Full Text DK-94-004

MORTALITY AND MORBIDITY IN HEMODIALYSIS PATIENTS:  FULL-SCALE TRIAL

NIH GUIDE, Volume 22, Number 45, December 17, 1993

RFA:  DK-94-004

P.T. 34

Keywords: 
  0715133 
  Clinical Trial 
  Cardiovascular Diseases 
  Infectious Diseases/Agents 


National Institute of Diabetes and Digestive and Kidney Diseases

Letter of Intent Receipt Date:  February 24, 1994
Application Receipt Date:  March 22, 1994

PURPOSE

The Division of Kidney, Urologic and Hematologic Diseases (DKUHD) of
the National Institute of Diabetes and Digestive and Kidney Diseases
(NIDDK), invites cooperative agreement applications from
investigators to serve as a Clinical Center and/or Data Coordinating
Center for the full-scale phase of the "Mortality and Morbidity in
Hemodialysis Patients (MMHD)" Trial.

The MMHD Trial is a prospective, multicenter, randomized, two-by-two
factorial clinical trial of increased delivered hemodialysis as
measured by the formula KT/V ((K is the dialyzer urea clearance
(ml/min), t is the treatment time (min), V is the body urea
distribution volume (ml)) and high-flux dialysis.  The objectives of
the study are to reduce mortality and morbidity in hemodialysis
patients.  Mortality due to all causes is the primary outcome.
Secondary outcomes include rate of non-access (vascular) related
hospital admissions, cardiovascular events including myocardial
infarction, acute angina, and congestive heart failure, occurrence of
severe infections, and decline in serum albumin.

The protocol for the ongoing MMHD Pilot Study provides details on
inclusion and exclusion criteria, baseline and follow-up procedures
for participants, and overall organization of the trial.  The
protocol and sample size requirements were developed by awardees
under a cooperative agreement mechanism with NIDDK assistance.  It is
recommended that applicants obtain a copy of the protocol, available
upon request from DKUHD, to assist them in preparing their response
to this RFA.

HEALTHY PEOPLE 2000

The Public Health Service (PHS) is committed to achieving the health
promotion and disease prevention objectives of "Health People 2000,"
a PHS-led national activity for setting priority areas.  This Request
for Applications (RFA), Mortality and Morbidity in Hemodialysis
Patients: Full-Scale Trial, is related to the priority areas 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).

ELIGIBILITY REQUIREMENTS

Only U.S. organizations are eligible to apply.  Domestic applications
may not include international components.  Applications may be
submitted by 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 and women
investigators and minority institutions are encouraged.  Applications
from community-based hemodialysis centers alone, or in combination
with academic institutions and/or academic affiliated hemodialysis
units, are encouraged.

The expertise appropriate for this research program for a Clinical
Center includes a knowledge of the medical aspects of hemodialysis.
Experience in carrying out clinical trials and clinical studies in
hemodialysis patients is also important.  Skills in management of
multicenter clinical trials, establishing and maintaining a large
data base, and analysis of complex data sets are appropriate for the
Data Coordinating Center.

An institution may apply for both a Clinical Center and Data
Coordinating Center.  However, a specific plan on how the independent
operation (i.e., confidentiality of study-wide data) of each unit
will be maintained is required.  Two separate applications will be
required from an institution applying for both a Clinical Center and
Data Coordinating Center.

MECHANISM OF SUPPORT

The administrative and funding instrument to be used for this program
will be a cooperative agreement (U01), which is an assistance
mechanism rather than an acquisition mechanism.  Under the
cooperative agreement, the NIH purpose is to support and/or stimulate
the recipient's activity by involvement in and otherwise working
jointly with the award recipient in a partner role, but it is not to
assume direction, prime responsibility, or a dominant role in the
activity.  Details of the responsibilities, relationships and
governance of the study to be funded under cooperative agreement(s)
are discussed later in this document under the section "Terms and
Conditions of Award."

FUNDS AVAILABLE

The estimated funds (total costs) available for the first year of
support for the entire program is approximately 3.65 million dollars.
It is anticipated that one award for a Data Coordinating Center for
approximately $650,000 (including direct and indirect costs) per year
and 15 awards for Clinical Centers will be made.  Funding for any
single Clinical Center will be no more than $200,000 in total costs
for each year.

Although this program is provided for in the financial plans of the
NIDDK, awards in response to this RFA are contingent on the
availability of funds for this purpose.

The total project period for applications submitted in response to
the present RFA will be seven years.  The anticipated award date is
September 1994.

At this time, the NIDDK anticipates that there will not be a renewed
competition after seven years.

RESEARCH OBJECTIVES

Background

I.  Mortality

The mortality rate of 23.4 percent per year among dialysis patients
in the United States is among the highest in developed countries.
The U.S. data reports exclude mortality occurring during the first
three months of dialysis and probably underestimate the problem.
This increased mortality, in fact, represents a trend that began in
1983 and has been steadily worsening since then.  End-stage renal
disease (ESRD) patients have from 1/4 to 1/5 the life expectancy of
the U.S. general population; at age 40, the expected life of an ESRD
patient is 8.8 years compared to 37.4 years for the U.S. general
population of the same age.

Factors implicated in the worsening mortality rates include the
increasing age and number of co-morbid conditions among the
hemodialysis population.  The mean age of those enrolled into the
ESRD registries has increased and 50 percent of new patients are now
over 61 years of age.  The U.S. also has the highest number of
diabetics with ESRD compared to other national registries, and these
patients are developing ESRD with more co-morbid conditions than just
five years ago.  Particularly important co-morbid conditions include
cardiovascular diseases, diabetes, and malnutrition.  The increasing
age and co-morbidity reflect, in part, the high acceptance rate into
dialysis programs (151/million/year in 1987).  In addition, the high
transplant rate (37/million/year in 1987) and the preferential
acceptance of younger patients and those with fewer co-morbid
conditions for renal transplantation contributes to the demographic
characteristics and high mortality of patients remaining on
hemodialysis.  Finally, racial differences are also evident, as black
patients appear to develop ESRD at a higher rate than white patients.

II.  Adequacy of Dialysis

The optimal KT/V for hemodialysis has not been determined. The
current recommended KT/V of 1.0, based on the results of the National
Cooperative Dialysis Study, corresponds to a urea clearance of only
10 ml/min, which is still far below the normal renal urea clearance
of 70-95 ml/min.  A report from the United States Renal Data System
indicates that prescribed KT/V is greater than 1.0 in only 47 percent
of patients in the U.S.  Furthermore, mean delivered KT/V, estimated
by two different formulas, was only 0.72 and 0.90, respectively.
Explanations for the low values for KT/V include inadequate delivery
by equipment and staff, and patient non-compliance.  These
considerations suggest that the high mortality of hemodialysis
patients in the U.S. may be related to inadequate dialysis, as judged
by KT/V.  Of particular importance is the recent recognition that
delivery of dialysis above a KT/V of 1.0 may improve survival.
However, many of these studies are either retrospective or
non-randomized prospective studies, and considerable uncertainty
still exists about the optimum level of dialysis.  Thus a randomized,
controlled clinical trial is necessary to determine whether higher
than usually delivered hemodialysis therapy (as measured by KT/V) is
beneficial in reducing mortality and morbidity.

III.  High-Flux Membranes

The clinical effects of hemodialysis membranes has also received
considerable attention.  Conventional cellulosic membranes most
frequently used for routine hemodialysis, remove an insignificant
fraction of substances with molecular weight over approximately 2,000
daltons.  In contrast, the normal kidney excretes and/or catabolizes
substances, particularly proteins, with molecular weights up to
approximately 60,000 daltons.  While high-flux membranes differ in
their sieving capacity and ability to adsorb large molecules, those
clinically available can remove molecules efficiently of at least the
molecular weight of beta-2 microglobulin.  Some membranes may even
remove substances of molecular weight of 60,000 daltons.  In all
cases these properties are much closer to those of the intact kidney
and very different from conventional membranes.  A recent
retrospective study showed that patients treated with high-flux
dialysis experienced a 76 percent reduction in relative risk of death
as compared with patients treated with conventional dialysis.  The
rate of hospital admissions, however, was not statistically
significant.  The influence of high-flux membranes on patient
mortality and morbidity deserves study in a randomized, controlled
clinical trial.

MMHD Pilot Study

In 1991 the NIDDK released the RFA, "Reduction in Mortality and
Morbidity among Hemodialysis Patients:  Pilot Study."  Four Clinical
Centers, one Data Coordinating Center, and one Intervention
Coordinating Center were selected to develop the study protocol and
carry out a pilot study.  The Pilot Study protocol was developed from
October 1992 through October 1993.  The pilot phase is planned as an
extended (6 month, March - August 1994) run-in period during which a
small number of patients (N=32) will be randomized, treated and
followed-up.  It is anticipated that the full-scale trial will begin
in September 1994.

Goal of the Activity

The goal of this RFA is to initiate a collaborative full-scale trial
to test whether hemodialysis with an increased KT/V and high-flux
dialysis significantly reduces mortality and morbidity among patients
receiving this form of therapy.  It is also important to evaluate
whether these interventions are safe and acceptable to patients.

Currently, the protocol stipulates that patients will be randomized
to either a KT/V of 1.3-1.5 or a KT/V of 0.9-1.1, calculated from
two-pool, variable volume, two-point urea kinetic modeling.  Patients
will also be randomized to high-flux membranes or low-flux dialysis
membranes.  High-flux membranes include the following:  polysulfone,
acrylonitrile (AN69), polymethylmethylacrylate (PMMA), or polyamide.
Low flux membranes include cuprophane.

To achieve uniformity, standards of care have been defined for
several aspects of dialysis therapy and common medical problems of
hemodialysis patients.  Highest priority will be devoted to
maintenance of acceptable blood urea nitrogen, protein, and energy
intake; fluid management and estimation of dry weight; treatment of
hypertension; dialysis duration (time) and standardization of water
and dialysis purity.  Standards of care are also defined for the
vascular access; anemia; calcium, phosphorus, hyperparathyroidism and
bone disease; hyperlipidemia; diabetes; and general health
maintenance.

Scope of the Activity

Nine hundred study participants, recruited by fifteen clinical
centers, will be required for the full-scale trial.  Thus each
Clinical Center is expected to randomize at least 60 study
participants during an 18-month initial period of recruitment.  In
addition, for each study participant who either dies, receives a
renal transplant, transfers to a nonparticipating center, or switches
to home dialysis or peritoneal dialysis prior to the final year of
the study, the Clinical Center is required to recruit a new study
participant into the study (so-called "recruit to replace" strategy).
Thus a total clinic population of at least 60 randomized study
participants will be maintained throughout the period of follow-up.

The full-scale study will consist of three phases:  (1) an 18-month
period of recruitment; (2) a 60-month period of intervention and
follow-up and (3) six months for data analysis, close-out of the
Clinical Centers, and reporting of results.

Unless otherwise noted in this RFA, applicants should prepare their
applications using patient eligibility criteria set forth in the MMHD
Pilot Study protocol.  Major entry and exclusion characteristics are
briefly described as follows.  The study participants in this trial
will be males and females of all races; age greater than 18 years old
and less than 75 years old; on in-center hemodialysis three times a
week; and on hemodialysis for more than three months.  Selected
exclusion criteria include patients currently in an acute or chronic
care hospital; an interdialytic 24-hour urine collection with a urea
clearance greater than 3 ml/min (required if patient has been on
dialysis less than two years or urine output greater than 400
ml/day); pregnant; scheduled living related donor renal transplant
within the period of the study; current malignancies requiring active
chemotherapy or radiation therapy and severe congestive heart
failure.

Each applicant should demonstrate the ability to follow an
established study protocol and manual of operations.  Applicants must
also demonstrate the ability to recruit and randomize the required
number of study participants, be able to implement the various study
procedures, and maintain high rates of follow-up during the course of
the trial.  It will be particularly important to minimize the number
of patients transferring to hemodialysis units not under the direct
supervision of the Clinical Center medical staff.  Applicants must
also specify the hemodialysis membrane reuse procedure(s) employed in
those units from which patients will be recruited.

Study Outline

Investigators should develop their applications for the full-scale
trial based on the inclusion and exclusion criteria and the general
design of the pilot study as outlined in this RFA and the Pilot Study
Protocol.  It is expected that investigators will carry out the
already developed protocol, however, modifications to this protocol
are expected.

Study Components

1.  Clinical Centers

A Clinical Center is an institution that is actively involved in the
recruitment, evaluation, treatment, and follow-up of study
participants.  It should consist of an interdisciplinary team of
clinical investigators and appropriate personnel, such as a research
coordinator, dietitian/data collector, dialysis technician, and
clerical staff.  Applications for Clinical Centers should provide
evidence that the investigators are capable of randomizing at least
60 participants into the study during the 18-month period of
recruitment and an ability to "recruit to replace" as described under
Scope of Activity.  Applicants for the Clinical Centers should
describe the target population from which they expect to randomize
the required number of study participants.  Clinical Centers will be
required to submit protocol data expeditiously.  The Principal
Investigator and Co-Investigators in each Clinical Center should be
skilled in collaborative clinical investigation and hemodialysis.
There should be evidence of strong institutional support for the
Clinical Center, including adequate space in which to conduct clinic
activities and office space for staff.  An organizational structure
for the Clinical Center should be set forth in the application
delineating lines of authority and responsibility for dealing with
problems in all general areas as well as stated willingness to follow
the stated common protocol.

The applicant should include a succinct discussion of previous
relevant investigational efforts.  The applicant also should discuss
in detail the recruitment strategies to procure the expected number
of randomized participants, approaches to attain high levels of
adherence to the intervention, and high rates of follow-up.

2.  Central Functions

The Data Coordinating Center will have primary responsibility for
collecting, editing, storing, and analyzing data generated by the
Clinical Centers.  This includes data collection for dietary intake
of protein and calories.  It should be prepared to assume a key role
in overseeing implementation and adherence to the protocol, and
assuring quality control.  The Data Coordinating Center will be
expected to provide appropriate biostatistical, data management, and
coordination expertise.  The Data Coordinating Center also will be
expected to provide appropriate detailed reports to the Steering
Committee and to the External Advisory Committee at regular intervals
and will be responsible for the logistics and planning of meetings of
these committees and their subcommittees.  Applicants for the Data
Coordinating Center should provide a detailed description of prior
experience in multicenter studies.

3.  Steering Committee

The primary governing body of the study will be the Steering
Committee comprised of each of the Principal Investigators of the
Clinical Centers and the Data Coordinating Center, the Chairperson of
the Steering Committee, and the NIDDK Project Coordinator (described
in detail under Terms and Conditions).

4.  External Advisory Committee

An independent committee supported by the NIDDK and composed of
experts in nephrology, hemodialysis, biostatistics, clinical trials,
and bioethics who are not otherwise involved in the study will be
established to review periodically the progress of the study
(described in detail under Terms and Conditions).

5.  Project Coordinator

The Clinical Trials Program Director, Division of Kidney, Urologic
and Hematologic Diseases will be the Project Coordinator for the
full-scale trial.  The Project Coordinator will assist the Steering
Committee and External Advisory Committee in carrying out the study
(described in detail under Terms and Conditions).

Study Phases

The randomized full-scale clinical trial will include fifteen
Clinical Centers and one Data Coordinating Center for a period of 84
months.  It will have the following three phases:

1.  Participant Recruitment:           18 months
2.  Intervention and Follow-up:       60 months
3.  Study Close-Out and Data Analysis:  6 months

It is expected that each Clinical Center will randomize 60
participants during an initial 18-month period and "recruit to
replace" thereafter.  Follow-up procedures will be carried out over a
period of 60-months (It is important to note, however, that as
participants are randomized, intervention and follow-up will begin
immediately).  A six-month period is planned for close-out of
Clinical Centers, data analysis, and reporting of results.

It is expected that all data will be submitted centrally and that
access to data and publications will be by the mechanism(s) defined
in the protocol.  The External Advisory Committee, appointed by the
NIDDK, will review progress at least semi-annually and provide advice
to the Institute.

Guidelines for Budget Preparation by Study Phases

Each applicant for a Clinical Center and for the Data Coordinating
Center should submit an adequately justified yearly budget for the
entire anticipated project period of 84 months.  The budgets for each
budget period of the study should be clearly delineated.  The
following information is provided to assist applicants in the
preparation of budgets.  Detailed budgets will vary according to
policies of the applicant and specific needs identified in the
response to this announcement.

Budget
Period         Time Period              Activity*

#1        9/30/94 through 9/29/95       Recruitment, Intervention and
                                        Follow-Up

#2        9/30/95 through 9/29/96       Recruitment, Intervention and
                                        Follow-Up

#3        9/30/96 through 9/29/97       Intervention & Follow-Up

#4        9/30/97 through 9/29/98       Intervention & Follow-Up

#5        9/30/98 through 9/29/99       Intervention & Follow-Up

#6        9/30/99 through 9/29/2000     Intervention & Follow-Up

#7        9/30/2000 thru 9/29/2001      6 months of Intervention &
                                        Follow-Up and
                                        6 months of Close-Out of
                                        Clinical
                                        Centers/Data Analysis and
                                        Reporting of Results

*An initial recruitment period of 18 months is delineated to obtain a
sample size of 900 among 15 Clinical Centers.  However, intervention
and follow-up will begin immediately after randomization.  In
addition, "recruitment to replace" will begin during budget period #1
and continue through 12/31/99, or the mid-point of budget period #6.

For a Clinical Center, the budget should request support for the
minimum number of full-and/or part-time staff to successfully carry
out the trial.  A Clinical Center could include a Principal
Investigator, Co-Investigator, study coordinator, dietitian/data
collector, lead dialysis technician, and data entry clerk.  Support
for travel for two key investigators to attend quarterly meetings of
the Steering Committee should also be included within the budget.
Steering Committee meetings will be held in the Washington, D.C.
area.  Travel for centralized training of the study coordinator,
dietitian, lead dialysis technician and data entry clerk must also be
budgeted (assume central training to be held in the Washington, DC
area).

For applications for the Data Coordinating Center, the budget should
also include the time and effort of key personnel needed to conduct
the trial and the required number and cost of computers to be used at
the Clinical Centers for distributed data entry.  Travel to the
Washington, DC area for External Advisory Committee meetings (two per
year), Steering Committee meetings (three per year), site visits
(four in year 1 and six in year 2) is also to be included in the
budget.  The Data Coordinating Center should also budget for travel
for the Chairperson of the Steering and Planning Committee (three
meetings per year).

Terms and Conditions of Award

The administrative and funding instrument to be used for this program
will be a cooperative agreement (U01), an "assistance" mechanism"
(rather than an "acquisition" mechanism), in which substantial NIH
scientific and/or programmatic involvement with the awardee is
anticipated during performance of the activity.  Under the
cooperative agreement, the NIH purpose is to support and/or stimulate
the recipient's activity by involvement in and otherwise working
jointly with the award recipient in a partner role, but it is not to
assume direction, prime responsibility, or a dominant role in the
activity.  Consistent with this concept, the dominant role and prime
responsibility for the activity resides with the awardee(s) for the
project as a whole, although specific tasks and activities in
carrying out the studies will be shared among the awardees and the
Institute Project Coordinator.

These special terms of award are in addition to, and not in lieu of,
otherwise applicable OMB administrative guidelines, HHS Grant
Administration Regulations at 45 CFR part 74, and other HHS, PHS, and
NIH grant administration policy statements.

1.  Awardee Activities

The tasks or activities in which awardees will have substantial and
lead responsibilities include protocol revision, patient recruitment
and follow-up, data collection, quality control, final data analysis
and interpretation, and preparation of publications.  The awardee
agrees to follow the common protocol and manual of operations
developed for the Pilot Study and as amended.  The awardees also
agree to transmit all study data to a central Data Coordinating
Center for combination and analysis.

2.  NIDDK Activities

The NIDDK Project Coordinator is the Clinical Trials Program
Director, Division of Kidney, Urologic and Hematologic Diseases whose
function will be to assist the Steering Committee and External
Advisory Committee in carrying out the trial.  The NIDDK Project
Coordinator will assist in quality control, interim data analysis,
safety monitoring, and final data analysis and interpretation,
preparation of publications, and coordination and performance
monitoring.

The NIDDK Project Coordinator will have voting membership on the
Steering Committee, and as appropriate, its subcommittees.

The NIDDK reserves the right to terminate or curtail the study (or an
individual award) in the event of a substantial shortfall in
participant recruitment, follow-up, data reporting, quality control
or other major breach in the program.  Early termination may also
occur due to adverse effects of the interventions and reaching study
endpoints.  If the NIDDK does not agree with the protocol approved by
the Steering Committee, the arbitration process described elsewhere
should be used to resolve the differences between the parties.

3.  Cooperative Activities

A Steering Committee, composed of the principal investigator of each
Clinical Center, the principal investigator of the Data Coordinating
Center, the NIDDK Project Coordinator and the Chairperson of the
Steering Committee will be the main governing board of the study and
will have primary responsibility for facilitating the conduct,
monitoring interim measures of trial progress, and reporting trial
results.  The chairperson, who will be someone other than the NIDDK
staff member, will be selected by the Steering Committee from among
their members, or alternatively, from among experts in the fields of
nephrology or clinical trials who are not participating directly in
the trial.  Subcommittees will be established by the Steering
Committee, as it deems appropriate; the NIDDK Project Coordinator
will serve on subcommittees as he/she deems appropriate.

Any changes to the collaborative protocol will be developed by the
Steering Committee.  Data will be submitted centrally to the Data
Coordinating Center.  Protocols will define rules regarding access to
data and publications.  An independent External Advisory Committee,
to be appointed by the NIDDK, will review progress at least annually
and report to the Institute.

It is anticipated that awardees will have lead responsibilities in
all joint tasks and activities.  The NIDDK Project Coordinator will
have voting membership on the Steering Committee, and as appropriate,
its subcommittees.

Awardees will be required to accept and implement the common protocol
and procedures approved by the Steering Committee.

4.  Governance

The primary governing body of the study will be the Steering
Committee.  Each member of the Steering Committee will have one vote.
It is anticipated that the Steering Committee will meet on a
quarterly basis during the course of the trial, or more often if
deemed necessary.  Subcommittees of the Steering Committee may be
established as necessary and will meet as necessary.  The NIDDK
Project Coordinator or in and the Data Coordinating Center will be
represented on each subcommittee.

An independent External Advisory Committee supported by the NIDDK and
composed of experts in relevant medical, statistical and bioethical
fields who are not otherwise involved in the study will be
established to review periodically the progress of the study.  The
committee will oversee participant safety, evaluate results, monitor
data quality, and provide operational and policy advice to the
Steering Committee and the NIDDK regarding the status of the study.
The Principal Investigator of the Data Coordinating Center, the NIDDK
Project Coordinator, and the Director of the Division of Kidney,
Urologic and Hematologic Diseases may participate as ex-officio,
non-voting members of this Committee.  Committee members will be
appointed by the NIDDK in consultation with members of the Steering
Committee.  The NIDDK will provide an executive secretary for the
External Advisory Committee.

5. Arbitration

Any disagreement that may arise in scientific-programmatic matters
between award recipients and NIDDK may be brought to arbitration.  An
arbitration panel will be composed of three members---one selected by
the Steering Committee (with NIDDK member not voting) or by the
individual awardees in the event of an individual disagreement, a
second member selected by NIDDK and the third member selected by the
two prior members.  This special arbitration procedure in no way
affects the awardees' right to appeal an adverse action that is
otherwise appealable in accordance with the PHS regulations at 42 CFR
part 50, Subpart D.

The special terms of award (1-5) described above are in addition to,
and not in lieu of, otherwise applicable OMB administrative
guidelines, HHS Grant Administration Regulations at 45 CFR parts 74
and 92, and other HHS, PHS, and NIH grant policy statements.

STUDY POPULATIONS

SPECIAL INSTRUCTIONS TO APPLICANTS REGARDING IMPLEMENTATION OF NIH
POLICIES CONCERNING INCLUSION OF WOMEN AND MINORITIES IN CLINICAL
RESEARCH STUDY POPULATIONS

NIH policy is that applicants for NIH clinical research grants and
cooperative agreements will be 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 provided.

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 Item 4 (Research Design and Methods) of the Research
Plan AND summarized in Item 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 populations; 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 epidemiology, prevention (and
preventive strategies), diagnosis, or treatment of diseases,
disorders, or conditions, including 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.

If the required information is not contained within the application,
the application will be returned without review.

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 will be
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.

LETTER OF INTENT

Prospective applicants are asked, but not required, to submit a
letter of intent.  This letter is to include the name, telephone
number, and mailing address of the Principal Investigator, the names
of key personnel, the name of the applicant institution, and the
number and title of this RFA.  Such a letter of is not binding and it
will not enter into the review of any application subsequently
submitted nor is it a requirement for application.  Letters of intent
are requested solely for planning purposes.  The information
contained in these letters is helpful in planning for review of
applications.  It allows NIDDK staff to estimate the potential review
workload and to avoid possible conflicts of interest in the review.
The NIDDK staff will not provide responses to such letters.

Letters of intent are to be received no later than February 24, 1994
and are to be addressed to:

Dr. Robert D. Hammond
Division of Extramural Activities
National Institute of Diabetes and Digestive and Kidney Diseases
Westwood Building, Room 406
Bethesda, MD  20892

APPLICATIONS PROCEDURES

The research grant application form PHS 398 (rev. 9/91) is to be used
in applying for these awards.  These forms are available at most
institutional offices of sponsored research; from the Office of
Grants Information, Division of Research Grants, National Institutes
of Health, 5333 Westbard Avenue, Room 449, Bethesda, MD 20892,
telephone 301/435-0714; and from the NIH program administrators named
below.

Use the conventional format for research project grant applications
and ensure that the points identified in the "Review Criteria"
section below are fulfilled.  To identify the application as a
response to the RFA, Check "YES" on item 2a of page 1 of the
application and enter the title "Mortality and Morbidity in
Hemodialysis Patients:  Full Scale Study" and enter the RFA number
DK-94-004 in the space provided.

The RFA label available in the PHS 398 (rev. 9/91) application form
must be affixed to the bottom of the face page of the original
completed application form.  Failure to use the label could result in
delayed processing of the application such that it may not reach the
review committee in time for review.

Send or deliver the completed, signed application and three complete
photocopies to the following office, making sure that the original
application with the RFA label attached is on top to:

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

Send two additional copies of the application to Dr. Hammond at the
address listed under LETTER OF INTENT.  It is important to send these
two copies at the same time as the original and three copies are sent
to the Division of Research Grants, otherwise the NIDDK cannot
guarantee that the application will be reviewed in competition for
the RFA.

Applications must be received by March 22, 1994.  An application not
received by this date will be returned to the applicant.

REVIEW CONSIDERATIONS

Upon receipt, the Division of Research Grants (DRG) will review the
application for completeness.  Applications will be reviewed by NIDDK
staff for responsiveness to the objectives of this RFA.  If an
application is judged to be incomplete or unresponsive, it will be
returned to the applicant.

If the number of applications is large compared to the number of
awards to be made, the NIDDK will conduct a preliminary scientific
peer review and will withdraw from further competition those
applications that are not judged to be competitive for award.  The
NIDDK will notify the applicant and institutional official of this
action.  Those applications judged to be both competitive and
responsive will be evaluated further according to the review criteria
stated below for scientific and technical merit by an appropriate
peer review group convened by the Division of Extramural Activities,
NIDDK.  Subsequently, they will be reviewed by the National Diabetes
and Digestive and Kidney Diseases Advisory Council.

Review Criteria

The Initial Review Groups evaluates the merit of each grant
application on the meeting agenda according to specific criteria.
The principal criteria for the initial review of research project
grant applications, as required in the PHS Scientific Peer Review
Regulations, include:

1.  scientific, technical, or medical significance and originality of
the proposed research;

2.  appropriateness and adequacy of the experimental approach and
methodology to be used;

3.  qualifications of the principal investigator and staff in the
area of the research;

4.  the principal investigator's experience and record in previous
research activity;

5.  reasonable availability of resources;

6.  reasonableness and adequacy of justification of the proposed
budget and duration of support; and

7.  adequacy of the proposed means for protecting against adverse
effects upon humans, vertebrate animals, or the environment.

The evaluation of applications for both Clinical Centers and the Data
Coordinating Center will be based primarily on the scientific merit
of the proposed study.  If an institution wishes to apply both as a
Clinical Center and Data Coordinating Center, separate applications
must be prepared.  Specific criteria for review of applications will
be as follows:

For Clinical Centers:

1.  Documentation of the specific competence and previous experience
of professional, technical, and administrative staff pertinent to the
operation of a Clinical Center in the proposed Clinical Trial.
Evaluation will include the following:  familiarity with and
experience in recruiting participants in a randomized trial; handling
laboratory specimens; working in collaboration with other
investigators under a common protocol; ability to implement study
procedures in hemodialysis units from which patients are to be
recruited and meticulous and expeditious handling of study data.

2.  Documentation of access to hemodialysis patient population(s)
from which a substantial number of trial participants can be
recruited in sufficient numbers to meet the goals specified in the
RFA.

3.  Understanding and awareness of the scientific, ethical, and
practical issues underlying the proposed trial and appropriateness of
plans to deal with them.

4.  Responsible budgeting, and staffing and distribution of available
resources appropriate for the work proposed.

5.  Adequacy of the proposed facility and space.

6.  Evidence of the degree of institutional commitment and support
for the proposed program, including the relative position of the
proposed project staff within the applicant's organizational
structure.

7.  Willingness to work cooperatively with other centers in the
manner summarized in the RFA.

8.  Willingness to carry out a developed study protocol.  Of
particular importance is the ability to send patient samples
(including samples routinely collected during hemodialysis) to a
Central Biochemistry Laboratory for testing, and implementation of
the interventions described in the protocol.

For the Data Coordinating Center:

1.  Documentation of the specific competence and previous experience
of professional, technical, and administrative staff pertinent to the
operation of a Data Coordinating Center for a collaborative clinical
trial, as well as available, on-site medical consultation, and the
time these professionals will devote to the project.  Prior
experience in similar studies in the collection of data and patient
specimens from multiple clinical sites, as well as experience in
monitoring the quality and timeliness of such data, must be
demonstrated.

2.  Ability to collect, maintain, and analyze dietary data including
protein and calorie intake of study participants. Centralized
training of Clinical Center staff in this data collection is also
required.

3.  Suitability of proposed data management and data analysis plans.

4.  Ability to design, implement and maintain a distributed data
entry system for the Clinical Centers.

5.  The approach to and likelihood of soliciting cooperation from the
participating clinical centers and exercising appropriate leadership
in matters of study design and protocol revision, and data
acquisition, management, and analysis.

6.  Appropriateness of the budget for the work proposed.

7.  The adequacy of the proposed facility, technical hardware, and
space.

8.  The organizational and administrative structure of the proposed
program.

9.  Evidence of the degree of commitment and support of the
organization/institution for the proposed program, including the
relative position of the proposed project staff within the
applicant's organizational structure.

AWARD CRITERIA

Applications recommended by the National Diabetes and Digestive and
Kidney Diseases Advisory Council will be considered for award based
upon (a) scientific and technical merit; (b) program balance,
including in this instance, sufficient compatibility of features to
make a successful collaborative program a reasonable likelihood; and
(c) availability of funds.

Schedule

The timetable for receipt, peer review, and funding of this RFA is as
follows:

Letter of Intent Receipt Date:  February 24, 1994
Application Receipt Date:       March 22, 1994
Initial Review:                 June 1994
NIDDK Advisory Council Review:  September 1994
Anticipated Award Date:         September 30, 1994

INQUIRIES

Written and telephone inquiries concerning this RFA are encouraged.
The opportunity to clarify any issues or questions from potential
applicants is welcome.  Applicants are encouraged to request a copy
of the pilot study protocol.

Direct inquiries regarding programmatic issues to:

John W. Kusek, Ph.D.
Division of Kidney, Urologic and Hematologic Diseases
National Institute of Diabetes and Digestive and Kidney Diseases
Westwood Building, Room 3A04
Bethesda, MD  20892
Telephone:  (301) 594-7522
FAX:  (301) 594-7501

Inquiries regarding fiscal matters may be directed to:

Nancy C. Dixon
Division of Extramural Activities
National Institute of Diabetes and Digestive and Kidney Diseases
Westwood Building, Room 649B
Bethesda, MD  20892
Telephone:  (301) 594-7543
FAX:  (301) 594-7594

AUTHORITY AND REGULATIONS

This program is described in the catalog of Federal Domestic
Assistance No. 93.849-Kidney, Urologic and Hematologic Diseases
Research.  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 52 and 45 CFR Part 74 and 92.
This program is not subject to the intergovernmental review
requirements of Executive Order 12372 or Health Systems Agency
review.

References

1.  Rettig, RA and Levinsky, NG (editors).  Kidney Failure and the
Federal Government.  Institute of Medicine. National Academy Press.
Washington, D.C. 1991.

2.  U.S. Renal Data System, USRDS 1993 Annual Data Report, The
National Institutes of Health, National Institute of Diabetes and
Digestive and Kidney Diseases, Bethesda, MD, March 1993.

3.  Hull, AR and Parker T. Introduction and Summary. Proceedings from
the Morbidity, Mortality and Prescription of Dialysis Symposium,
Dallas, TX, September 15-17, 1989. American Journal of Kidney
Diseases 15:375-383, 1990.

4.  Collins AJ, Hanson, G, Umen et al. Changing risk factor
demographics in end-stage renal disease patients entering
hemodialysis and the impact of long-term mortality. American Journal
of Kidney Diseases 15:422-432, 1990.

5.  Gotch, FA, Yarian S and Keen, M. A kinetic survey of US
hemodialysis prescriptions.  American Journal of Kidney Diseases
15:511-515, 1990.

6.  Hornberger JC, Chernew M, Petersen J, and Garber AM. A
multivariate analysis of mortality and hospital admissions with
high-flux dialysis.  Journal of the American Society of Nephrology
3:1227-1237, 1992.

7.  Hakim, RM.  Clinical implications of hemodialysis membrane
biocompatibility.  Kidney International 44:484- 494, 1993.

8  Hakim RM, Depner TA, Parker TF.  Adequacy of hemodialysis.
American Journal of Kidney Diseases 20:107- 123, 1992.

9.  Collins A., Liao M, Umen A, Hanson G, Keshaviah P. Diabetic (DM)
hemodialysis (HD) patients (PTS) treated with a high KT/V have a
lower risk of death than standard KT/V (Abstract). Journal of the
American Society of Nephrology 2:318, 1991.

10. Lowrie EG and Laird NM (editors).  Cooperative Dialysis Study.
Kidney International 23:(supplement) S-1-S-122, 1983.

11. Held PJ, Port FK, Garcia J, Gaylin DS, Levin NW, Agodoa L.  U.S.
Renal Data System:  Hemodialysis prescription in the U.S.:  Results
from USRDS case mix study (abstract). Journal of the American Society
of Nephrology 2:328, 1991.

12.  Protocol for the Mortality and Morbidity in Hemodialysis
Patients Multicenter Clinical Trial.  Division of Kidney, Urologic
and Hematologic Diseases, National Institutes of Diabetes and
Digestive and Kidney Diseases, National Institutes of Health.  1993.

.

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