes of
administration of existing chelators, and combinations of chelators.
Such studies must include measurement of patient compliance with drug
therapy and accurate assessment of changes in body iron stores.
 
2) Research on improved technology for the non-invasive measurement
of tissue iron deposits.
 
3) Clinical studies of fetal hemoglobin enhancing drugs and
combinations of these agents.
 
4) Clinical studies to improve the safety and effectiveness of
transfusion therapy and to develop alternative methods of blood
transfusion to reduce the degree of iron loading.
 
The demographics of beta-thalassemia in the United States have been
changing because of the large increases in the Asian population in
the last ten years.  Therefore, applicants are encouraged to include
patients with hemoglobin E beta-thalassemia, hemoglobin H, and
hemoglobin H-Constant Spring genotypes if their inclusion would not
diminish the scientific merit of the proposed clinical study.
 
References
 
(1) "Thalassemia Management I," Seminars in Hematology, P Beris, Ed.,
Vol 32, No 4 (October), 1995 and "Thalassemia Management II,"
Seminars in Hematology, P Beris, Ed., Vol 33, No 1 (January), 1996.
 
(2) Olivieri NF, Long-term follow-up of body iron in patients with
thalassemia major during therapy with the orally active iron chelator
deferiprone (L1).  BLOOD 88 (Suppl. 1):1229a, 1996.
 
(3) Olivieri NF, Nisbet-Brown E, Srichairatanakool S, Dragsten P,
Hallaway P, Hedlund B, Porter JB.  Studies of iron excretion and non-
transferrin-bound plasma iron (NTBPI) following a single infusion of
hydroxyethyl starch-deferoxamine (HES-DFO): A new approach to iron
chelation therapy.  BLOOD 88 (Suppl. 1):1228a, 1996).
 
(4) Hershko C, Rivkin G, Link G, Simhon E, Cyjon RL, Klein JY.
IRC11, a new synthetic chelator with selective interaction with
catabolic red blood cell iron.  BLOOD 88 (Suppl. 1):1951a, 1996.
 
(5) Olivieri NF, Rees DC, Ginder GD, Thein SL, Waye JS, Chang L,
Brittenham GM, Dover GJ, Weatherall DJ.  First report of long-term
elimination of red cell transfusions in thalassemia major through
augmentation of fetal hemoglobin with sodium phenylbutyrate (SPB) and
hydroxyurea (HU).  BLOOD 88 (Suppl. 1):1227a, 1996.
 
SPECIAL REQUIREMENTS
 
Upon initiation of the program, the NHLBI and the NIDDK will sponsor
periodic meetings to encourage exchange of information among
investigators who participate in this program.  In the budget for the
grant application, applicants should request travel funds for a 1-day
meeting each year, most likely to be held in Bethesda, Maryland.
Applicants should also include a statement in their applications
indicating their willingness to participate in these meetings.
 
INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN
SUBJECTS
 
It is the policy of the NIH that women and members of minority groups
and their subpopulations must be included in all NIH-supported
biomedical and behavioral research projects involving human subjects,
unless a clear and compelling rationale and justification is provided
that inclusion is inappropriate with respect to the health of the
subjects or the purpose of the research.  This new policy results
from the NIH Revitalization Act of 1993 (Section 492B of Public Law
103-43).  All investigators proposing research involving human
subjects should read the "NIH Guidelines for Inclusion of Women and
Minorities as Subjects in Clinical Research", which have been
published in the Federal Register of March 28, 1994 (FR 59
14508-14513) and in the NIH Guide to Grants and Contracts, Volume 23,
Number 11, March 18, 1994.  Investigators also may obtain copies of
the policy from the program staff listed under INQUIRIES. Program
staff may also provide additional relevant information concerning the
policy.
 
LETTER OF INTENT
 
Prospective applicants are asked to submit, by October 15, 1997, a
letter of intent that includes a descriptive title of the proposed
research, the name, address, and telephone number of the Principal
Investigator, the identities of other key personnel and participating
institutions, and the number and title of the RFA in response to
which the application may be submitted.  Although a letter of intent
is not required, is not binding, and does not enter into the review
of a subsequent application, the information that it contains allows
staff to estimate the potential review workload and to avoid conflict
of interest in the review.  The letter of intent may also be helpful
to the applicant since it may alert NHLBI staff to the possibility of
an application being unresponsive to the goals of the RFA.  In such
an instance, the applicant would be notified before preparing the
application.
 
The letter of intent is to be mailed, or faxed, to:
 
Dr. C. James Scheirer
Chief, Review Branch
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Room 7220, MSC 7924
Bethesda, MD  20892-7924
Telephone: (301) 435-0266
FAX: (301) 480-3541
E-mail: James_Scheirer@NIH.GOV
 
APPLICATION PROCEDURES
 
The research grant application form PHS 398 (rev. 5/95) is to be used
in applying for these grants.  Application kits are available at most
institutional offices of sponsored research and may be obtained from
the Office of Extramural Outreach and Information Resources, National
Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD
20892-7910, telephone: 301-710-0267, E-mail:
ASKNIH@odrockm1.od.nih.gov; and from the program staff listed under
INQUIRIES.
 
The RFA label found in the PHS 398 application form must be affixed
to the bottom of the face page of the application. Failure to use
this label could result in delayed processing of the application such
that it may not reach the review committee in time for review.  In
addition, the RFA title and number must be typed on line 2a of the
face page of the application form and the YES box must be marked.
 
Submit a signed, typewritten original of the application and three
signed, photocopies, in one package to:
 
DIVISION OF RESEARCH GRANTS
NATIONAL INSTITUTES OF HEALTH
6701 ROCKLEDGE DRIVE, ROOM 1040 - MSC 7710
BETHESDA, MD  20892-7710
BETHESDA, MD  20817 (for express/courier service)
 
At the time of submission, two additional copies of the application
must be sent to Dr. C. James Scheirer, at the address given above in
the section on LETTER OF INTENT. Applications must be received by
January 8, 1998.  If an application is received after that date, it
will be returned to the applicant without review.  The Division of
Research Grants (DRG) will not accept any application in response to
this RFA that is essentially the same as one currently pending
initial review, unless the applicant withdraws the pending
application.  This does not preclude the submission of substantial
revisions of applications already reviewed, but such applications
must include an introduction addressing the previous critique.
 
REVIEW CONSIDERATIONS
 
Upon receipt, applications will be reviewed for completeness by DRG
and for responsiveness by the NHLBI. Incomplete applications will be
returned to the applicant without further consideration.  If NHLBI
staff find that the application is not responsive to the RFA, it will
be returned without further consideration.
 
Applications that are complete and responsive to the RFA will be
evaluated for scientific and technical merit by an appropriate peer
review group convened in accordance with NIH peer review procedures.
As part of the initial merit review, all applications will undergo a
peer review streamlining process in which only those applications
deemed to have the highest scientific merit, generally the top half
of applications under review, will be discussed, assigned a priority
score, and receive a second level review by the National Advisory
Councils of the NHLBI and the NIDDK.  A written critique will be
provided for all applications, including those that are not discussed
and not scored.  The NIH will withdraw from further competition those
applications that were unscored and the applicant Principal
Investigator and institutional official will be notified.
 
The personnel category will be reviewed for appropriate staffing
based on the requested percent effort and any changes requested in
future years.  The total budget request will be reviewed for
consistency with the proposed methods and specific aims.  The
duration of support will be reviewed to determine if it is
appropriate to ensure successful completion of the recommended scope
of the project.
 
Applicants from institutions that have a General Clinical Research
Center (GCRC) funded by the NIH National Center for Research
Resources may wish to identify the GCRC as a resource for conducting
the proposed research.  If so, a letter of agreement from the GCRC
program director could be included with the application.
 
Peer Review Criteria
 
The goals of NIH-supported research are to advance our understanding
of biological systems, improve the control of disease, and enhance
health. In judging the likelihood that the proposed research will
have a substantial impact on the pursuit of these goals and those of
the RFA, the reviewers will address each of the listed criteria, and
consider them in assigning the overall priority score, weighting them
as they feel appropriate for each application.  Please note that your
grant application may not need to be strong in all categories to be
judged likely to have a major scientific impact and thus deserve a
high priority score.  For example, an investigator may propose to
carry out important work, that by its nature is not innovative but is
essential to move a field forward.
 
(1) Significance
 
Does the study address an important problem?  If the aims of the
application are achieved, how will scientific knowledge be advanced?
What will be the effect of these studies on the concepts or methods
that drive this field?
 
(2) Approach
 
Are the conceptual framework, design, methods, and analyses
adequately developed, well integrated, and appropriate to the aims of
the project?  Does the applicant acknowledge potential problem areas
and consider alternative tactics?
 
(3) Innovation
 
Does the project employ novel concepts, approaches or methods?  Are
the aims original and innovative?  Does the project challenge
existing paradigms or develop new methodologies or technologies?
 
(4) Investigator
 
Is the investigator appropriately trained and well suited to carry
out this work?  Is the proposed study appropriate to the experience
level of the principal investigator and other researchers (if any)?
 
(5) Environment
 
Does the scientific environment in which the work will be performed
contribute to the probability of success?  Do the proposed
experiments take advantage of unique features of the scientific
environment or employ useful collaborative arrangements?  Is there
evidence of applicant institutional support?
 
The initial review group will also examine the provisions for the
protection of human and animal subjects and the safety of the
research environment.
 
AWARD CRITERIA
 
Applications will compete for available funds with all other
applications submitted in response to this RFA.  The following will
be considered in making funding decisions: quality of the proposed
project as determined by peer review, availability of funds, and
program priority.
 
Schedule
 
Letter of Intent Receipt Date: October 15, 1997
Application Receipt Date: January 8, 1998
Initial Review: March 1998
Review by NHLBI and NIDDK Advisory Councils: May 1998
Anticipated Award Date: July 1, 1998
 
INQUIRIES
 
Inquiries concerning this RFA are encouraged.  The
opportunity to clarify any issues or questions from
potential applicants is welcome.
 
Direct inquiries regarding scientific and programmatic
issues to either of the Program staff below.  However, for
specific questions regarding the responsiveness of the
planned research grant application to the goals of this
RFA, please contact the NHLBI Program Administrator.
 
Dr. Helena O. Mishoe
Blood Diseases Program
Division of Blood Diseases and Resources, NHLBI
6701 Rockledge Drive, Room 10156
Bethesda, MD  20892-7950
Telephone: (301) 435-0050
FAX: (301) 480-0868
E-mail: helena.mishoe@nih.gov
 
or
 
Dr. David G. Badman
Division of Kidney, Urologic and Hematologic Diseases
National Institute of Diabetes and Digestive and Kidney Diseases
45 Center Drive, Room 6AS-13C MSC 6600
Bethesda, MD  20892-6600
Telephone: (301) 594-7717
FAX: (301) 480-3510
E-mail: David_Badman@nih.gov
 
Direct inquiries regarding fiscal matters to:
 
Ms. Jane R. Davis
Grants Management Office
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, MSC 7926
Bethesda, MD  20892-7926
Telephone: (301) 435-0166
FAX: (301) 480-3310
E-mail: jane_davis@nih.gov
 
or
 
Aretina Perry-Jones
Division of Extramural Activities, NIDDK
45 Center Drive, Room 6AN-38B, MSC 6600
Bethesda, MD  20892-6600
Telephone: (301) 594-8862
FAX: (301) 480-3504
E-mail: PerryA@extra.niddk.nih.gov
 
AUTHORITY AND REGULATIONS
 
The programs of the Division of Blood Diseases and
Resources, NHLBI, and the Division of Kidney, Urologic and
Hematologic Diseases, NIDDK are described in the Catalog
of Federal Domestic Assistance Nos. 93.839 and 93.849,
respectively.  Awards are made under the authority of the
Public Health Service (PHS) Act, Section 301 (42 USC 241)
and administered under PHS grant policies and Federal
regulations, most specifically 42 CFR Part 52 and 45 CFR
Part 74.  This program is not subject to the
intergovernmental review requirements of Executive Order
12372 or Health Systems Agency review.
 
The PHS strongly encourages all grant and contract
recipients to provide a smoke-free workplace and promote
the non-use of all tobacco products.  In addition, Public
Law 103-227, the Pro-Children Act of 1994, prohibits
smoking in certain facilities (or in some cases, any
portion of a facility) in which regular or routine
education, library, day care, health care or early
childhood development services are provided to children.
This is consistent with the PHS mission to protect and
advance the physical and mental health of the American
people.
 
.

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