Full Text PA-95-003


NIH GUIDE, Volume 23, Number 37, October 21, 1994

PA NUMBER:  PA-95-003

P.T. 34

  Clinical Trial 

National Institute of Diabetes and Digestive and Kidney Diseases


The purpose of this Program Announcement (PA) is to encourage
investigators in digestive diseases to undertake prospective,
randomized, controlled, long-term follow-up, multicenter clinical
trials on the nonsurgical procedure, transjugular intrahepatic
portosystemic shunt (TIPS) placement in the management of portal
hypertension, variceal bleeding, and ascites.  The procedure is
already being performed for these indications, even though it has not
been compared sufficiently with standard treatments such as
sclerotherapy, pharmacologic therapy, and various forms of surgical
shunting for efficacy, patient acceptance, safety and cost benefit.


The Public Health Service (PHS) is committed to achieving the health
promotion and disease prevention objectives of "Healthy People 2000,"
in a PHS-led national activity for setting priority areas.  This PA,
Clinical Trials Using TIPS Procedure for Portal Hypertension, is
related to the priority area of chronic disabling conditions.
Potential applicants may obtain a copy of "Healthy People 2000" (Full
Report:  Stock No. 017-001-00474-0) or "Healthy People 2000" (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 and
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.
Applications from minority individuals and women are encouraged.


Support for this Program Announcement will be through the NIH
research project grant (R01).


The direct cost should not exceed $500,000 in the first budget


The TIPS procedure has recently been introduced as a treatment of
portal hypertension, variceal bleeding and ascites.  The National
Digestive Diseases Advisory Board recently sponsored a conference on
the role of TIPS for treatment of portal hypertension and its
complications.  In summary of the conference, the TIPS procedure is a
new and exciting modality for treatment of portal hypertension and
its complications.  It is thus beneficial in the medical management
of patients with acute variceal hemorrhage.  However, indications for
TIPS remain to be better defined in terms of efficacy and cost-
benefit in relationship to other established modes of therapy of
portal hypertension.  TIPS is an invasive procedure and is associated
with several potential complications.  Placement of TIPS has an acute
mortality rate of approximately one percent and a serious
complication rate of 3 to 10 percent.  Thus, prospective, randomized
controlled clinical trials with long-term follow-up for the
prevention and treatment of rebleeding esophageal varices comparing
the TIPS procedure with standard therapies, i.e., sclerotherapy,
pharmacologic therapy, and surgical shunting, are needed.

An example of a specific clinical trial could be the comparison of
the TIPS procedure with surgical shunting for prevention of
rebleeding in patients who have recurrent variceal bleeding despite
conventional medical therapies.  In addition, a well-defined study in
patients with refractory ascites is needed to compare TIPS with the
standard therapy such as large-volume paracentesis.

At present, long-term efficacy of TIPS is related to shunt patency.
For the first year after undergoing the procedure, delayed stenosis
or occlusion of the shunt has been reported in 33 to 66 percent of
the patients. The pathological process results from endothelial
hyperplasia and collagen deposition within the stent.  Studies
evaluating means of monitoring for stenosis and dilation of narrowed
stents are also needed.


It is the policy 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
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) and
supersedes and strengthens the previous policies (Concerning the
Inclusion of Women in Study Populations, and Concerning the Inclusion
of Minorities in Study Populations), which have been in effect since
1990.  The new policy contains some provisions that are substantially
different from the 1990 policies.

All applications 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 reprinted
in the NIH Guide for 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.


Applications are to be submitted on the grant application form PHS
398 (rev. 9/91).  Application kits are available at most
institutional offices of sponsored research and may be obtained from
the Office of Grants Information, Division of Research Grants,
National Institute of Health, Westwood Building, Room 449, Bethesda,
MD 20892, telephone 301/710-0267.  The title and number of this
program announcement must be typed in Section 2a on the face page of
the application.

These will be accepted at the regular application deadlines as
indicated in the application kit.  The receipt dates for applications
for AIDS-related research are found in the PHS 398 instructions.

The completed original application and five legible copies must be
sent or delivered to:

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


Applications will be assigned on the basis of established PHS
referral guidelines.  Applications will be reviewed for scientific
and technical merit by study sections of the Division of Research
Grants, NIH, in accordance with the standard NIH peer review
procedures.  Following scientific-technical review, the applications
will receive a second-level review by the appropriate national
advisory council.

Review Criteria

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;

o  Adequacy of plans to include both genders and minorities and their
subgroups as appropriate for the scientific goals of the research.
Plans for the recruitment and retention of subjects will also be


Applications will compete for available funds with all other approved
applications assigned to the National Institute of Diabetes and
Digestive and Kidney Diseases. 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 Program priority.


Inquiries are encouraged.  The opportunity to clarify any issues or
questions from potential applicants is welcome.  Administrative
suggestions for preparing an R01 clinical trial grant application
that include review criteria for clinical trials and, also, the
summary of the recently held TIPS conference are available.

Direct inquiries regarding programmatic issues to:

Ms. Tommie Sue Tralka
Division of Digestive Diseases and Nutrition
National Institute of Diabetes and Digestive and Kidney Diseases
Westwood Building, Room 3A15
Bethesda, MD  20892-6600
Telephone:  (301) 594-7592
Email:  S2T@CU.NIH.GOV

Direct inquiries regarding fiscal matters to:

Ms. Paulette Badman
Grants Management Branch
National Institute of Diabetes and Digestive and Kidney Diseases
Westwood Building, Room 639
45 Center Drive MSC 6600
Bethesda, MD  208920-6600
Telephone:  (301) 594-7543


This program is described in the Catalog of Federal Domestic
Assistance No. 93.848.  Awards are made under authorization 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 52 and 45
CFR Part 74.  This program is not subject to the intergovernmental
review requirements of Executive Order 12372 or Health Systems Agency

The Public Health Service (PHS) strongly encourages all grant
recipients to provide a smoke-free workplace and promote the non-use
of all tobacco products.  This is consistent with the PHS mission to
protect and advance the physical and mental health of the American


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