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REQUEST FOR APPLICATIONS FOR A
GRANT-IN-AID
Subject: Clinical Trial of Treatment for
Tinnitus
Source: Tinnitus Research Consortium
Letter of Intent Receipt Date: December 15,
2007
Application Receipt Date: February 1, 2008
PURPOSE
The Tinnitus Research Consortium, supported by
private philanthropy, invites applications for the
support of a clinical trial of therapy for
individuals who suffer from tinnitus. The goal of
this Request for Applications is to add to the
clinical options in the treatment of such
individuals.
ELIGIBILITY REQUIREMENTS
Applications may be submitted by domestic (US),
for-profit and non-profit organizations, such as
universities, colleges, hospitals, clinics,
laboratories and units of state and local
governments.
SUPPORT
The total project period for an application
submitted in response to this request may not
exceed three years. There are no plans for
continuation of the project beyond three years.
Responsibility for planning, direction and
execution of the proposed project will rest solely
with the applicant. The total funds planned for
support of the successful response to this request
for applications are $300,000. An award of up to
$100,000 per year may be made for direct costs of
the research. Grants-in-aid made through the
Tinnitus Research Consortium do not provide
overhead expenses. An award made pursuant to this
request for applications is contingent upon the
availability of funds for this purpose. The award
will be made on or about June 1, 2008, and the
starting date of the clinical trial should be July
1, 2008 or later. Prior to the actual funding, the
clinical trial must be registered in a public
trials registry, preferably at www.clinicaltrials.gov
with the Protocol Registration System of the
National Institutes of Health. Registration is a
condition for consideration for publication of the
results of a clinical trial set by the
International Committee of Medical Journal Editors.
Please see www.icmje.org
(particularly, III.J. Obligation to Register
Clinical Trials).
RESEARCH OBJECTIVES
Background
Tinnitus is the perception of a sound in the
absence of an environmental acoustic stimulus. It
is estimated that approximately 30 million people
in the United States experience tinnitus. At least
three million of these individuals suffer from
tinnitus to the extent that it interferes
substantially with the activities of daily living
including sleep. In some individuals, tinnitus
causes irritability, agitation, stress, depression
and insomnia. Tinnitus is a symptom that is
associated with virtually all diseases and
disorders affecting the auditory system and can
arise from a lesion in any part of the auditory
system. The site of origin of the sound percept
may be in the central auditory pathways even if the
initial lesion is in the end organ of the auditory
system. Tinnitus is usually associated with a loss
of hearing. Many of the causes of tinnitus are
well known. Although the mechanisms of the
production of tinnitus are far from being fully
understood, there is growing evidence that a
correlate of tinnitus is a change in activity in
the dorsal cochlear nucleus, inferior colliculus,
thalamus and/or auditory cortex.
Therapy for tinnitus has included a wide variety
of approaches utilizing pharmacological or physical
agents and psychological methods.
It is possible that different pharmacologic
agents or classes of pharmacologic agents act
selectively to alter the psychoacoustic parameters
of the tinnitus or influence the emotional or
autonomic reactions to tinnitus. Whereas one class
of drugs may address the pitch, loudness, or
minimal masking level of tinnitus or even eliminate
the perception of tinnitus, other drugs may
ameliorate the anxiety, depression, insomnia,
inattention or memory loss associated with
tinnitus. It may be that some drugs could
effectively modify both the perceptual parameters
of and the emotional or autonomic reactions to
tinnitus.
A large number of pharmacological agents have
been utilized to treat individuals with tinnitus.
Clinical trials of psychotropic drugs have
demonstrated various benefits for individuals who
suffer from tinnitus. Tocainide and related drugs,
carbamazepine, benzodiazepines and tricyclic
antidepressants have been evaluated in controlled
clinical trials. The tricyclic antidepressants,
nortriptyline and amitriptyline, have been found to
be useful. The benefit in the nortriptyline
clinical trial appears to be in large measure due
to the relief of depression and the associated
insomnia.
Since these clinical trials were carried out,
new antidepressant agents (the selective serotonin
reuptake inhibitors) have been developed that have
clinical advantages in the management of
depression. Anticonvulsant agents may be effective
in reducing tinnitus annoyance and loudness.
Acamprosate, which may interact with glutamate and
gamma-aminobutyric acid (GABA) neurotransmitter
systems centrally, has intriguing theoretical
potential and initial clinical trial success in
short-term tinnitus relief. Its effectiveness in
maintenance of abstinence in chronic alcoholism is
thought to result from balancing neuronal
excitation and inhibition. Perhaps regulating
glutamate excitation and GABA inhibition could
alter or eliminate the perception of tinnitus.
These agents and newer psychotropic and
anticonvulsant drugs deserve further study.
Among physical agents, electrical and magnetic
stimulation, acoustic masking and acupuncture have
been studied to varying extents. Electrical and
magnetic stimulation for the suppression of
tinnitus have shown promise and deserve further
evaluation.
Psychological methods including biofeedback,
hypnosis, psychotherapy and retraining have been
successfully employed and also deserve further
evaluation.
In general, in randomized clinical trials the
agents under study have failed to demonstrate
elimination of tinnitus more frequently than have
placebos. This may in part be due to the unusually
high positive response to placebos in the
management of tinnitus. Nevertheless, there is no
generally recognized standard therapy for tinnitus
to which new promising treatments can be compared.
Small but real treatment effects may be missed in
randomized clinical trials with a small number of
subjects. Some subgroups of individuals with
tinnitus have been found to have large treatment
effects with specific agents or methods. If
favorable responders represent a small percentage
of subjects, a randomized clinical trial could fail
to identify a large treatment effect.
Research Goals and Scope
There is a need to determine the efficacy of
promising therapeutic approaches through clinical
trials involving individuals who suffer from
tinnitus, controlled with placebo and for variables
known to influence the outcome and masked for the
subjects and evaluators. Nevertheless, an open
clinical trial to identify responders may have to
precede a randomized, placebo-controlled, masked
trial limited to responders to avoid missing a
large treatment effect in a subgroup of subjects.
In addition to determining whether the promising
therapeutic approach offers benefit to tinnitus
sufferers, diagnostic criteria for prognosis in
therapy are needed. Specifically, there is a need
to determine what subgroup of individuals who
suffer from tinnitus can be expected to benefit
from the treatment. The application should
include, but not be limited to:
- careful description of the possible
mechanisms of action of the proposed agent and
how these mechanisms relate to our present
understanding of tinnitus;
- preliminary evidence of benefit for patients
with tinnitus of the agent or method under
study;
- identification of the diagnostic criteria of
the patient population under study, tinnitus
measurements utilized and stratification of
subjects for variables known to affect
outcome;
- criteria for the duration and severity of
tinnitus required for accession of subjects to
the study;
- the design of the study regarding
randomization, masking, placebo control,
possible crossover or washout, and statistical
management of the data including the statistical
power of the study;
- dosage and frequency of treatment
administration and schedule of evaluation during
and after treatment;
- estimate of the magnitude of the placebo
effects;
- outcome variables including prognostic
factors; and
- a data and safety monitoring plan.
SPECIAL REQUIREMENTS
The principal investigator must obtain the
approval of his or her Institutional Review Board
for the project and provide documentation of it.
(Reference: Code of Federal Regulations Title 45
Part 46 at http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm).
The "National Institutes of Health Guidelines on
the Inclusion of Women and Minorities as Subjects
in Clinical Research" amended October 2001 should
be followed. (Please see http://grants2.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm).
Semiannual progress reports and annual financial
reports are required, and the principal
investigator is expected to meet with the Tinnitus
Research Consortium annually at the discretion of
the Tinnitus Research Consortium to discuss the
progress in the project. Funding for the second
and third years is contingent on evidence of
satisfactory progress in the semiannual progress
reports. A final progress report is required at
the end of the grant period.
LETTER OF INTENT
Prospective applicants are requested to submit
by December 15, 2007 a letter of intent containing
the title of the proposed research, the name,
address and telephone number of the principal
investigator, the names of other key personnel and
the participating institutions. This information
allows the Tinnitus Research Consortium to plan for
the review and avoid conflicts of interest. The
letter of intent is not required, is not binding
and is not considered in the subsequent review.
The letter of intent should be sent to: James B.
Snow, Jr., M.D., Tinnitus Research Consortium, 327
Greenbriar Lane, West Grove, PA 19390-9490 or
e-mail jandssnow@comcast.net.
APPLICATION PROCEDURES
The application and a list of the members of the
Tinnitus Research Consortium may be obtained from
James B. Snow, Jr., M.D., Tinnitus Research
Consortium, 327 Greenbriar Lane, West Grove, PA
19390-9490, telephone and fax 610-345-0085 and
e-mail jandssnow@comcast.net.
Please submit the application in electronic format
in a single Word file on a CD and a signed printed
version and three signed copies to James B. Snow,
Jr., M.D., Tinnitus Research Consortium, 327
Greenbriar Lane, West Grove, PA 19390-9490 by
February 1, 2008.
REVIEW CONSIDERATIONS
Applications will be evaluated for scientific
and technical merit by experts in the subject
matter of the application selected by the Tinnitus
Research Consortium and receive an evaluation
score. A second level of review will be provided
by the Tinnitus Research Consortium, which will
make funding recommendations to the sponsor.
Evaluation Criteria
A carefully designed and feasible clinical trial
of the effectiveness of a treatment for individuals
who suffer from tinnitus will be considered
responsive to this request for applications.
Additional evaluation criteria include:
- scientific, technical and medical
significance and originality of the proposed
research;
- appropriateness and adequacy of the design
of the clinical trial and the methods to be
employed in clinical evaluation;
- qualifications and research experience of
the principal investigator and key staff in the
area of proposed research;
- inclusion of the opportunity to elucidate
some fundamental information on the mechanisms
operating in the generation of the percept of or
reaction to tinnitus;
- availability of clinical resources and the
patient population necessary to perform the
research;
- adequacy of the plans to include both
genders and minorities for the scientific goal
of the research;
- plans for the recruitment and retention of
subjects;
- provisions for the protection of the
subjects and safety of the research
environment;
- appropriateness of the plan for the
statistical management of the data; and
- appropriateness of the budget and the
duration of the proposed research project.
Special consideration will be given to
applicants who are successful in obtaining partial
support for the clinical trial from the
manufacturer of the therapeutic agent under study
or from other sources.
INQUIRIES
Postal mail, telephone or e-mail inquiries
regarding this request for applications are
encouraged. The opportunity to clarify any issues
for potential applicants is welcomed. Direct
inquiries to James B. Snow, Jr., M.D., Tinnitus
Research Consortium, 327 Greenbriar Lane, West
Grove, PA 19390-9490, telephone and fax
610-345-0085 and e-mail jandssnow@comcast.net.
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