Full Text DK-93-11


NIH GUIDE, Volume 21, Number 42, November 20, 1992

RFA:  DK-93-11

P.T. 34

  Chemotherapeutic Agents 
  Clinical Trial 

National Institute of Diabetes and Digestive and Kidney Diseases

Letter of Intent Receipt Date:  February 18, 1993
Application Receipt Date:  March 17, 1993


The National Institute of Diabetes and Digestive and Kidney Diseases
(NIDDK) invites investigator-initiated research grant applications to
study the effects of vanadium salts as potential therapeutic agents for
the treatment of diabetes mellitus.  A significant amount of prior
research in experimental animals, isolated tissues, and cell
preparations has strongly suggested that various forms of vanadium have
a beneficial impact on the abnormal metabolic state associated with
this disease.  This solicitation intends to support preliminary studies
of efficacy, dosimetry, and toxicity in human subjects with diabetes.


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), Vanadium Salts in the Clinical Treatment of
Diabetes Mellitus, is related to the priority area of diabetes and
chronic disabling conditions.  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 202/783-3238).


Applications may be submitted by domestic and foreign for-profit or
non-profit organizations, public and private, such as universities,
colleges, hospitals, laboratories, units of State and local
governments, and eligible agencies of the Federal government.  Minority
individuals and women are encouraged to submit as Principal


This RFA will use the National Institutes of Health (NIH) individual
research grant (R01).  Responsibility for the planning, direction, and
execution of the proposed project will be solely that of the applicant.
The total project period for applications submitted in response to the
present RFA may not exceed two years.  The anticipated award date is
September 30, 1993.

This RFA is a one-time solicitation.  Future unsolicited competing
continuation applications will compete with all investigator-initiated
applications and be reviewed according to the customary peer review

In order to adhere to prudent principles of cost-containment, requested
direct costs must not exceed $160,000 per year for any single
application.  Applications exceeding this limit will not be reviewed as
part of this RFA.  With respect to post-award administration, the
current policies and requirements that govern the research grant
programs of the NIH will prevail.


A total of up to $500,000 in first year and $500,000 in the second year
will be committed by the NIDDK to fund applications submitted in
response to this RFA.  The NIDDK plans to make one to three awards in
FY 93 contingent on the receipt of highly meritorious applications in
response to this solicitation.  The award of grants pursuant to this
RFA is contingent on the availability of funds for this purpose.



The term "diabetes mellitus" encompasses a group of disorders
characterized by abnormal metabolism of carbohydrates, lipids, and
proteins.  The classical clinical manifestations of diabetes include
chronic elevations of blood glucose levels and a defined constellation
of long-term sequelae.  Two major forms of diabetes are recognized.
Insulin-dependent diabetes mellitus (IDDM) is the result of the
virtually total destruction of the insulin-producing beta cells of the
pancreas, usually by an autoimmune process of still obscure
pathogenesis.  The existing treatment of this form of diabetes requires
insulin replacement therapy.  Non-insulin-dependent diabetes mellitus
(NIDDM) appears to be the result of both significant resistance by the
relevant tissues to the action of insulin and the coincident inability
of the pancreatic beta cells to sufficiently compensate for this
resistance by increasing secretion.  Current treatment for this form of
diabetes includes lifestyle modification (i.e., diet, exercise, weight
loss) to ameliorate insulin resistance, oral hypoglycemic agents to
stimulate insulin secretion and perhaps improve insulin resistance, and
insulin replacement therapy, if necessary.

Vanadium, a trace metal for a broad range of organisms, including
humans, has been postulated to be a co-factor for a number of enzymatic
processes.  Salts of this element have been known for a decade to
inhibit the action of a number of phosphatases in vitro.

In particular, vanadate has been used frequently in laboratory settings
with isolated tissues and cell cultures as a tool in biochemical
studies of the mechanisms of insulin action and experimental insulin
resistant states.  This ion has shown insulinmimetic properties in
preparations of muscle, liver, and adipose tissue as well as whole
animals with various forms of diabetes.  Non-diabetic laboratory
animals appear to show much less response.

Initial hypotheses to explain this property of vanadate centered around
inhibition of tyrosine phosphatase activity associated with the
membrane-bound insulin receptor.  Although such inhibition occurs, this
does not appear to adequately account for the actions of vanadate to
induce insulin-like responses.  Several research groups are presently
exploring possible post-receptor mechanisms for a definitive answer to
this question.

Despite the lack of consensus on the precise biochemical mechanism of
action for vanadate, it is clear that a broad array of cellular and
physiologic processes are modified in an insulinmimetic pattern.  These
include glycemia, transmembrane glucose transport, glucose utilization,
glycolysis, gluconeogenesis, glycogen metabolism, fatty acid and lipid
metabolism, and bile acid metabolism in a number of different
laboratory preparations and models of diabetes.  The magnitude and
universality (i.e., across tissues, across species, across diabetes
type or model) of these effects are still being debated in the
literature.  In addition, vanadium can exist in a number of oxidation
states (both cationic and anionic) and the state most relevant to
insulin action is not established.

Before embarking on human studies, it will be important to consider the
known and potential toxicities of vanadium.  There is a growing
literature on the toxicology of this heavy metal which has been
identified as a pollutant byproduct of coal combustion with significant
health risks.

Most of this work concerns the impact of pulmonary exposure through
aerosols, but systemic effects after absorption have been documented in
the kidney, bone, and blood cells.  The oxidative state of vanadium may
relate to toxicity, with some ions being less detrimental.  Therefore,
clinical studies of any vanadium compound with regard to diabetes will
need to carefully monitor for incipient toxicity.


The objective of this RFA is to stimulate investigator-initiated
research designed to provide feasibility data on the clinical utility
of vanadium-containing compounds for the treatment of diabetes mellitus
in humans.  Therefore, all applications in response to this RFA must
primarily concern the clinical study of patients with this disease
(NIDDM and/or IDDM) and may include normal (non-diabetic) volunteers as
appropriate to the experimental design.  Relevant research topics
listed below are examples and should not be construed as required or
limiting.  Responsive applications to this solicitation include:

o  placebo controlled, double-blind comparisons of alternative
treatments with vanadium salts for diabetes mellitus

o  assessment of metabolic effects of vanadium salts in human subjects
including dose-response relationships

o  studies of therapeutic combinations including vanadium salts

o  toxicologic assessments of oral vanadium salts in humans with



NIH policy is that applicants for NIH clinical research grants and
cooperative agreements are required to include minorities and women in
study populations so that research findings can be of benefit to all
persons at risk of the disease, disorder or condition under study;
special emphasis must be placed on the need for inclusion of minorities
and women in studies of diseases, disorders and conditions which
disproportionately affect them.  This policy is intended to apply to
males and females of all ages.  If women or minorities are excluded or
inadequately represented in clinical research, particularly in proposed
population-based studies, a clear compelling rationale must be

The composition of the proposed study population must be described in
terms of gender and racial/ethnic group.  In addition, gender and
racial/ethnic issues must be addressed in developing a research design
and sample size appropriate for the scientific objectives of the study.
This information must be included in the form PHS 398 (rev. 9/91) in
Sections 1-4 of the Research Plan and summarized in Section 5, Human
Subjects.  Applicants are urged to assess carefully the feasibility of
including the broadest possible representation of minority groups.
However, NIH recognizes that it may not be feasible or appropriate in
all research projects to include representation of the full array of
United States' racial/ethnic minority population (i.e., Native
Americans [including American Indians or Alaskan natives],
Asian/Pacific islanders, blacks, Hispanics).

The rationale for studies on single minority population groups should
be provided.

For the purpose of this policy, clinical research is defined as human
biomedical and behavioral studies of etiology, epidemiology, prevention
(and preventive strategies), diagnosis, or treatment of disease,
disorders or conditions, included, but not limited to, clinical trials.

The usual NIH policies concerning research on human subjects also
apply.  Basic research or clinical studies in which human tissues
cannot be identified or linked to individuals are excluded.  However,
every effort should be made to include human tissues from women and
racial/ethnic minorities when it is important to apply the results of
the study broadly, and this should be addressed by applicants.

For foreign awards, the policy on inclusion of women applies fully;
since the definition of minority differs in other countries, the
applicant must discuss the relevance of research involving foreign
population groups to the Unites States' populations, including

If the required information is not contained within the application,
the application will be returned.

Peer reviewers will address specifically whether the research plan in
the application conforms to these policies.  If the representation of
women or minorities in a study design is inadequate to answer the
scientific question(s) addressed AND the justification for the selected
study population is inadequate, it will be considered a scientific
weakness or deficiency in the study design and reflected in assigning
the priority score to the application.

All applications for clinical research submitted to NIH are required to
address these policies.  NIH funding components will not award grants
or cooperative agreements that do not comply with these policies.


Potential applicants are strongly encouraged to submit a letter of
intent by February 18, 1993.  The letter of intent is to include: (1)
name of the Principal Investigator/program director, and principal
collaborators, (2) descriptive title of the potential application, (3)
identification of the organization(s) involved, and (4) 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 NIDDK staff to estimate the potential review
workload and to avoid conflict of interest in the review.

The letter of intent is to be sent to:,

Chief, Review Branch
Division of Extramural Activities
National Institute of Diabetes and Digestive and Kidney Diseases
Westwood Building, Room 605
Bethesda, MD  20892
Telephone:  (301) 496-7083
FAX:  (301) 402-1277


The research grant application form PHS 398 (rev. 9/91) is to be used
in applying for these grants.  These forms are available at most
institutional offices of sponsored research; from the Office of Grants
Inquiries, Division of Research Grants, National Institutes of Health,
5333 Westbard Avenue, Room 449, Bethesda, MD  20892, telephone
301/496-7441; and from the NIDDK program administrator named below.

The RFA label found in the form PHS 398 application kit must be affixed
to the bottom of the face page of the original completed application
form.  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, "Vanadium and Clinical
Diabetes," and number, "DK-93-11," must be typed on line 2a of the face
page of the application form, and the YES box must be marked.

Applicants from institutions that have a General Clinical Research
Center (GCRC) funded by the NIH National Center of Research Resources
may wish to identify the Center as a resource for conducting the
proposed research.  If so, a letter of agreement from the GCRC Program
Director should be included in the application material.

Applications must be received by March 17, 1993.  If an application is
received after this date, it will be returned to the applicant without
review.  Submit a signed original of the application, including the
Checklist, and three signed photocopies, in one package to:

Division of Research Grants
National Institutes of Health
Westwood Building, Room 240
Bethesda, MD  20892**

At the time of submission, two additional copies of the application
must also be sent to:

Chief, Review Branch
Division of Extramural Activities
National Institute of Diabetes and Digestive and Kidney
Westwood Building, Room 605
Bethesda, MD  20892

The Division of Research Grants (DRG) will not accept any application
in response to this announcement that is essentially the same as one
currently pending initial review, unless the applicant withdraws the
pending application.  The DRG will not accept any application that is
essentially the same as one already reviewed. This does not preclude
the submission of substantial revisions of the applications already
reviewed, but such application must include an introduction addressing
the previous critique.


Upon receipt, applications will be reviewed for completeness by the DRG
and responsiveness by the NIDDK. Incomplete applications will be
returned to the applicant without further consideration.  If the
application is not responsive to the RFA, NIDDK staff will contact the
applicant to determine whether to return the application to the
applicant or submit it for review in competition with unsolicited
application at the next review cycle.

Applications may be triaged by an NIDDK peer review group on the basis
of relative competitiveness.  The NIDDK will withdraw from further
competition those applications judged to be non-competitive for award
and notify the applicant Principal Investigator and Institutional
official.  Those applications judged to be competitive will undergo
further scientific merit review.  Those applications that are complete
and responsive will be evaluated in accordance with the criteria stated
below for scientific/technical merit by an appropriate peer review
group convened by the NIDDK.  The second level of review will be
provided by the National Diabetes and Digestive and Kidney Diseases
Advisory Council.

Review criteria for RFAs are generally the same as those for
unsolicited research grant applications.

o  scientific, technical, or medical significance and originality of
proposed research;

o  appropriateness and adequacy of the experimental approach and
methodology proposed to carry out the research;

o  qualifications and research experience of the Principal Investigator
and staff, particularly, but not exclusively, in the area of the
proposed research;

o  availability of the resources necessary to perform the research;

o  appropriateness of the proposed budget and duration in relation to
the proposed research.


The anticipated date of award is September 30, 1993. The following will
be considered in making funding decisions:

o  Quality of the proposed project as determined by peer review
o  Availability of funds
o  Programmatic priorities of the NIDDK


Inquiries regarding programmatic issues related to this announcement
may be directed to:

Joan T. Harmon, Ph.D.
Executive Director, Diabetes Research Program
Diabetes Programs Branch, DDEM
National Institute of Diabetes and Digestive and Kidney Diseases
Westwood Building, Room 622
Bethesda, MD  20892
Telephone:  (301) 496-7731
FAX:  (301) 480-0383

Inquiries regarding fiscal matters may be directed to:

Betty Bailey
Grants Management Specialist
Grants Management Branch
Division of Extramural Activities
National Institute of Diabetes and Digestive and Kidney Diseases
Westwood Building, Room 649
Bethesda, MD  20892
Telephone:  (301) 496-7467
FAX:  (301) 496-9721


Letter of Intent:               February 18, 1993
Application Receipt Date:       March 17,1993
Initial Review:                 June/July 1993
NIDDK Advisory Council Review:  September 1993
Anticipated Award Date:         September 30, 1993


This program is described in the Catalog of Federal Domestic Assistance
No. 93.847.  Awards are made under the authority of the Public Health
Service Act, Title IV, Part A (Public Law 78-410, as amended by Public
Law 99-158, 42 USC 241 and 285) and administered under PHS grants
policies and federal regulations 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.


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