Research Proposal Requirements

Transcription

1 Research Proposal Requirements I. Title of Project Use of Metformin Therapy in Patients with Congenital Adrenal Hyperplasia: A Pilot Study II. List principle investigator(s). Provide CV on each investigator. Maria Vogiatzi MD and Oksana Lekarev DO III. Contact information Weill Comell Medical College Division of Pediatric Endocrinology, Deparlment of Pediatrics 505 East td h Street, HT3 New York, NY Tel: Maria Vogiatzi: mvogiatz@med.comell.edu Oksana Lekarev: oki9003@med.comell.edu 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 ofthe 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).

2 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 ofglucocorlicoids 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 ofmetformin 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 ofsteroids for reasons other than treatment of 210HD Administration ofmedications causing insulin resistance Parlicipation in other clinical interventiona! trials Inability to provide consent

3 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 ofpuberty, total testosterone within normal range for gender and stage ofpuberty. 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 Medication administration: Study meds: metformin vs. placebo Metformin at fol/owing doses i) 500 mg PO BID for children kg, ii) 500 mg in am and 1000 mg in PM for children 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 orplacebo. 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 #2 Visit #3 Visit #4 Visit #5 Baseline Month: 3 Month: 6 Month: 9 Month: 12 History History History History History Weight, height, Weight, height Weight, Weight, height, Weight, height, body composition height body composition body composition Labs: i) serum Labs: serum Labs:i) Labs: serum Labs: : i) serum +. + urinary androgens serum +. androgens urinary androgens androgens Fasting urinary. Fasting ii) OGTT ii) OGTT glucose/insulin androgens glucose/insulin iii) lipids, CMP,..... ui) lipids, CMP, Ii) OGTT. HCG HCG iii) lipids, CMP, HCG I i Start Study Med#1 Study Med #1 End Study Study Med#2 Study Med#2 Med #1; start 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 to include Tanner stage, Ferriman-Gallwey score, BP, weight/height/bmi, waistlhip circumference

4 Additionallabslblood: 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 ofdextrose (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 ofandrogens, 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 comorbidities 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.

5 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 ofthe 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 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

6 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 Mid-study o 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 dina@caresfoundation --- CAR ESFoundation research, education and support for CAH Grant Application Cover Sheet

7 I Date of submission: Application is hereby made for a research grant from CARES Foundation, in the total amount of $_15, (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 ofresearch for which the grant is sought: Use of Metformin Therapy in Patients with Congenital Adrenal Hyperplasia: A Pilot Study Name, title and signature ofprincipal investigator: Name: Oksana Levarev, MD Title: Assistant Professor I Signature: ~.Gc~~-y _... -= I Official Mailing Address of principle Investigator (department, street, city, state and zip code): i Weill Cornell Medical College Pediatric Endocrinology, Box E 68 th Street. New York, NY I Contact numbers ofprincipal investigator: Phone: Fax: 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 E 68 th Street New York, NY 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 E 68 th Street New York, NY 10065

8 Name, title and signature of department head: Name: Maria Vogiatzi, MD Tit1e: Associate Professor Signature: CARES Foundation, Inc Morns Avenue, Suite 110 Union, New Jersey (908) toll free (866) Fa)(; (908) f\i\nl Cl f-j'l/) y tf