Investigator Agreement - ClinicalTrials.gov
IRB-HSR# 13789: Effect of Metformin on Sensitivity of the GnRH Pulse Generator to Suppression byEstradiol and Progesterone in Hyperandrogenic Adolescent GirlsIRB-HSR PROTOCOLInvestigator AgreementBY SIGNING THIS DOCUMENT, THE INVESTIGATOR CONFIRMS:1. I am not currently debarred by the US FDA from involvement in clinical research studies.2. I am not involved in any regulatory or misconduct litigation or investigation by the FDA.3. That if this study involves any funding or resources from an outside source, or if you will be sharing dataoutside of UVA prior to publication that you will contact the Dean’s office regarding the need for a contractand letter of indemnification. If it is determined that either a contract or letter of indemnification is needed,subjects cannot be enrolled until these documents are complete.4. The proposed research project will be conducted by me or under my close supervision. It will be conductedin accordance with the protocol submitted to and approved by the IRB including any modifications,amendments or addendums submitted and approved by the IRB throughout the life of the protocol.5. That no personnel will be allowed to work on this protocol until they have completed the IRB-HSR On-linetraining and the IRB-HSR has been notified.6. That all personnel working on this protocol will follow all IRB-HSR Policies and Procedures as stated onthe IRB-HSR Website http://www.virginia.edu/vprgs/irb/ and on the School of Medicine Clinical TrialsOffice Website: ranet/hes/cto/sops/sop index.cfm7. I will ensure that all those delegated tasks relating to this study, whether explicitly or implicitly, are capablethrough expertise, training , experience or credentialing to undertake those tasks.8. I confirm that the implications of the study have been discussed with all Departments that might be affectedby it and have obtained their agreement for the study to take place.9. That no subjects will be recruited or entered under the protocol until the Investigator has received the signedIRB-HSR Approval form stating the protocol is open to enrollment10. That any materials used to recruit subjects will be approved by the IRB-HSR prior to use.11. That all subjects will sign a copy of the most current consent form that has a non-expired IRB-HSRapproval stamp.12. That any modifications of the protocol or consent form will not be initiated without prior written approvalfrom the IRB-HSR, except when necessary to eliminate immediate hazards to the subjects.13. Any significant findings that become known in the course of the research that might affect the willingnessof subjects to enroll or to continue to take part, will be promptly reported to the IRB.14. I will report immediately to the IRB any unanticipated problems involving risk to subjects or to othersincluding adverse reactions to biologics, drugs or medical devices.15. That any serious deviation from the protocol will be reported promptly to the Board in writing.16. That any data breach will be reported to the IRB, the UVa Corporate Compliance and Privacy Office , UVaPolice as applicable.17. That the continuation status report for this protocol will be completed and returned within the time limitstated on the form.18. That the IRB-HSR office will be notified within 30 days of a change in the Principal Investigator or of theclosure of this study.19. That a new PI will be assigned if the current PI will not be at UVA for an extended period of time. If thecurrent PI is leaving UVa permanently, a new PI will be assigned PRIOR to the departure of the current PI.20. All study team members will have access to the current protocol and other applicable documents such as theIRB-HSR Application, consent forms and Investigator Brochures.Page 1 of 47Version Date: 12/14/2015
IRB-HSR# 13789: Effect of Metformin on Sensitivity of the GnRH Pulse Generator to Suppression byEstradiol and Progesterone in Hyperandrogenic Adolescent Girls21. Signed consent forms and other research records will be retained in a confidential manner. Records will bekept at least 6 years after completion of the study.22. No data/specimens may be taken from UVa without a signed Material Transfer Agreement betweenOSP/SOM Grants and Contracts Office and the new institution. Original study files are consideredinstitutional records and may not be transferred to another institution. I will notify my departmentadministration regarding where the originals will be kept at UVa. The material transfer agreement willdelineate what copies of data, health information and/or specimens may be taken outside of UVa. It willalso approve which HIPAA identifiers may be taken outside of UVa with the health information orspecimens.23. If any member of study team leaves UVa, they are STRONGLY ENCOURAGED to use Exit Checklistfound on IRB-HSR website at e IRB reserves the right to terminate this study at any time if, in its opinion, (1) the risks of furtherexperimentation are prohibitive, or (2) the above agreement is breached.Investigators ExperienceThe PI is a board certified general pediatrician and fellowship-trained board eligible pediatric endocrinologistwho has been working with children clinically for the last 10 years. The PI has performed clinical research as amedical student, as a pediatric endocrinology fellow, and as a UVA faculty member (Department of Pediatrics,Division of Endocrinology). The PI has been actively involved in the current clinical research protocols of Dr.John Marshall studying the early manifestations and abnormalities of PCOS in pubertal girls. All subinvestigators have experience via participation in the pediatric protocols of the adolescent PCOS research groupwithin the UVA Center for Research in Reproduction led by Drs. John Marshall and Chris McCartney.SignaturesPrincipal InvestigatorPrincipal InvestigatorPrincipal InvestigatorDateSignatureName PrintedDepartment ChairBY SIGNING THIS DOCUMENT THE DEPARTMENT CHAIR AGREES:1. To work with the investigator and with the board as needed, to maintain compliance with thisagreement.2. That the Principal Investigator is qualified to perform this study.3. That the protocol is scientifically relevant and sound.Department Chair or DesigneeSignatureDepartment Chair or DesigneeName PrintedDateThe person signing as the Department Chair cannot be the Principal Investigator or a sub-investigator on thisprotocol.Page 2 of 47Version Date: 12/14/2015
IRB-HSR# 13789: Effect of Metformin on Sensitivity of the GnRH Pulse Generator to Suppression byEstradiol and Progesterone in Hyperandrogenic Adolescent GirlsThe Department Chair or Designee signature is ONLY required if this is a new protocol or a modificationchanging the Principal InvestigatorBrief Summary/AbstractWomen with PCOS have decreased GnRH pulse generator sensitivity to suppression by estradiol andprogesterone. Adolescent hyperandrogenemia is thought to be a precursor of adult PCOS. In previous studies,while some hyperandrogenic girls have decreased hypothalamic sensitivity to progesterone similar to their adultcounterparts with PCOS, others maintain normal hypothalamic progesterone sensitivity. The girls withdecreased hypothalamic progesterone sensitivity have higher fasting insulin levels despite similar BMIs,suggesting that hyperinsulinemia may in part mediate the reduction in sensitivity. We hypothesize thatmetformin will improve hypothalamic progesterone sensitivity in hyperandrogenic adolescentgirls by improving insulin sensitivity and lowering insulin levels. LH (GnRH) pulse frequency will be assessedbefore and after 7 days of oral estradiol and progesterone in hyperandrogenic adolescent girls both before andafter 3 months treatment with Metformin 1000 mg BID. Progesterone adjusted change in 11-hour LH pulsefrequency will be used as the measure of hypothalamic progesterone sensitivity.BackgroundEtiology of PCOSPolycystic ovarian syndrome (PCOS) is a common clinical disorder affecting 6-7% of reproductive agedwomen. PCOS is associated with hyperandrogenism, multiple ovarian cysts, and oligo- or amenorrhea (Steinand Leventhal 1935). It is also a leading cause of infertility. The etiology for PCOS has not yet been elucidated.It has been proposed that hyperinsulinemia, altered ovarian steroidogenesis, and neuroendocrine abnormalitiesmay play key roles either alone or in combination.Neuroendocrine Abnormalities in PCOSNeuroendocrine abnormalities, whether primary or secondary, play an important role in PCOS. A group ofneurons collectively known as the GnRH pulse generator control the pulsatile secretion of GnRH (gonadotropinreleasing hormone) from the hypothalamus. GnRH, in turn, controls the synthesis and secretion of luteinizinghormone (LH) and follicle stimulating hormone (FSH) from the pituitary gland. LH and FSH are both made bythe same gonadotrope cell, and which hormone is preferentially synthesized and secreted depends in part on theGnRH pulse frequency. In primates, a GnRH pulse frequency of 1 pulse per hour favors secretion of LH,whereas slower pulses, on the order of 1 pulse every three hours, favor release of FSH(Wildt 1981). In normally cycling women, the GnRH pulse frequency in the follicular phase is relatively fast,favoring LH secretion. Following the rise in estrogen and progesterone after ovulation, there is a slowing ofGnRH pulse frequency, resulting in a decrease in LH and increase in FSH synthesis, which is important forsubsequent follicular development. Physiologic doses of exogenous progesterone have been shown to slow LH,and by inference GnRH, pulsatility when given during the follicular phase (Soules et al 1984). Therefore,progesterone plays an important role in regulating the GnRH pulse generator.Page 3 of 47Version Date: 12/14/2015
IRB-HSR# 13789: Effect of Metformin on Sensitivity of the GnRH Pulse Generator to Suppression byEstradiol and Progesterone in Hyperandrogenic Adolescent GirlsPCOS is characterized by persistently rapid LH (GnRH) pulse frequency without the cyclic luteal phase slowingseen in ovulatory women. Our group has shown that women with PCOS have reduced hypothalamic sensitivityto progesterone mediated suppression of LH (GnRH) pulsatility compared to ovulatory controls (Pastor et al1998). Thus, they require higher plasma progesterone concentrations to achieve the same degree of GnRHsuppression seen in controls. Especially when coupled to the fact that women with PCOS generally have lowlevels of progesterone secondary to infrequent ovulation, this relative insensitivity contributes to the persistentlyrapid GnRH pulsatility characteristic of PCOS. The resultant increase in LH leads to augmented ovarianandrogen production, while the resultant decrease in FSH leads to impaired follicular development andanovulation. Androgens play an important role in mediating hypothalamic progesterone insensitivity, asprogesterone sensitivity can be restored in women with PCOS with the use of the androgen blocker flutamide(Eagleson et al 2000). In adult women, short term treatment with the insulin sensitizer Metformin does notnormalize hypothalamic progesterone sensitivity (Eagleson et al, 2003).Adolescent Hyperandrogenemia as a Precursor for PCOSExcess androgen production during adolescence is thought to be a precursor of adult PCOS. Women withPCOS often report a history of irregular menstrual cycles during adolescence. A study of girls with menstrualirregularities showed that while some subjects normalized endocrine function as they mature, the majoritymaintained hyperandrogenism along with the elevated LH levels and polycystic ovaries characteristic of PCOS(Venturoli et al. 1987). Adolescent hyperandrogenemia has also been shown to be associated with higherandrogen levels and lower fertility rates in adulthood (Apter and Vihko 1990).Similar to women with PCOS, girls with hyperandrogenemia have an increased frequency of LH pulses whencompared to age matched controls (Apter et al. 1994). An ongoing study by our group (IRB-HSR# 8588) isinvestigating whether the progesterone insensitivity of the GnRH pulse generator in adult women with PCOS isalso seen in adolescent girls with hyperandrogenemia. Analysis of the data to date suggests that overall thehyperandrogenic adolescent girls have decreased hypothalamic progesterone sensitivity when compared toadolescent controls. However, one subgroup of the hyperandrogenic girls have marked progesteroneinsensitivity similar to that seen in adult women with PCOS, while another subgroup retains relatively normalhypothalamic progesterone sensitivity despite similarly elevated androgen levels. In an effort to understand thefactors that may make some girls more susceptible to the adverse neuroendocrine consequences ofhyperandrogenemia, we have analyzed the differences between these two subgroups. Fasting insulin levelswere higher in the progesterone-insensitive group than in the progesterone-sensitive group (31.2 3.3 vs.20.9 3.7 uIU/ml, p 0.02) despite similar BMIs (33 4 vs. 34 2 kg/m2). This suggests that hyperinsulinemiamay have neuroendocrine actions during adolescence that are not present in adults. Alternatively, these findingsmay indicate differential sensitivity to the adverse effects of androgens on both hypothalamic P sensitivity andinsulin resistance.A better understanding of the factors that make adolescent girls more or less susceptible to the adverseneuroendocrine effects of elevated androgens will hopefully lead to improved prevention and treatmentstrategies for PCOS. In this study, we propose to explore the role of hyperinsulinemia on neuroendocrinefunction in hyperandrogenic adolescent girls by assessing the effect of the insulin sensitizer Metformin onhypothalamic progesterone sensitivity. Other differences between the progesterone sensitive and progesteroneinsensitive subgroups, including racial and ethnic differences between the two populations and a trend towardsPage 4 of 47Version Date: 12/14/2015
IRB-HSR# 13789: Effect of Metformin on Sensitivity of the GnRH Pulse Generator to Suppression byEstradiol and Progesterone in Hyperandrogenic Adolescent Girlsolder gynecologic age in the progesterone insensitive population, are being pursued through other ongoingstudies (IRB-HSR# 8588 and 12160).Hypothesis to be TestedWe hypothesize that metformin will improve the sensitivity of the GnRH pulse generator to suppression byestradiol and progesterone in hyperandrogenic adolescent girls. LH pulse frequency will be assessed before andafter 7 days of oral estradiol and progesterone both before and after treatment with metformin. The primarylinear contrast will compare the progesterone adjusted change in 11-hour LH pulse frequency between the 1stand the 2nd admissions (Δ(2-1)) (pre-metformin) to the progesterone adjusted change in the 11-hour LH pulsefrequency between the 3rd and the 4th admissions (Δ(4-3)) (post-metformin).1. Will controls be used? Yes.Study Design: Biomedical IF YES, explain the kind of controls to be used.The subject will serve as her own control, as assessments will be made both before and after Metformin.2. What is the study design? This study is not blinded.3.Does the study involve a placebo? No.Human ParticipantsAges 10-17 yearsSexFemaleRace All races will be recruited and enrolled.Subjects- see below1. Provide target # of subjects (at all sites) needed to complete protocol.302. Describe expected rate of screen failure/ dropouts/withdrawals from all sites.In a similar study (JCM010), we have historically obtained complete, usable data in approximately 65% ofthe subjects who enrolled in the study. However, that study was shorter in duration and did not involve takingmetformin. Because of the added length of this study, as well as the possibility that some participants maydevelop side effects with Metformin (most likely nausea or diarrhea) and choose to withdraw, we suspect thatthe screen failure/dropout/withdrawal rate will approach 50%. Therefore, we plan to enroll 60 subjects, with agoal of obtaining complete, usable data in 30.3. How many subjects will be enrolled at all sites? 604. How many subjects will sign a consent form under this UVa protocol?Inclusion/Exclusion CriteriaPage 5 of 47Version Date: 12/14/201560
IRB-HSR# 13789: Effect of Metformin on Sensitivity of the GnRH Pulse Generator to Suppression byEstradiol and Progesterone in Hyperandrogenic Adolescent Girls1. List the criteria for inclusion Girls ages 10 to 17 Hyperandrogenemic (free testosterone greater than 2 standard deviations above the mean for normalcontrol subjects of the same Tanner Stage and/or hirsutism) Creatinine clearance 90 ml/min as calculated by the Cockcroft-Gault equation Hemoglobin 11.0 g/dL for African American subjects; Hemoglobin 11.5 for non-African Americansubjects Normal screening labs (with exception of the expected hormonal abnormalities inherent inhyperandrogenemia) Sexually active subjects must agree to abstain or use double barrier contraception during the study Subjects must agree not to take any other medications during the course of the study without approvalby the study investigators.2. List the criteria for exclusion Abnormal screening labs (with the exception of the expected hormonal abnormalities inherent inhyperandrogenemia) Creatinine clearance less than 90 ml/min as calculated by Cockcroft-Gault equation Hemoglobin 11.5 g/dL for non-African American subjects; Hemoglobin 11.0 g/dL for AfricanAmerican subjects Abnormal liver function tests (including AST, ALT, Bilirubin, Albumin, and Alkaline Phosphatase) Weight 34 kg History of renal dysfunction, liver dysfunction, congestive heart failure, deep venous thrombosis, breastcancer, endometrial cancer, or cervical cancer Pregnant or breast feeding On medications known to affect the reproductive axis within 3 months of the study (including oralcontraceptive pills, metformin, and spironolactone) Are currently participating in another study or have been in one in the last 30 days. Subjects using restricted medication (see restrictions below) are excluded unless the subject’s primarycare provider approves stopping the medication.3. List any restrictions on use of other drugs or treatments.Subjects must not take medications known to affect the reproductive axis (including oralcontraceptives, metformin, and spironolactone) for 90 days prior to and during the study.Subjects must not take medications that have the potential to increase metformin blood concentration(including cationic drugs such as amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine,triamterene, trimethoprim, vancomycin which are eliminated by renal tubular secretion have the potential forinteraction with metformin by competing for common renal tubular transport systems; cimetidine, whichincreases (by 60%) peak metformin blood concentrations; furosemide which can increase metformin bloodconcentration without altering metformin renal clearance; and nifedipine, which can increase metforminabsorption). Subjects should limit their intake of alcohol.Page 6 of 47Version Date: 12/14/2015
IRB-HSR# 13789: Effect of Metformin on Sensitivity of the GnRH Pulse Generator to Suppression byEstradiol and Progesterone in Hyperandrogenic Adolescent GirlsStatistical Considerations1.Is stratification/randomization involved? No.2. What are the statistical considerations for the protocol?Sample Size Calculation. The primary aim will be to compare the change in 11-hour LH pulse frequencybetween the 1st and the 2nd admissions (Δ(2-1)) to the change in the 11-hour LH pulse frequency between the 3rdand the 4th admissions (Δ(4-3)). To perform the sample size calculation, we assumed that the linear contrast Δ(4-3)- Δ(2-1) will follow a normal distribution with standard deviation 1.02 units. Base on the sample size formula forthe paired one-sample standard normal z-test, our calculation indicates that if 30 subjects complete the study,we will have at least an 80% chance of detecting a 1.02 unit or greater difference between Δ(4-3) and Δ(2-1) withthe two sided type I error rate of the statistical test not exceeding 0.05.Our prior studies indicate that the subject dropout rate in this study population should not exceed 50%, so 60subjects will be enrolled to insure that we have 30 completers.Statistical Analysis: The 11-hour LH pulse frequency data from study admissions 1-4, will be analyzed byway of a mixed-effects linear model. The four 11-hour LH pulse frequency measurements; one measurementfrom each admission, will function as the respond data. The study admission will be treated as a categoricalexplanatory factor in the analysis, while the mean 11-hour progesterone level from each admission will betreated as a continuous covariate. Hypothesis testing will be conducted by constructing apriori defined withinsubject linear contrasts of the 11-hour LH pulse frequency measurements. The primary linear contrast willcompare the progesterone adjusted change in 11-hour LH pulse frequency between the 1st and the 2ndadmissions (Δ(2-1)) to the progesterone adjusted change in the 11-hour LH pulse frequency between the 3rd andthe 4th admissions (Δ(4-3)). We will base our decision whether to reject the null hypothesis that Δ(4-3) - Δ(2-1) 0 ona two-sided p 0.05 decision rule. We will used the same decision rule to determine whether Δ(2-1) 0 and Δ(4The SAS PROC-MIX procedure (SAS Institute Inc., Cary NC) will be used to conduct the3) 0.aforementioned data analysis.3. Do you have an adequate sample size, or is your sample size larger than necessary?We calculated that we will need a sample size of 60 subjects in this study in order to achieve a statisticalsignificance with a power of 80% and Type 1 error rate of 0.05. Given the historical screenfailure/dropout/withdrawal rate for 8588/JCM010 of 35% and the additional demands of this study secondary tothe addition of metformin, we anticipate a screen failure/dropout/withdrawal rate of around 50%. Therefore, wepropose enrolling up to 60 girls with the goal of obtaining complete, analyzable data in 30. We believe thissample size is adequate and not excessive.4. What is your plan for primary variable analysis?The primary linear contrast will compare the progesterone adjusted change in 11-hour LH pulse frequencybetween the 1st and the 2nd admissions (Δ(2-1)) to the progesterone adjusted change in the 11-hour LH pulsefrequency between the 3rd and the 4th admissions (Δ(4-3)).5. What is your plan for secondary variable analysis? Not applicable.6. Have you been working with a statistician in designing this protocol? Yes.IF YES, what is their name? Jim PatriePage 7 of 47Version Date: 12/14/2015
IRB-HSR# 13789: Effect of Metformin on Sensitivity of the GnRH Pulse Generator to Suppression byEstradiol and Progesterone in Hyperandrogenic Adolescent GirlsBiomedical Research1. What will be done in this protocol?All procedures performed in this protocol are being done solely to answer a research question and generategeneralizable knowledge.Outpatient Consent and ScreeningAfter a potential subject is identified, we will arrange for her to come to the CRU or alternate UVAclinical unit for an outpatient consent and screening exam. The goals and procedures of the study will beexplained to the potential subject and her parents, and they will be given the opportunity to ask any questions.The potential subject and her parents will be asked to sign the assent and consent forms. A physician willrecord a medical history and perform a physical exam. Subjects will need to fast for a minimum of 8 hours priorto screening blood draw. Blood will be drawn for screening tests (CBC, Comprehensive metabolic panel,prolactin, LH, FSH, E1, E2, P, total T, androstenedione, 17-OHP, DHEA-S, fasting insulin, Insulin-like GrowthFactor 1 (IGF-1), glucose, SHBG, TSH, hCG, cholesterol, LDL, HDL, and a number of cytokines andadipokines (including adiponectin, leptin, resistin, PAI-1, IL-1b, IL-6, IL-8, TNFa, MCP-1, HGF and NGF). Inthe rare event a subject has an elevated 17-OHP on screening, she will be given a repeat 17-OHP. If the valueremains elevated, she will be referred to her pediatrician for further testing to rule out congenital adrenalhyperplasia. They will only be able to continue with the study if they have documented normal 17-OHP levelsfollowing cortrosyn stimulation. Potential subjects must fall within the normal range on all blood tests to beadmitted to the study, except for hyperandrogenemic girls who will be expected to have some abnormalhormone levels. Subjects will be administered 1 month of iron supplementation following screening, providedtheir screening labs show they are eligible to participate in the study. As soon as screening lab results areavailable, and subjects are found to be eligible for study participation, subjects weighing 36 kg will be given1- 325 mg tablet a day and subjects weighing 36 kg will be given 2- 325 mg tablets a day. The first overnightadmission may occur anytime within this 30 day period or after the 30 day period. Subjects will be given theoption to pick up this supply of iron in the Clinical Research Unit or have it mailed to them.If admission is scheduled to occur greater than one month after the most recent hemoglobin (such as thatobtained during screening), a hemoglobin will be repeated 2-5 days before the overnight admission.Documentation of hemoglobin 11.5 g/dL for non-African American subjects and documentation ofhemoglobin 11.0 g/dL for African American subjects in the previous month is required for the frequentsampling protocol. If overnight admission is scheduled to occur greater than 3 months after screening, then thesafety labs (complete blood count, comprehensive metabolic panel) will be repeated at this time.Day 0: Admission #1Note: Admission #1 will occur on Day 7-11 of the cycle in girls who are cycling with some regularity and onday 7 in those with infrequent cycles (girls with 10 cycles per year) provided they have aprogesterone level of 1.5 ng/mL within 3 days of their scheduled first admission. If the progesteronelevel is 1.5 ng/mL within 3 days of the first admission, the first admission will be cancelled.Page 8 of 47Version Date: 12/14/2015
IRB-HSR# 13789: Effect of Metformin on Sensitivity of the GnRH Pulse Generator to Suppression byEstradiol and Progesterone in Hyperandrogenic Adolescent Girls At each overnight admission a urine HCG will be done to rule out pregnancy and must be negative forthe study to continue.Subjects will be instructed to eat a diet including at least 150 gm of carbohydrate a day for the 3 days precedingthe admission. Written and oral instructions regarding this diet will be given at the time of the screening. Thesubject will be admitted to the CRU, alternate UVA hospital unit, or off-site hotel at 1700 hr. In general, parentsare welcome to stay with their child at the off-site hotel if they wish. If the overnight portion of the study is to be done atan off-site hotel, the subject may stay without a parent or legal guardian, as long as two CRU staff are present. Whetheror not a parent needs to remain during the overnight admission will be discussed when the visit is scheduled.A smallamount of topical lidocaine/prilocaine cream (EMLA cream) may be applied to facilitate IV line placement. IfIV placement is found to be difficult, the IV team may be called to assist in obtaining adequate access.Frequent blood draws will begin at 1900 hr. Samples will be taken every 10 minutes. Most samples will be0.75 mL, used to analyze levels of FSH and LH. 2.5 mL samples will be taken every 2 hours to analyze levelsof estradiol, progesterone, testosterone, cortisol and DHEA An additional 5 mL sample at 6 AM will beanalyzed for lipids, estrone, SHBG, DHEA-S, androstenedione, IGF-1, and a number of cytokines andadipokines, including adiponectin, leptin, resistin, PAI-1, IL-1b, IL-6, IL-8, TNFa, MCP-1, HGF and NGF. Aformal "lights out" will occur at 2300 hr so that we may observe any nocturnal changes in hormonal secretionpatterns. During the admission, the subject will wear a wrist actigraph (Motionlogger Basic-L; AmbulatoryMonitoring, Inc.) to estimate periods of sleep (Motionlogger Basic-L; Ambulatory Monitoring, Inc.). TheMotionlogger Basic-L is a watch-like device that includes an accelerometer. Q10 minute blood sampling willend at 0600 hr, although one additional Q2H sample will be drawn at 0700 hr. At 07:00 hr, the subject will alsoundergo a 2-hour oral glucose tolerance test. 75 grams of glucose will be administered at 07:00 (Time 0), with2.5 ml blood draws for glucose, insulin, and c-peptide at times 0, 10, 20, 30, 60, 90, and 120 minutes. Thesubject will be offered dinner at standard CRU meal time and will be offered breakfast following completion ofthe blood draws. They will not have anything to eat or drink except water from 2300 hr until the completion ofthe blood draws. At the time of discharge, the subjects will be given oral estrogen, progesterone, and ironsupplements.Day 1: Begin Estradiol and ProgesteroneStarting the day of discharge from the first inpatient admission, subjects will be given oral estrogen (estrace,0.5-1 mg once a day) and oral progesterone suspension (20 mg/ml, 25-100 mg) three times a day at 0700, 1500,and 2300 hr for seven days. The first dose will be given at 1500 on the day of discharge. If the 1500 dose isincompatible with school schedules, alternative dosing schedules can be arranged. Generally this will entailtaking the afternoon dose immediately upon returning home from school without any change in the morning andevening dosing times. Dosages will be based on weight. The target mean plasma progesterone concentration is2-8 ng/dL. Each subject will be instructed to eat a small snack with the progesterone syrup as it has beenobserved that the abso
Page 1 of 47 Version Date: 12/14/2015 . IRB-HSR PROTOCOL . Investigator Agreement . BY SIGNING THIS DOCUMENT, THE INVESTIGATOR CONFIRMS: 1. I am not currently debarred by the US FDA from involvement in clinical research studies. 2. I am not involved in any regulatory
vcu Office of the Vice President for Research and Innovation VCU/VCUHS NSR IDE Sponsor-Investigator Responsibilities . A sponsor-investigator assumes BOTH investigator and sponsor responsibilities as outlined in the FDA . Code of Federal Regulations 21 CFR 812. This means th
Private Investigator (PI) 1. What are the licensing requirements for a Private Investigator? The general requirements for a Private Investigator are: Be at least 18 years old. Three years of compensated experience totaling not less than 6,000 hours in investigative work, while employed by law enforcement agencies, collection
The Louisiana State Board of Private Investigator Examiners set forth ethical standards for licensed private investigators in two main sources: Louisiana "Private Investigator Law" and Private Investigator Rules and Regulations. Both sources mentioned are available online in pdf format at the LSBPIE website (www.LSBPIE.com). a.
clinical work, project management and research. Tracy Glass is the co-investigator of the Towards 90-90-90 project and the principal investigator of HOSENG. She is a biostatistician with 15 years of experi-ence working in clinical and observational studies in HIV, the last 5 years in resource-limited settings.
before or during the trial Results Database – Captures summary results of a completed trial Zarin DA, Tse T. Medicine. Moving toward transparency of clinical trials. Science. 2008 Mar 7;319(5868):1340-2. 4 History of ClinicalTrials.gov FDAMA 113 (1997): Mandates Registry – IND trials for serious and life-threatening diseases or .
CTCAE Common Toxicity Criteria for Adverse Events CV Coefficient of variation CYP Cytochrome P450 D/C Discontinue eCRF Electronic case report form DLT Dose Limiting Toxicity ECG Electrocardiogram Eg Exempli gratia (for example) EORTC European Organization for Research and
project ID: 124967, NHS REC reference number:13/EE/0110, ClinicalTrials.gov Identifier: NCT01950143), a previous intervention study conducted at QIB, investigated the influence of once-a-week consumption of broccoli soup on health parameters in a prostate cancer cohort on active surveillance.
discretion, the option to replace the Mini Wi-Fi Home Hotspot 500 Kit or any component thereof which is identified as faulty or below standard, or as a result of inferior workmanship or materials. Products over 28 days old from the date of purchase may be replaced with a refurbished or repaired product. The conditions of this guarantee are:
