University of California, Los Angeles
Office for Protection of Research Subjects
HUMAN SUBJECT PROTECTION COMMITTEE (HSPC)
APPLICATION TO INVOLVE HUMAN SUBJECTS IN RESEARCH
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INVESTIGATOR'S
ASSURANCE |
I certify that the information
provided in this application is complete and correct.
I understand that as
Principal Investigator, I have ultimate responsibility for the conduct of the
study, the ethical performance of the project, the protection of the rights and
welfare of human subjects, and strict adherence to any stipulations imposed by
the HSPC.
I agree to comply with
all UCLA policies and procedures, as well as with all applicable federal,
State, and local laws regarding the protection of human subjects in research,
including, but not limited to, the following:
·
performing the project
by qualified personnel according to the approved protocol,
·
implementing no changes
in the approved protocol or consent form without prior HSPC approval (except in
an emergency, if necessary to safeguard the well-being of human subjects),
·
obtaining the legally
effective informed consent from human subjects or their legally responsible
representative, and using only the currently approved, stamped consent form
with human subjects,
·
promptly reporting significant or untoward adverse
effects to the HSPC in writing within 5 working days of occurrence.
·
if I will be unavailable
to direct this research personally, as when on sabbatical leave or vacation, I
will arrange for a co-investigator to assume direct responsibility in my
absence. Either this person is named as
a co-investigator in this application, or I will advise HSPC by letter, in
advance of such arrangements.
____________________________________________________________________
Principal Investigator Date
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FACULTY SPONSOR’S
ASSURANCE |
By my signature as sponsor on this research
application, I certify that the student
or guest investigator is
knowledgeable about the regulations and policies governing research with human
subjects and has sufficient training and experience to conduct this particular
study in accord with the approved protocol.
In addition,
·
I agree to meet with the
investigator on a regular basis to monitor study progress.
·
Should problems arise
during the course of the study, I agree to be available, personally, to
supervise the investigator in solving them.
·
I assure that the
investigator will promptly report significant or untoward adverse effects to
the HSPC in writing within 5 working days of occurrence.
·
If I will be
unavailable, as when on sabbatical leave or vacation, I will arrange for an
alternate faculty sponsor to assume responsibility during my absence, and I
will advise the HSPC by letter of such arrangements.
____________________________________________________________________
Faculty Sponsor *
(if PI is a student or a fellow)
Date
* The faculty sponsor must be a member of the UCLA
faculty. The faculty member is
considered the responsible party for legal and ethical performance of the
project.
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SECTION
II - FUNDING |
THIS SECTION
MUST BE COMPLETED
1. Check all of the appropriate
boxes for funding sources for this research, include pending funding source(s):
X Extramural* UCLA Academic Senate Department
Gift Other:
* P.I. of Contract or Grant: Paul Krogstad, M.D.
Funding Source: National
Institutes of Health
2. If using an IDENTICAL protocol for more than one extramural funding proposal,
list all funding sources below. Attach
an additional sheet if more space is needed.
a. P.I. of Contract or Grant:
Funding Source:
Contract or Grant No.:
Contract or Grant Title:
b. P.I. of Contract or Grant:
Funding Source:
Contract or Grant No.:
Contract or Grant Title:
3. STATEMENT OF FINANCIAL INTERESTS: If
you are required to submit either a Form 730-U* or a Form 740-U* to the Office
of Sponsored Research, please attach a copy of those form(s) with this
application. See #9 of the Guidelines
for additional information regarding this requirement.
* Form
730-U, "Principal Investigator's Statement of Economic Interests" for
non-governmental funded projects
* Form
740-U, "Investigator's Statement of Financial Interests" for NSF or
PHS funded projects
4. Is this
application for the administrative approval for a training grant, a program
project, a multiple project grant, or a center grants? Yes X No
If yes,see Guidelines #14.
If
this application is applying for an administrative approval for funding
purposes only and does not involve the participation of human subjects,
do
not complete the rest of this application.
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SECTION
III - SUMMARY INFORMATION |
THIS SECTION
MUST BE COMPLETED
The review of research involving human subjects is
conducted by either the Medical Human Subject Protection Committee (MHSPC) or
the General Campus Human Subject Protection Committee (GCHSPC) depending on the
nature of the protocol. The MHSPC is
composed of primarily medical specialists, and the GCHSPC has principally
socio-behavioral experts and some medical professionals. To aid the OPRS staff in evaluating which
HSPC is most likely appropriate for the review of your protocol, please check
all appropriate boxes in this section.
1. Will you
perform medical procedures as part of this research proposal? XYes
No
2. SUBJECT POPULATION: (Check all appropriate boxes.)
X Children (see
Manual Chapters 4,6,8, & 10) Cognitively or psychologically impaired (see Manual Chapter 4)
Elderly (see
Manual Chapters 4 & 10) Institutional residents (see Manual Chapters 4 &
8)
Fetuses (see
Manual Chapter 8) Human in vitro fertilization (see Manual Chapter 8)
Pregnant women (see
Manual Chapter 8) Exclusion of minorities (see Manual Chapter 8)
Terminally ill (see
Manual Chapter 8) Prisoners or parolees (see manual Chapter8)
Comatose (see
Manual Chapter 4) Non-English speaking (see Guidelines #11 & Manual Chapter 8)
Cancer patients (see
Guidelines #4) UCLA students/staff (see Guidelines #10 & Manual Chapter 8)
3. If the research involves any of the
following, check the appropriate boxes:
Interviews X
HIV/AIDS
Survey/questionnaire X Clinical studies
Behavioral observation Investigational drugs (if checked, complete Section V)
Deception Investigational devices (if checked, complete Section VI)
Waiver of consent Radiation (see
Guidelines #5)
Study of existing data (see Guidelines #12) Controlled substances (see Guidelines #6)
Study of human biological specimens Microorganisms or recombinant DNA (see Guidelines #7)
(see Guidelines #12) Potential development of commercial product from human
X Venipuncture (<450cc) biological materials (see
Guidelines #8)
X
Genetic research X PI or Co-PI is the treating physician
4. LOCATION(S)
OF RESEARCH TO BE CONDUCTED AT:
X UCLA campus Santa Monica-UCLA Medical Center
X
Other locations, specify: Children’s Hospital, Los Angeles
5. LAY
LANGUAGE SUMMARY: (Please use non-technical
language that is understood by nonscientific members to summarize the proposed
research project. The information must
include: (1) a brief statement of the problem and related theory supporting the
intent of the study, and (2) a brief but specific description of the
procedure(s) involving the human subjects.
Attach an additional page as necessary.
However, please do not exceed one single-spaced, type-written page.)
The thymus is a
large gland found in the chest. It is
the source of CD4+ and CD8+ T cells, which play a key role in the body’s
defense against infection and cancer.
These cells are progressively lost due to HIV infection. In people with HIV, treatment leads to an
increase in T cells. It remains unclear
how much of the increase is due to production of new T cells by the thymus and
how much is due to the improved survival of existing T cells.
The intent of
this study is to compare several aspects of the function of the thymus in
subjects 13-24 years old who acquired HIV at birth versus subjects who acquired
HIV through sexual activity or drug abuse versus subjects who are HIV
negative. This will be done using blood
collections as well as a CT scan of the thymus. In addition, a substudy will be performed during which subjects
will be admitted to the Clinical Research Center overnight. They will be given either a sugar solution
or a water solution with a non-radioactive marker. Blood will be collected so that this marker can be detected.
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SECTION
IV - PROTOCOL SUMMARY |
THIS SECTION
MUST BE COMPLETED
INSTRUCTIONS: In order to
review your proposal, the Human Subject Protection Committee (MHSPC) must have
all of the following information. Each topic must be titled using the boldface subheadings listed below. State “Not Applicable” for topics that are
not applicable to your application.
Address each topic independently in the sequence listed without reliance
on information covered under other subparts.
Attaching sections of the grant application is not an acceptable
substitute. Provide sufficient
information for effective review by all members of the HSPC, including
non-specialists. Define all
abbreviations and terms not part of common language and use simple words and
sentence structure as much as possible.
Unless justification is provided, Section IV of this application must
not exceed 10 pages (excluding references).
Number each page, beginning with page one for the first page of Section
IV.
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INFORMATION
REGARDING RENEWAL APPLICATION (1) |
1. Renewal Application: What benefits to the participating subjects
or to the society have been derived?
Please also provide a summary of the research activities during the
previous approval periods regarding the following issues:
a) How many
subjects have been enrolled since the date of last approval and since the
initial approval?
b) Has there
been any difficulty obtaining/retaining subjects or obtaining informed consent
during the previous approval period? If
yes, describe:
Approximately
how many potential subjects have refused participation?
How many
subjects have voluntarily withdrawn participation at their own request?
How many
subjects have withdrawn participation at the request of the PI?
c) Have there
been any unexpected reactions or complications since last scheduled annual
review?
If yes, please attach Adverse Event Reports (Form
HS-5). If you have submitted the
Adverse Event Reports, please state so.
d) Approximately
how many more subjects are required to complete the study?
Not
applicable – not a renewal
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PURPOSE OF
THE STUDY, THE BACKGROUND AND THE LITERATURE REVIEW (2-3) |
2. Purpose of the Study: What are the specific scientific objectives
(aims) of the research?
1.
To compare quantitative parameters of thymopoiesis from adolescents/young
adults with perinatal HIV infection (PI-A) with those from age-matched
seronegative control subjects (SN-A), and youth with HIV infection acquired via
recent adult behaviors (AB-A).
2.
To evaluate the impact of viral factors on thymopoiesis of HIV infected
adolescents.
3.
To examine the T cell receptor repertoire and CTL responses of
perinatally infected adolescents.
3. Background: State the background of the
study. Include a critical evaluation of
existing knowledge, and specifically identify the information gaps which the
project is intended to fill. Describe
previous work in animal and/or human studies that provide a basis for the
proposed research and that support the expectation of obtaining useful results
without undue risk to human subjects.
Note:
Include appropriate citations to the scientific literature or attach a
copy of literature review.
Long term survival after
HIV perinatal infection.
Most cases of pediatric
HIV-1 infection result from perinatal infection, occurring either in utero or at the time of
delivery. Other cases are acquired
postnatally via transfusion or breast-feeding.
Regardless of the means by which infection is acquired, untreated
pediatric HIV infection is generally followed by the development of symptomatic
disease in the first year of life, and the development of AIDS in as many as
50% of children by 5 years of age [1,
2] . In the
pre-HAART era, the median and mean survival times for perinatally infected
children were 8.0 and 9.4 years, respectively [2,
3] . However,
survival into adolescence is now occurring in many cases. The number of these
individuals is unclear, but the most recent HIV/AIDS Surveillance Report [4] notes 180
people who acquired HIV infection perinatally who have had AIDS diagnosed after
age 13. It is likely that a much larger
number of children were diagnosed with AIDS prior to age 13, and are now
surviving into adolescence because of improvements in preventative care, and the
advent of highly active antiretroviral therapy (HAART). In concert with the marked decrease in
perinatal transmission seen in the last seven years, this increasingly large
population of perinatally infected adolescents is changing the face of
Pediatric HIV/AIDS in the United States.
Survival into
adolescence is likely to be attributable to a combination of viral, host, and
treatment factors. Chemokine and chemokine receptor gene polymorphisms, HLA
type, and mutation of the viral nef
gene are potentially important variables [5]
. However,
CCR5 deletions are uncommon in non-Caucasian populations that are most affected
by the HIV epidemic [5, 6] , and large deletions in nef appear to be rare.
There have been two small reports [7,
8] in which
mutations of the nef gene were found
in 8 long-term survivors of perinatal infection. In these reports, two patients had large nef gene deletions, and had strikingly mild disease. One was asymptomatic and on no antiretroviral
therapy at 10 years of age, and did not have detectable plasma HIV RNA. The other was 12 years of age and had only
moderately symptomatic disease (CDC class B).
Missense mutations and small deletions of nef were found in some of the others. In contrast, most long-term
surviving children have much more advanced disease than the subjects described
in these reports. Nielsen et al [9] reported a
multicenter study of pediatric long-term survivors, defined to be 8 or more
years of age. Only 31/143 (21)% of
children with maternally derived HIV infection and 9/54 (17%) with transfusion
acquired infection had > 500 CD4+ T cells and no prior AIDS defining
conditions. Thus, in most cases,
progressive immunodeficiency and AIDS are seen in adolescents who acquired HIV
infection perinatally or via transfusion in early childhood, suggesting that
these individuals are infected with fully pathogenic HIV variants.
Immunological changes
associated with HAART.
The accumulated experience with HAART in adults has shown us that the prolonged suppression of HIV viremia to “undetectable” levels will often (though not invariably) arrest disease progression and bring about significant immunological restoration. Initially, the marked increase in CD4+ T cells seen with potent anti-retroviral agents was attributed to the reduction in virus-induced destruction or clearance of cells [10, 11] . Later reports made it clear that redistribution of lymphocytes from lymphoid o