Full Text AA-97-004
 
COMBINED BEHAVIORAL/PHARMACOLOGIC TREATMENT OF ALCOHOLISM
 
NIH GUIDE, Volume 26, Number 1, January 10, 1997
 
RFA:  AA-97-004
 
P.T. 34

Keywords: 
  Alcohol/Alcoholism 
  Treatment, Medical+ 
  Behavioral/Experimental Psychology 

 
National Institute on Alcohol Abuse and Alcoholism
 
Letter of Intent Receipt Date:  March 21, 1997
Application Receipt Date:  April 24, 1997
 
PURPOSE
 
The National Institute on Alcohol Abuse and Alcoholism (NIAAA)
invites applications from institutions wishing to participate in a
multi-center, cooperative clinical trial to assess the efficacy of
combined behavioral and pharmacologic interventions in the treatment
of alcohol dependence.  The goal of the research is to determine if
improvement in treatment outcomes can be achieved by therapeutic
strategies that integrate various combinations of pharmacotherapy and
behavioral interventions.  One of the behavioral therapies should be
a less intensive treatment which could be implemented in a managed
care setting. This Request for Applications (RFA) solicits
applications for both Clinical Research Units (CRUs) and a
Coordinating Center (CC).
 
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), for a multisite study of Combined
Behavioral/Pharmacologic Treatment of Alcoholism, is related to the
priority area of research on alcoholism treatment.  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
202-512-1800).
 
ELIGIBILITY REQUIREMENTS
 
Applications may be submitted by domestic 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. Racial/ethnic minority
individuals, women, and persons with disabilities are encouraged to
apply as Principal Investigators.
 
This RFA is for both Clinical Research Units (CRUs) and a
Coordinating Center (CC). Separate applications are required for
each.  Awards for Clinical Research Units and the Coordinating Center
under this RFA will not be made to the same Principal Investigator,
although the same institution may apply for both.
 
MECHANISM OF SUPPORT
 
The administrative and funding instrument to be used for this program
will be a clinical research cooperative agreement (U10), 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.  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."
 
The total project period for applications submitted in response to
the present RFA may not exceed 6 years.  The anticipated award date
is September 1997.  At this time, the NIAAA has not determined
whether or how this solicitation will be continued beyond the present
RFA.
 
Because the nature and scope of the research proposed in response to
this RFA may vary, it is anticipated that the sizes of awards will
vary.  Awards and level of support depend on receipt of a sufficient
number of applications of high scientific merit. Although this
program is in the financial plans of the NIAAA, awards pursuant to
this RFA are contingent upon the availability of funds for this
purpose.
 
FUNDS AVAILABLE
 
It is anticipated that up to $2.5 million per year for the first 2
years and up to $5.0 million per year for years 3-6 will be available
for direct and facilities and administrative costs under this RFA. It
is anticipated that:(a) one award for the Coordinating Center will be
made for approximately $375,000 per year in years 1 and 2 and for
approximately $750,000 to 1,000,000 per year in years 3-6, (b) 6-8
awards for Clinical Research Units will be made of approximately
$250,000 per year in years 1-2, and an average of $500,000 per year
in years 3-6, with levels adjusted appropriately for the differing
requirements of the activities (e.g., recruitment, intervention,
followup, and data analysis) in each of the years.
 
RESEARCH OBJECTIVES
 
Background
 
Important advances have been made in the development of both
medications and behavioral interventions to treat alcoholism.  Among
the medications are naltrexone, nalmefene, and acamprosate.  The
behavioral interventions include motivationally based, targeted
behavioral strategies and interpersonal support treatments.  These
two types of treatments are not competitive and may enhance each
other.  Pharmacotherapies may reduce craving for alcohol and/or the
reinforcement experienced by drinking alcohol. Behavioral therapies
provide skills for patients to maintain sobriety for extended periods
of time.  Combinations of the two may improve outcome over either
modality alone.  Recent research is consistent with this and
indicates that pharmacologic agents can be combined effectively with
behavioral interventions and that their combination enhances
treatment outcome.
 
Based on accumulating evidence in the literature, it is appropriate
at this time to consider a systematic large scale study of the
benefits of combined pharmacologic and behavioral interventions.
Relevant literature is summarized below.
 
Promising Pharmacologic Therapies
 
Over the past decade research on medications to treat alcoholism has
rapidly expanded (Litten et al., 1996).  In particular, advances have
been made in understanding the biology underlying drinking behavior,
thereby suggesting new possibilities for pharmacologic treatments.
For example, it is now known that multiple neurotransmitter systems
are involved in problem drinking.  These include opioid, serotonin,
dopamine, gamma-aminobutyric acid (GABA), and glutamate systems.
Several medications that affect these neurotransmitter systems have
been tested in humans, including opioid antagonists, selective
serotonin reuptake inhibitors, 5-HT3 antagonists, 5-HT2 antagonists,
5-HT1A agonists, dopamine agonists, and GABAergic agents.
 
Currently, the two most promising and reasonably well researched
medications are naltrexone and acamprosate.  Two landmark clinical
trials of naltrexone (Volpicelli et al., 1992 and O'Malley et al.,
1992) with alcohol dependent patients produced similar results.
Analysis of data combined from the two studies showed that the rate
of abstinence for the 12-week trials was 54 percent for the
naltrexone group contrasted with 31 percent for the placebo group
(O'Malley et al., 1995).  If drinking was initiated, the rate of
relapse to heavy drinking of the placebo-treated subjects was twice
that of the naltrexone group.  A possible explanation is that
naltrexone blocks the reinforcing effects of alcohol.
Naltrexone-treated patients spent 3.1 percent of their days drinking
in contrast to 7.5 percent for those on placebo.  Finally, craving
for alcohol was lower for the naltrexone group than for
placebo-treated subjects.
 
In December 1994, naltrexone was approved by the Food and Drug
Administration (FDA) for the adjunctive treatment of alcoholism.
This is the first medication so designated in over 50 years since the
approval of disulfiram.  Within the past year, Canada and Austria
also approved naltrexone as a treatment for alcoholism.
 
Acamprosate (calcium acetylhomotaurinate) has been studied
extensively in Europe. Paille et al., (1995) conducted a 31-site
trial of acamprosate in which 538 alcohol dependent patients received
either 1.3 g/day or 2.0 g/day or placebo for 1 year.  At the end of 6
months, abstinence was sustained in 32 percent of the high dose
acamprosate group, in 27 percent of the low dose acamprosate group,
and in 19 percent of the placebo group.  At the end of 1 year,
approximately 19 percent maintained sobriety versus 11 percent of
placebo-treated subjects.  In addition, treatment retention was
significantly higher for both acamprosate groups.  Acamprosate
produced no major adverse effects.  The most common side effect was
diarrhea.
 
Whitworth et al., (1996) completed a study with 455 alcohol dependent
patients. At the end of the 1 year treatment, 18 percent of
acamprosate-treated patients had been abstinent in contrast with 7
percent of placebo-treated subjects.  One year after termination of
treatment the acamprosate group still demonstrated a significantly
higher rate of abstinence than did the placebo group (12 percent
versus 5 percent).
 
Sass et al., (1996) reported results from a 12-site study with 272
detoxified alcohol dependent patients.  Following 48 weeks of
treatment, 43 percent of the acamprosate-treated subjects had
sustained sobriety versus 21 percent for the placebo group.  The
side-effect profiles were identical for acamprosate- and
placebo-treated subjects.
 
Mann et al., (1995) analyzed pooled European data consisting of over
three thousand alcohol dependent subjects from 11 independent
acamprosate studies.  The acamprosate group had significantly more
sustained abstinence, better treatment retention, and those who drank
did so on significantly fewer days than did the placebo-treated
subjects.
 
The site of action of acamprosate is different from that of
naltrexone, an opioid antagonist.  Although the precise mechanism of
action is still under investigation, it appears to interact with
excitatory amino acids, such as glutamate, and the inhibitory GABA
system.
 
Research is needed to determine if the combination of naltrexone and
acamprosate will improve treatment outcome.
 
Promising Behavioral Interventions
 
Recently, Project MATCH findings showed marked differences in
drinking pre- and post-treatment for three therapies: Cognitive
Behavioral Therapy, Motivational Enhancement Treatment, and Twelve
Step Facilitation (Project MATCH Research Group, in press).  It would
be highly desirable to build on these findings and to consider using
one or more of the MATCH treatments in the proposed trial.  These
interventions have demonstrated good retention, patient acceptability
and feasibility of implementation. These treatments have been fully
described in published therapist manuals which have received wide
distribution in the treatment community.
 
Controlled investigations of other behavioral treatments for alcohol
problems have been comprehensively reviewed by Hester and Miller
(1995).  Following review of almost 200 such trials, these
commentators identified interventions which offered good evidence for
efficacy. Among these were: brief intervention, social skills
training, motivational enhancement, and behavior contracting.  Social
skills training and motivational enhancement techniques were
incorporated into the Project MATCH therapies. While other verbal
therapies have evidence for their efficacy, none have been studied in
a multisite, large sample study as have the three MATCH therapies.
 
Social skills training employs behavioral techniques such as
instruction, prompting, practice, and feedback to enhance the
patient's general repertoire of interpersonal relationship skills as
well as ability to cope with peer pressure that may induce drinking.
 
Motivational enhancement techniques include non-confrontational
interviewing of patients, feedback in an attempt to deepen their
awareness of need for change, reinforcement of their commitment to
and sense of self efficacy for positive change, and establishment of
personal goals.
 
Brief intervention is generally undertaken in a primary care setting.
While there are many variants of what has been termed "brief
intervention," Bien et al., (1993)  state that effective brief
interventions are characterized by several elements encompassing
feedback and patient responsibility for change.
 
Finally, behavior contracting, as the name implies, involves
establishing written agreements with the patient to achieve specific
goals in treatment or practice a treatment element, such as attend
aftercare sessions, complete extra-treatment "homework" assignments,
or take disulfiram.  Often a significant other also signs the
contract. This technique could be utilized as a procedure to enhance
compliance with therapy and medications.
 
Research Questions
 
The objective of this study is to conduct a prospective, multi-center
cooperative clinical trial to assess the efficacy of combined
behavioral and pharmacologic interventions in the treatment of
alcohol dependence.  It is envisioned that the study will test two
behavioral interventions (one of moderate intensity and the other of
minimal intensity which would be practical for use in managed care
settings and may be either group or individual settings therapy)
crossed with two individual pharmacologic agents, the combination of
the two agents, and placebo, resulting in an eight cell design.
Applicants should address the research questions that flow from this
design. Examples of relevant questions include, but are not limited
to, the following questions:
 
1) Can improvement in treatment outcomes be achieved by combining
behavioral interventions with pharmacotherapy;
 
2) Does the relative efficacy of particular combinations of
behavioral-pharmacologic therapies differ;
 
3) Is a moderate intensity behavioral intervention more effective
than a more minimal intervention;
 
4) Does combining two pharmacotherapies lead to greater improvements
in outcome than that achieved by use of either of the agents singly;
and
 
5) Are different types of alcoholic patients likely to be more
responsive to behavioral or pharmacologic intervention in general as
well as to specific types of medicational and behavioral
interventions in combination.
 
Outline of Study Design
 
To address the research questions of this program, the application
should include, at a minimum, the following major components:
 
1) A study design which is double blind, placebo controlled,
utilizing two medications, such as naltrexone and acamprosate and two
behavioral therapies.  One behavioral therapy should be a MATCH
treatment or one based on a MATCH treatment and the other should be a
less intense treatment which could be implemented in a managed care
setting.  The behavioral interventions may be in either individual or
group formats. Strategies should be developed for enhancing
compliance with medication and behavioral treatments. Abstinence
should be the goal of the interventions.
 
2) Duration of active treatment should be at least 6 months and
minimum follow-up should be at least 1 year post treatment.
 
3) A comprehensive assessment battery should include as a minimum,
instruments to: evaluate patients' drinking history, establish
appropriate diagnosis, measure patient variables, e.g., family
history likely to be associated with responsivity to current
treatment, and assess compliance with treatment, and evaluate
drinking outcome. Biochemical markers to validate consumption should
be selected.  Applicants should strive for practicality and
efficiency in their use of markers and collaterals.  One of the
primary outcomes to be measured is abstinence.
 
4) Applicants should develop a plan for augmenting the treatment of
patients who are nonresponders to the initial medication and
psychotherapy combinations, including objective criteria to define
nonresponse.
 
5) The study should be conducted with an outpatient population who
meet criteria for alcohol dependence, but who do not meet criteria
for current major depression or drug abuse except for nicotine,
caffeine, or marijuana.
 
6) Study duration should be 6 years including the 12 months for a
preliminary study.
 
7) Applicants also should identify and develop a preliminary study to
be conducted in months 7-18 related to the study research questions
listed above.  Examples of such preliminary studies include, but are
by no means restricted to, medication compliance management, and
issues related to drug administration such as dosing and patient
acceptance.  The total cost for the preliminary study proposed should
not exceed $300,000 including facility and administrative costs, and
the duration should not exceed 12 months. Specific hypotheses for the
preliminary study, design, and assessment are left to the discretion
and creativity of the applicants. Final determinations concerning the
nature, scope and timing of the specific preliminary study (or
studies) will be made by the Steering Committee during the initial
planning period.
 
Elaboration of the Model Study Design
 
Although the outline of a model strategy is given above, applicants
should develop and fully elaborate the key elements of the study
design such as:
 
1) Research question and detailed plan for the preliminary study;
2) Nature of the behavioral interventions for the main study;
3) Estimates of sample size for the main study;
4) Details of assessment battery for the main study;
5) Details of the plan for treatment augmentation of nonresponders in
the main study; and
6) Data analysis plan.
 
Final Protocol Development
 
In keeping with the goals of the cooperative agreement mechanism, the
protocol will be discussed by the Steering Committee, composed of
awardees and NIAAA staff.  After awards are made the Steering
Committee may collaboratively develop a study protocol that differs
from the model outlined here (e.g., a different design, alternative
drugs, etc)provided the research questions of the RFA are addressed
and the Institute agrees that the resultant design is still within
the general scope and will serve the purposes described in this RFA.
 
After awards are made participating institutions will collaborate to
develop and then follow a mutually acceptable common study protocol
with standardized study design, data collection procedures, and
intervention approaches.  The collaborative protocol will be
developed during the first 6 months of the study by the Steering
Committee of the study.
 
Coordinating Center
 
In addition to the CRUs, a Coordinating Center will be needed to: (1)
organize and provide logistical support for Steering Committee
meetings and relevant Executive Secretariat functions; promote
communication across sites, including preparation and distribution of
meeting minutes and support for the work of trial committees, such as
conference call arrangements and distribution of minutes; (2)
coordinate the development of trial wide forms, procedures and
training exercises; design and maintain a manual of operations; (3)
monitor quality control of treatment delivery and data collection;
(4) monitor and support enrollment, randomization and follow up
activities; (5) design, document, and assemble the data base
resulting from the common protocol; (6) perform core trial wide
analyses in a centralized manner; (7) coordinate analyses done in a
decentralized manner to avoid overlap and assure continuity and
quality; (8) procurement, packaging and distribution of the drugs and
their matched placebos; (9) application, on behalf of the CRUs, for
any necessary IND approval; and (10) establish a centralized and
standardized mechanism for performance of bioassays.
 
TIMETABLE
 
Phase 1: The first 6 months of the collaborative effort will be
devoted mainly to developing a common protocol, developing the
necessary training and implementation procedures, finalizing manuals
to ensure cross-site consistency in study execution and identifying
the essential preliminary study or studies.  Phase 2: In months 7-18
the preliminary study (or studies) will be implemented and completed,
based on decisions made by the Steering Committee; in months 18-24
the protocol for the main trial will be finalized.  Phase 3: In
months 19 through 60 the recruitment for the main study, delivery of
treatments, and follow-up will be done.  In year 6 data will be
analyzed and manuscripts written.
 
SPECIAL REQUIREMENTS
 
This section summarizes special scientific considerations that must
be addressed in the applications for Clinical Research Units, in
addition to other elements of the research plan.
 
1. The application should include a proposed protocol that meets the
objectives and scope outlined in this RFA and responds to the
required major components as stated in the "Research Questions" and
"Study Design" sections.  Award of the cooperative agreement does not
imply that any particular proposed protocol will be implemented.
Since the final study will be designed by the Steering Committee, the
final protocol may not reflect any single proposal submitted in
response to this RFA.
 
2. Applicants should identify and develop a preliminary study.
Specific hypotheses for the preliminary study, details of the study
design, and assessment are in the hands of the investigator.  This
preliminary study should not exceed 12 months in duration.
 
3. Applicants should develop a plan for augmenting the treatment of
patients who are nonresponders to the initial medication and
psychotherapy combinations, including objective criteria to define
nonresponse.
 
TERMS AND CONDITIONS OF AWARD
 
The following terms and conditions will be incorporated into the
award statement and provided to the Principal Investigator(s) as well
as the institutional official at the time of award.  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 Parts 74 and 92, and other HHS, PHS, and NIH
Grant Administration policy statements.
 
The administrative and funding instrument used for this program is a
clinical research cooperative agreement (U10), 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
NIAAA project staff. Details of the roles of the parties are
described later in this section.
 
A. Awardee Rights and Responsibilities
 
Awardees will have primary and lead responsibilities for the project
as a whole including protocol development, participant recruitment
and follow-up, data collection, quality control, interim data and
safety monitoring, final data analysis and interpretation,
preparation of publications, as well as collaboration with other
awardees and with assistance from NIAAA staff.
 
The Principal Investigator defines the details for the project in
accordance with these Terms and Conditions of Award; retains primary
responsibility for the performance of the activity; and agrees to
close coordination, cooperation, and assistance of NIAAA extramural
staff in aspects of scientific and technical management of the
project as described herein.
 
1. Steering Committee Membership and Meeting Attendance
 
Each Principal Investigator (or designee) will be responsible for
attending all Steering Committee meetings. The Steering Committee
will meet five times in year 1 and four times yearly in subsequent
years.  The Steering Committee shall be responsible for determining
the frequency and scheduling of meetings.  Each Principal
Investigator (or designee) will be expected to participate in all
other Steering Committee activities, e.g., conference calls, special
subcommittees as may be necessary, etc.
 
2. Role of Clinical Research Units
 
Each awardee institution and its corresponding investigators will be
responsible for developing and implementing research aims; adjusting
research priorities in accordance with current developments and
available budget funds; participating in analyses; and accepting the
participatory and cooperative nature of the group process and
policies relevant to this program.
 
3. Role of the Coordinating Center
 
In addition to the CRUs, a Coordinating Center will be needed to: (1)
organize and provide logistical support for Steering Committee
meetings and relevant Executive Secretariat functions; promote
communication across sites, including preparation and distribution of
meeting minutes and support for the work of trial committees, such as
conference call arrangements and distribution of minutes; (2)
coordinate the development of trial wide forms, procedures and
training exercises; design and maintain a manual of operations; (3)
monitor quality control of treatment delivery and data collection;
(4) monitor and support enrollment, randomization and follow up
activities; (5) design, document, and assemble the data base
resulting from the common protocol; (6) perform core trial wide
analyses in a centralized manner; (7) coordinate analyses done in a
decentralized manner to avoid overlap and assure continuity and
quality; (8) procurement, packaging and distribution of the drugs and
their matched placebos; (9) application, on behalf of the CRUs, for
any necessary IND approval; and (10) establish a centralized and
standardized mechanism for performance of bioassays.
 
B. NIAAA Staff Responsibilities
 
The NIAAA staff role in this cooperative agreement will extend beyond
the level normally required for stewardship of a grant because of the
need for coordination of study protocols among performance sites,
technical assistance in the analysis of data, and monitoring and
possible reassessment of project objectives as the study proceeds.
The NIAAA extramural staff perform different functions in research
projects supported under the cooperative agreement mechanism.
 
1. Program Official
 
The Program Official provides normal stewardship of the award and has
overall responsibility for monitoring the conduct, progress, and
fiscal management of the program.  Progress of the project will be
reviewed by the Program Official annually at the time of each
continuation application to assure that satisfactory progress is
being made in achieving the objectives of the project and that each
performance site is following the program goals and procedures
recommended for use by all participants in the cooperative program
and approved by the Steering Committee.
 
2. NIAAA Staff Collaborator
 
The NIAAA Staff Collaborator has substantial scientific input in
collaboration with award recipients, in both planning and conduct of
the research.  The NIAAA Staff Collaborator will (1) participate as a
voting member on the Steering Committee which oversees this research
effort, the Executive Committee and relevant technical subcommittees
or working groups as appropriate; (2) participate in the formulation
of protocols and other planning related to the completion of the
research; and (3) participate in monitoring the progress of the
research and quality control, and (4) the analysis and interpretation
of data, and possibly in associated publications and presentations.
 
3. NIAAA Senior Scientific Advisor
 
The NIAAA Senior Scientific Advisor will advise on policy, budget,
and technical matters relating to trial conduct.
 
4. NIAAA Consultants for Behavioral and Pharmacologic Treatments
 
The consultants will advise on technical issues related to these
topics, serve on working committees, attend Steering Committee
meetings, and participate in analyses and publications.
 
The NIAAA staff will be subject to the same publication/authorship
policies governing all participants in the study, as well as to the
official NIH Publication Policy governing extramural employees.
 
C. Collaborative Responsibilities
 
1. Governance/Steering Committee
 
A Steering Committee will be the main governing board of the study
and will have primary responsibility for all scientific decisions.
The Steering Committee will be composed of the Principal Investigator
(or designee) of each Clinical Research Unit, the Coordinating
Center, and the NIAAA Staff Collaborator.  Each will have one vote,
should a vote of the Steering Committee be necessary to make a
decision.  The functions of the Steering Committee include: defining
protocol objectives and approaches; designing and implementing the
consensus protocol; developing procedures for data collection and
management and quality control; establishing procedures for assessing
performance with respect to accrual, timely submission and quality of
data, and conscientious observance of protocol requirements;
analyzing and interpreting study data; and publishing/presenting
study findings. The Steering Committee also approves the preliminary
study (studies) based on studies approved during initial peer review.
Each member of the Steering Committee will have one vote.  The
chairperson will be selected by the Steering Committee from among the
non-NIAAA members.  Subcommittees will be commissioned and monitored
by the Steering Committee, as it deems appropriate. Subcommittees
will report to the Steering Committee and will function under the
direction of the Steering Committee. Additional representatives of
NIAAA's Treatment Research Branch may participate as members of
subcommittees.
 
A subset of the Steering Committee will be elected by the group to
serve as an Executive Committee which will meet via conference call
on a regular basis (i.e., weekly or biweekly) between meetings of the
full Steering Committee. Both the NIAAA and the Coordinating Center
will be represented on the Executive Committee.
 
The collaborative protocols will be developed by the Steering
Committee.  Data will be submitted centrally according to a specified
schedule to the Coordinating Center. Protocols will define rules
regarding access to data and publications.
 
By acceptance of this award, awardees will be required to accept and
implement the common protocol, procedures and policies approved by
the Steering Committee.
 
2. Data Coordination and Management
 
To insure consistency and timeliness, the content, methods and
timetable of core analyses will be stipulated in advance by the
Steering Committee and will be performed by the Coordinating Center.
No data relating to the core analyses from the trial-wide merged data
set will be distributed to individual CRUs until these core analyses
are completed.
 
Awardees will retain custody of and primary rights to their data
under these awards subject to Institute rights of access, consistent
with current HHS, PHS, and NIH policies.  Applicants are encouraged
to plan to publish their findings in a timely manner and to make the
data available to the scientific community in a timely way at the end
of the grant period.
 
The trial-wide data set, consisting of the pooled data from all
sites, is considered the common data base to which all investigators
contribute and have access to.  Details of the Publication Policy
will be developed by the Steering Committee and will be binding upon
members.  The Steering Committee will define a key set of
publications on the main trial findings which will be authored by the
Project Research Group as a whole, with individual investigators
precluded from preempting such trial-wide, corporate publications.
 
Review and approval by the Steering Committee will be required for
all analyses prior to the publication or presentation according to
criteria that will be developed by the Committee.
 
D. Monitoring Study Progress
 
1. The Steering Committee will establish mechanisms for assessing
performance of the CRUs, with particular attention to accrual of
adequate numbers of eligible patients, timely submission and quality
of required data, and conscientious observance of protocol.
 
2. The Data and Safety Monitoring Board (DSMB) is an independent
board of experts established by the NIAAA which oversees the
integrity of data and safety of clients. The Institute convenes the
DSMB twice a year.  Its major function is to review reports of
patient safety and data integrity on a regular basis. The Board is
also responsible for reviewing and approving the final protocol prior
to the start of the recruitment phase, and for approving the
progression from one phase of the trial to the next.
 
E. Arbitration
 
Any disagreement that may arise on scientific/programmatic matters
(within the scope of the award), between award recipients and the
NIAAA may be brought to arbitration.  An arbitration panel will be
composed of three members; one selected by the Steering Committee
(with the NIAAA member not voting) or by the individual awardee in
the event of an individual disagreement, a second member selected by
NIAAA, and the third member selected by the two prior selected
members. This special arbitration procedure in no way affects the
awardee's right to appeal an adverse action that is otherwise
appealable in accordance with the PHS regulations at 42 CFR Part 50,
Subpart D and HHS regulation at 45 CFR Part 16.
 
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) 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 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 20, 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.
 
LETTER OF INTENT
 
Prospective applicants are asked to submit, by March 21, 1997, a
letter of intent that includes a descriptive title of the proposed
research, name, address, and telephone number of the Principal
Investigator, identities of other key personnel and participating
institutions, and 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
subsequent applications, the information allows the NIAAA staff to
estimate the potential review workload and to avoid conflict of
interest in the review.
 
A separate letter of intent must be submitted for applications for
the Clinical Research Units and the Coordinating Center.
 
The Letter of Intent is to be sent to:
 
RFA-AA-97-004
Office of Scientific Affairs
National Institute on Alcohol Abuse and Alcoholism
Willco Building, Room 409
6000 Executive Boulevard MSC 7003
Bethesda, MD  20892-7003
Telephone:  (301) 443-4375
FAX:  (301) 443-6077
 
APPLICATION PROCEDURES
 
The research grant application form PHS 398 (rev. 5/95) is to be used
in applying for these grants.  Applications 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 301/435-0714, email:
ASKNIH@odrockm1.od.nih.gov.
 
Applications must address the requirements as outlined in study
design, research
objectives, special requirements and terms, and conditions.
 
Additional Materials to Include in the Application
 
1.  All costs required for the proposed protocol must be included in
the application and must be fully justified.  Requested budgets
should include travel to the Washington, D.C. area for four 2 day
Steering Committee meetings each year during the duration of the
trial, except for the first year when five meetings may be required.
 
The acquisition and packaging of the drugs will be handled by the
Coordinating Center. Thus CRU applicants need not address this in
their application's budget section.  The Coordinating Center should
include in its budget an estimated cost for drugs of approximately
$300,000 per year for years 3, 4 and 5.  For budget year 06,
applicants should put the 06 budget year on an additional copy of
form page 5EE of the PHS 398 application.
 
2. The applicant institution and each participating institution
associated with an applicant consortium must document their
experience and capacity to recruit and retain study participants,
provide a description of the population currently available for the
proposed protocol (including yearly figures on numbers of patients
screened, treated, and discharged), and describe proposed mechanisms
for recruiting a minimum of 75 patients per year and monitoring
accrual performance and criteria for continued participation by each
institution contributing patients.
 
3. The application should discuss the capability of the applicant
organization to participate and interact effectively in multi-center
clinical trials.
 
4. The application must include a written commitment to accept the
participation and assistance of NIAAA staff in accordance with the
guidelines outlines under "NIAAA Staff Responsibilities" as stated
above.  The application must also include a written commitment to the
cooperative organization and willingness to serve on the Steering
Committee and adhere to the decisions reached by that Committee,
including following a consensus protocol.
 
5. The application for a CRU must name a single Principal
Investigator (PI) who will have scientific responsibility for the
application as a whole including all research activities included
under it.  Applications from a consortia of institutions must name a
single senior Investigator for each participating institution (other
than the applicant institution) who will be responsible for on-site
scientific direction and implementation for the consensus protocol.
Senior Investigators in consortia must also document relevant
experience in alcoholism treatment research.
 
6. The application must provide a clear concise plan showing the
scientific discipline of the PI and of all key scientific, technical
and administrative personnel, and a mechanism for replacing key
professional or technical personnel should the need arise.
 
The RFA label available in the PHS 398 (rev. 5/95) 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, including
the checklist, 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 20817-7710 (for express/courier service)
 
At the time of submission, two additional copies of the application
must also be sent to:
 
RFA-AA-97-004
Office of Scientific Affairs
National Institute on Alcohol Abuse and Alcoholism
Willco Building, Room 409
6000 Executive Boulevard MSC 7003
Bethesda, Maryland  20892-7003
Rockville, Maryland  20852-7003 (for express/courier service)
 
Applications must be received by April 24, 1997.  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.  The DRG will not accept
any application that is essentially the same as one already reviewed.
This does not preclude the submission of a substantial revision of an
application already reviewed, but such an application must follow the
guidance in the PHS Form 398 application instructions for the
preparation of revised applications, including an introduction
addressing the previous critique.
 
REVIEW CONSIDERATIONS
 
All applications will be judged on the basis of the scientific merit
of the proposed project and the documented ability of the
investigators to meet the RESEARCH OBJECTIVES of the RFA.  Although
the scientific and technical merit of the proposed protocol is
important, it will not be the sole criterion for evaluation of a
study.  Other considerations, such as the relevance and importance of
the preliminary study proposed, access to patients, and understanding
of the nature of a cooperative agreement and the complex requirements
of a multisite trial will also be taken into account.
 
Review Method
 
Upon receipt, applications will be reviewed for completeness by the
DRG and responsiveness by the NIAAA.  Incomplete applications will be
returned to the applicant 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 by the Institute in accordance with the review
criteria stated below. As part of the initial merit review, a
streamlined review process may be used by the initial review group in
which applications may or may not be discussed based on their
scientific merit relative to other applications received in response
to the RFA.  Applications which are fully discussed will be assigned
a priority score.  Applications which are not discussed will be
withdrawn from further considerations and the Principal Investigator
and the official signing for the applicant organization will be
notified.  The second level of review will be provided by the
National Advisory Council on Alcohol Abuse and Alcoholism.
 
Review Criteria
 
The major functional units in the trial are the Clinical Research
Units (CRUs) and the Coordinating Center (CC).  The review criteria
for each are described below.  Note that an institution may submit an
application for a CRU and/or the CC, but no individual PI may serve
as both a CRU PI and the CC PI.  A separate application is required
for each.
 
Factors to be considered in evaluating the scientific and technical
merit of applications for Clinical Research Units are:
 
(1) responsiveness to the goals of the RFA and the scientific and
technical merit of the approach proposed for the key elements of the
main study design, including nature of the behavioral interventions;
estimates of sample size; details of the assessment battery; plans
for the argumentation of treatment for nonresponders and data
analysis.
 
(2) the scientific merit, creativity and relevance of the proposed
preliminary study;
 
(3) scientific qualifications and research experience of the
principal investigator and other key research personnel to conduct a
pharmacologic-behavioral clinical trial and adequacy of their time
commitment to the cooperative program;
 
(4) adequacy of facilities and resources, including computer
facilities;
 
(5) documented access to a sufficient number of subjects (at least 75
per year) and established treatment sites and ability to retain
subjects;
 
(6) understanding of the scientific, logistical, and technical issues
underlying a multicenter collaborative agreement and previously
demonstrated expertise in closely coordinating with fellow
investigators and recruiting sites;
 
(7) adequacy of provisions for the protection of human subjects;
 
(8) adequacy of the plans for the inclusion of both genders and
minorities in the project; and
 
(9) appropriateness of budget estimates for the proposed activities.
 
Criteria for scientific merit review of applications for the
Coordinating Center include:
 
(1) soundness of the proposed plans for the administrative management
and coordination of the trial, including support of the Steering
Committee and working committees;
 
(2) adequacy of the plan for administrative structure within the
Coordinating Center and methods for coordination with the performance
sites;
 
(3) appropriateness of the plans for: collecting and maintaining
data; establishing an appropriate database and assuring data
integrity; instructing field staff on the correct use of research
protocols; and monitoring adherence to research design
specifications;
 
(4) appropriateness of plans for: (a) implementation of analyses of
trial wide core analyses, based on decisions made by the Steering
Committee and (b) distribution of the trialwide data set to CRU's
including methods and policy considerations;
 
(5) experience, competence, willingness, and availability of the
Principal Investigator and other key personnel to perform the
functions of the Coordinating Center, including expertise in
statistics, data management, administration of large scale multisite
studies, conduct of pharmacologic studies, including drug handling
and IND procedures, management of centralized bioassay performance,
and training and supervision of therapists;
 
(6) availability and adequacy of facilities relating to data
management, data analysis, and other needed resources;
 
(7) reasonableness of budget estimates for the proposed activities;
and
 
(8) adequacy of procedures for the protection of human subjects.
 
AWARD CRITERIA
 
Applications recommended by the National Advisory Council on Alcohol
Abuse and Alcoholism will be considered for award based upon
scientific and technical merit; program balance, including in this
instance, sufficient compatibility of features to make a successful
collaborative program a reasonable likelihood; and availability of
funds.
 
INQUIRIES
 
Written and telephone inquiries concerning this RFA are encouraged.
The opportunity to clarify any issues or questions from potential
applicants is welcomed.
 
Direct inquiries regarding programmatic issues to:
 
Margaret Mattson, Ph.D.
Division of Clinical and Prevention Research
National Institute on Alcohol Abuse and Alcoholism
6000 Executive Boulevard - MSC 7003
Bethesda, MD  20892-7003
Rockville, MD  20852-7003 (for express/courier service)
Telephone:  (301) 443-0796
FAX:  (301) 443-8774
Email:  mmattson@willco.nih.niaaa.gov
 
Direct inquiries regarding fiscal matters to:
 
Linda Hilley
Grants Management Branch
National Institute on Alcohol Abuse and Alcoholism
6000 Executive Boulevard MSC 7003
Bethesda, MD  20892-7003
Telephone:  (301) 443-0915
FAX:  (301) 443-3891
Email:  lhilley@willco.niaaa.nih.gov
 
AUTHORITY AND REGULATIONS
 
This program is described in the Catalog of Federal Domestic
Assistance, No. 93.273. Awards are made under the authorization of
the Public Health Service Act, Sections 301 and 464H, and
administered under the PHS policies and Federal Regulations at Title
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 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.
 
References
 
Bien, T.H., Miller, W.R., and Tonigan, J.S. (1993).  Brief
interventions for alcohol problems:  A review.  Addiction, 88,
315-336.
 
Hester, R.K. and Miller, W.R. (1995).  Handbook of Alcoholism
Treatment Approaches: Effective Alternatives, Hester, R.K. and
Miller, W.R. (Eds.).  Allyn & Bacon, Needham Heights, MA.
 
Litten, R.Z., Allen, J., and Fertig, J. (1996).  Pharmacotherapies
for alcohol problems: A review of research with focus on developments
since 1991. Alcoholism: Clinical and Experimental Research
20(5):859-876.
 
Mann, K., Chabac, S., Lehert, P., Potgieter, A., and Sass, H.
Acamprosate improves treatment outcome in alcoholics: A pooled
analysis of 11 randomized placebo controlled trials in 3338 patients.
Presented at 34th Annual Meeting of American College of
Neuropsychopharmacology, San Juan, Puerto Rico, December 1995.
 
O'Malley, S.S., Jaffe, A.J., Chang, G., Schottenfeld, R.S., and
Meyer, R.E. (1992). Naltrexone and coping skills therapy for alcohol
dependence: A controlled study. Archives of General Psychiatry
49:881-887.
 
O'Malley, S.S., Croop, R.S., Wroblewski, J.M., Labriola, D.F.,
Volpicelli, J.R. (1995). Naltrexone in the treatment of alcohol
dependence: A combined analysis of two trials. Psychiatric Annuals
25: 681-688.
 
Paille, F.M., Guelfie, J.D., Perkins, A.C., Royer, R., Steru, L. and
Parot, P. (1995). Double-blind randomized multicentre trial of
acamprosate in maintaining abstinence from alcohol.  Alcohol and
Alcoholism, 30, 239-247.
 
Project MATCH Research Group (in press).  Matching Alcoholism
Treatments to Client Heterogeneity:  Project MATCH Post-treatment
Drinking Outcomes.  Journal of Studies on Alcohol.
 
Sass, H., Soyka, M., Mann, K., and Zieglgansberger, W. (1996).
Relapse Prevention by Acamprosate:  Results from a placebo-controlled
study on alcohol dependence.  Archives General Psychiatry, 53,
673-680.
 
Volpicelli, J.R., Alterman, A.I., Hayashida, M., O'Brien, C.P.(1992).
Naltrexone in the treatment of alcohol dependence. Archives of
General Psychiatry 49: 876-880.
 
Whitworth, A.B., Fischer, F., Lesch, O.M., Nimmerrichter, A.,
Oberbauer, H., Platz, T., Potgieter, A., Walter, H. and
Fleischhacker, W.W. (1996).  Comparison of acamprosate and placebo in
long-term treatment of alcohol dependence.  Lancet, 347(9013),
1438-1442.
 
.

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