Download Research Proposal Requirements

Research Proposal Requirements I.
Title of Project
Use of Metformin Therapy in Patients with Congenital Adrenal Hyperplasia: A Pilot Study
II.
III.
List principle investigator(s). Provide CV on each investigator.
Maria Vogiatzi MD and Oksana Lekarev DO
Contact information
Weill Comell Medical College
Division of Pediatric Endocrinology, Deparlment of Pediatrics
505 East tdh Street, HT3
New York, NY 10021
Tel: 212-746-3462
Email:
Maria Vogiatzi: [email protected]
Oksana Lekarev: [email protected]
IV.
Introduction
Identify the research problem under investigation, why the research is important, and what the
research hopes to accomplish.
It has been well-recognized that patients with congenital adrenal hyperplasia (CAH) are
at risk for metabolic syndrome (insulin resistance, dyslipidemia, obesity, and
hyperlension) and polycystic ovarian syndrome (PCOS). Such long-term complications
are thought to be due to elevated androgens as well as glucocorlicoid treatment.
Metformin, an insulin sensitizer, has been demonstrated to improve insulin resistance,
androgen levels, and body composition in both males and female and improve signs and
symptoms of PCOS in females. We propose to conduct a study to demonstrate that the
addition of metformin to standard glucocorlicoid replacement will improve insulin
sensitivity, androgen levels and body composition in insulin-resistant patients with CAH
and PCOS in women with CAH. The aim of the study is to provide evidence to support
the development of a new therapeutic intervention in CAH.
V.
Technical abstract of proposal (do not exceed 600 words).
VI.
Description of research and study design
Hypothesis:
The addition of Metformin to standard glucocorlicoid therapy improves insulin sensitivity, body
composition and androgen levels in insulin-resistant patients with CAH
Specific objectives:
1. To determine changes in fasting insulin and HOMA-IR in patients with CAH who receive
adjunct metformin therapy
2. To determine changes in adrenal androgen secretion and dose of glucocorlicoids in
patients with CAH who receive adjunct metformin therapy
3. To determine changes in body weight and body composition by bioimpedence in patients with CAH who receive adjunct metformin therapy Study design:
Placebo-controlled, cross-over pilot study (single-blind; only patients are blinded)
• Patients will continue to take prescribed glucocorlicoid and mineralocorlicoid therapy
• Patients randomized to adjunctive treatment of metformin or placebo for a 6 month
period and then will cross-over for a second 6 month period
• Patients recruited at Weill-Cornell, CHLA and through CARES
Inclusion Criteria:
• 21-hydroxylase deficiency form of CAH - classical and non-classical disease
• On glucocorlicoid replacement therapy Female and male subjects Age: 10 to 30 years of age • Evidence of insulin resistance:
• fasting HOMA-IR ~3 for pediatriC population and ~ 2.5 for adults (18 and
older)
OR OGTT based evidence of insulin resistance: peak insulin/glucose ratio
of 0.25 for pediatric population and insulin peak concentration >150 U/ml
and/or a 2-hour insulin concentration> 75 U/ml for adults. Consider
utilizing insulin area under the curve (AUC) calculations
Exclusion Criteria:
• Pregnancy
• Ages < 10 or >30
• GFR<75%
• Elevated liver enzymes(2 times above upper limit of normal)
• HIV, AIDS, cancer, other end-stage disease Diabetes melfitus on treatment Administration of steroids for reasons other than treatment of 210HD • Administration of medications causing insulin resistance Parlicipation in other clinical interventiona! trials • Inability to provide consent
Medication administration:
• Study meds: metformin vs. placebo Metformin at fol/owing doses i) 500 mg PO BID for children 30-50 kg, ii) 500 mg in am and 1000 mg in PM for children 50-70 kg and iii) 1000 mg PO BID for children> 70 kg and aI/ adults
Dose titrated from once daily in the morning to twice daily over a one week period to
minimize GI side-effects
Glucocorticoid therapy will continue and will be adjusted to maintain optimal adrenal
control (see below)
Study Visits
Subjects will be started on either Metformin or placebo. Cross -over after 6 months without
wash out period.
Patients will be seen every 3 months. Study visits and procedures as per table below:
Visit #1
Visit #5
Visit #2
Visit #3
Visit #4
I
Baseline
Month: 3 Month: 6
Month: 9
Month: 12
History History History
History
History
PE
PE PE PE
PE
Weight, height, Weight, height
Weight,
Weight, height,
Weight, height,
body
height
body
body composition
composition
composition
Labs: serum
Labs:i)
Labs: serum
Labs: i) serum
Labs: : i) serum +
serum +
androgens urinary androgens
. + urinary
. androgens
. Fasting
urinary
ii) OGTT
androgens Fasting
ii) OGTT
glucose/insulin
androgens
glucose/insulin
iii) lipids, CMP,
... . .
. HCG ui) lipids, CMP,
Ii) OGTT
iii) lipids,
HCG CMP, HCG
i
Start Study
Med#1
Study Med #1
End Study
Med #1; start
med#2
Study Med#2
Study Med#2
History to include: Compliance with medications, concomitant conditions, age of
menarche/menstrual history, adverse effects, relevant family history such as risk for CVD, OM,
PCOS
PE to include Tanner stage, Ferriman-Gallwey score, BP, weight/height/BMI, waistlhip
circumference
Laboratory studies:
• Serum adrenal androgens and optimal ranges (i. e. do not require dose adjustment): 17­
hydroxyprogesterone~ 1,OOOng/dl, androstenedione within normal range for gender and
stage of puberty, total testosterone within normal range for gender and stage of puberty.
• Labs to be drawn 1-2 hours after glucocorticoid administration in the morning; if patient
is taking dexamethasone at bedtime only, the labs are to be drawn the fol/owing morning
• Additionallabsl blood: Complete Biochemical profile (CMP; includes renal and liver
function tests), plasma glucose and fasting insulin, lipid profile, urine pregnancy test,
DHEA, DHEA-S, free testosterone, SHBG, LH, FSH
• At baseline, 6 month interval and 12 month interval: 24 hour urine collection for 17­
ketosteroid and 17-hydroxycorlicosteroids (may be better reflection of adrenal control)
• OGTT: administration of dextrose (Glucola) at 1.75 g/kg (maximum dose 75 g) and 120
minutes later the following labs are to be obtained: plasma preserved glucose, serum
insulin
Consider storing plasma/serum for additional studies
Study End Points: Changes in insulin sensitivity, adrenal and gonadal androgen production,
lipids, body composition and required dose of glucorlicoids with study meds will be
determined. Information obtained from the study may lead to a new, effective
treatment adjuvant to existing therapy.
VII.
Non-technical summary that may be used for public information and educational
purposes.
Patients with congenital adrenal hyperplasia (CAH) are at risk for obesity, high blood
pressure, elevated levels of insulin and resistance to insulin, elevated lipid levels, and
menstrual irregularities due to polycystic ovarian syndrome. These complications are
thought to be due to elevated male-like hormones (androgens) produced by the adrenal
glands as well as due to treatment with steroids. Metformin has been shown to improve
insulin resistance, lower the levels of androgens, improve menstrual irregularities and
lower weight in patients with insulin resistance. We propose to conduct a study to show
that adding metformin to standard steroid therapy in patients with CAH will improve the
above-mentioned long-term complications of CAH.
VIII.
How does this research benefit the CAH community?
The study addresses significant long-term complications in patients with CAH and
proposes an adjuvant therapy that addresses and will hopefully improve various co­
morbidities in this special patient population.
IX.
Proof of IRB approval if research includes investigations on human subjects. If research
involves laboratory animals, provide copy ofthe Animal Welfare Assurances filed with
the Office of Protection from Research Risks of NIH.
We are currently finalizing the study design and our collaboration with the
investigators at CHLA. Once these elements are final, we will complete the IRS
application which has already been initiated.
CHLA has shown a strong interest in this project. We expect that this
collaboration will expedite enrollment and will foster multicenter collaborations in
research in CAH.
The CHLA investigators are Mitch Ge"ner and Mimi Kim.
X. Budget
Total cost _ _30,500_ _ _ __ If multi-year, cost per year ___15,250_ _ _ _ __ Support is requested for purchasing the study medication, preparation of
the placebo and research pharmacy. There are no funds for these
expenses, and otherwise, the study cannot be done.
• The cost for the laboratory assays for the study will be covered by the
Weill Cornell Clinical and Translational Center (CTSC).
• There is no charge for physcians's or research coordinator time.
• The cost for statistical analysis will also be covered by the Weill
Cornell CTSC.
The project is developed in collaboration with CHLA. Should CARES supports the
project, some of the awarded money will be dedicated to getting study drug and cover
research pharmacy costs for subjects enrolled at CHLA. Otherwise, CARES would
support not only our program but CHLA as well with this grant.
Type of support requested from CARES Foundation.
'" Financial ~ Other Le. recruitment, publicity, etc. Please describe: We would like to recruit patients for the study thro~gh CARES
email advertisements. Patients must meet the inclusion criteria and be willing to come to
Weill Cornell or Children's Hospital-Lost Angeles every 3 months over a course of 12
months and will be given both Metformin and placebo, as outlined in the protocol
XI. Progress report A report on the status of the project should be submitted annually. Progress Report Guidelines
When a grant is awarded, scientific progress and financial accounting reports are required
annually (within one month ofthe grant award anniversary). Ifthe duration ofthe study is less
than one year, a mid-study report must be filed. Please include a detailed report of all
information described below. In addition, list pertinent publications resulting from the
research.
I. Project number: _ _ _ _ _ _ __
II. Check one:
o
o
Mid-study
Annual
III. Project title:
IV. State the research design of the proposal and where on the originally proposed
timeline the project currently lies.
V. Explain any deviation from the original timeline; any unexpected outcomes; any
preliminary findings; any publications relevant to the project that have been
generated by the PI and colleagues since funding initiated.
VI. Provide a full accounting ofthe funds released to date.
Return all progress and financial accounting reports to:
Dina Matos
Executive Director
CARES Foundation
2414 Morris Avenue, Suite 110
Union, New Jersey 07083
dina@caresfoundation ---­
CAR ESFoundation
research, education and support for CAH
Grant Application Cover Sheet
I Date of submission:
Application is hereby made for a research grant from CARES Foundation, in the total amount of
$_15,250.00
(including 10% indirect costs on all budgetary items, except equipment.) The
• amount requested is for a period of (check one): Done year XOtwo yearsD other
I Title of research for which the grant is sought:
Use of Metformin Therapy in Patients with Congenital Adrenal Hyperplasia: A Pilot Study
Name, title and signature of principal investigator:
Name: Oksana Levarev, MD
Title: Assistant Professor
Signature: ~
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I Official Mailing Address of principle Investigator (department, street, city, state and zip code):
i
Weill Cornell Medical College
Pediatric Endocrinology, Box 103
525 E 68 th Street
. New York, NY 10065
I
Contact numbers of principal investigator:
Phone: 212-746-3462
Fax: 646-962-0265
IMPORTANT:Exact name, title, phone number, and mailing address (no PO Box) o/individuals and location
where checks are to be sent iflwhen a grant is awarded:
Weill Cornell Medical College
Pediatric Endocrinology, Box 103
th
525 E 68 Street
New York, NY 10065
Check payable to (institution name): Pediatric Endocrinology, Weill Cornell Medical College
Once a grant is awarded, an annual progress report is required (previous ~age I!!r additional in/ormation.)
Name, title and signature of official authorized to sign for Name:
institution:
Title:
Signature:
Name and address of financial officer (department, street, city, state and zip code):
Mary Montalvo
Weill Cornell Medical College
Pediatric Endocrinology, Box 103
525 E 68 th Street
New York, NY 10065
Name, title and signature of department head:
Name: Maria Vogiatzi, MD
Tit1e: Associate Professor
Signature:
f\I\Nl Cl
CARES Foundation, Inc.
2414 Morns Avenue, Suite 110 Union, New Jersey 07083
(908) 364-0272 toll free (866) 227-3737 Fa)(; (908) 686-2019
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