Birth Control Pill vs Birth Control Patch Study (PvP)
|Venous Thrombosis||Drug: Ethinyl estradiol and norgestimate Drug: Ethinyl estradiol and norelgestromin|
|Study Design:||Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Single (Investigator)
Primary Purpose: Treatment
|Official Title:||The Effects of Oral Contraceptive Pills vs Hormonal Patch on Coagulation Parameters|
- Change in coagulation parameters on transdermal versus oral contraceptive [ Time Frame: 2003--2005 ]
- Compare ethinyl estradiol levels for transdermal versus oral contraceptives [ Time Frame: September 2007 ]
|Study Start Date:||April 2003|
|Study Completion Date:||August 2005|
Active Comparator: 1
Use of transdermal hormonal contraceptive
Drug: Ethinyl estradiol and norelgestromin
Transdermal hormonal contraceptive changed weekly
Other Name: Ortho Evra
Active Comparator: 2
Use of oral hormonal contraceptive
Drug: Ethinyl estradiol and norgestimate
Other Name: Ortho Cyclen
Hide Detailed Description
Twenty-four non-pregnant women 18-35 years of age, who had not been on hormonal contraception for at least 2 months prior to the study or who were least 3 months postpartum and non-lactating, were enrolled in this study between October 2003 and February 2005. The study protocol was approved by the University of Vermont Institutional Review Board, and all participants gave written informed consent. Exclusion criteria for participation were personal or family history of venous thromboembolism or coagulation disorders, pregnancy, uncontrolled hypertension, cardiovascular disease, complicated migraine headaches, breast cancer, diabetes, abnormal uterine bleeding, liver disease, or desire for pregnancy in less than 6 months.
This study was a randomized investigator-blind, cross-over clinical trial. The daily oral contraceptive contained 35 micrograms ethinyl estradiol and 250 micrograms norgestimate (Ortho Cylen®). The weekly transdermal hormonal contraceptive contained 0.75 milligrams ethinyl estradiol and 6.0 milligrams norelgestromin (Ortho Evra®). Norelgestromin is the active progestin metabolite of orally administered norgestimate. For the oral form the average steady state plasma concentration (Css) of ethinyl estradiol was 49.3 picograms/milliliter and of norelgestromin 0.73 nanograms/milliliter and for the transdermal form these concentrations were 80.0 picograms/milliliter and 0.888 nanograms/milliliter, respectively at the end of the second month of use.17 The average weekly exposure, calculated as area under the curve (AUC0-168pg.h/mL) for ethinyl estradiol was 55% higher with transdermal than with the oral contraceptive. The maximum ethinyl estradiol and norelgestromin levels (Cmax) were 133 pg/ml and 2.16 ng/ml for the oral form and 97.4 pg/ml and 1.12 ng/ml for the transdermal form.17 The application location of the patch does not alter the Css or Cmax.18 Medications were supplied to the patients by a research nurse and the completed packets were returned to document compliance. The contraceptives and the funding for the study were supplied by research grants from the University of Vermont Department of Obstetrics and Gynecology.
Prior to enrollment, participants underwent a physical examination including gynecologic examination. Women on hormonal contraceptives at recruitment were given barrier contraceptives for two months prior to starting the study. Participants were assigned a random identification number which indicated the sequence in which transdermal or oral contraceptives would be given. The daily oral contraceptive or weekly transdermal contraceptive was given with the typical dosing of three weeks active treatment followed by one week without hormone use. Following the first two months of hormonal contraceptive, each participated returned to barrier contraceptive for a two month washout period, then received two months of the alternative hormonal contraceptive. The investigators were blind to the order of contraceptive assigned for each participant.
There were four phlebotomies performed for each subject. Blood was drawn on menstrual cycle day 18 to 21 prior to the study, within 4 days of either the last pill or removal of the last patch, and on cycle day 18 to 21 in the second month of the washout period. Blood was collected using standardized methods with minimal stasis into vacutainer tubes, immediately placed on ice and centrifuged at 4oC. Plasma and serum was stored at -70oC until completion of the study.
Laboratory assays were performed in batch with each participant's serial samples analyzed in the same run. D-dimer, von Willebrand factor and antithrombin were measured using immuno-turbidometric assays on the STA-R analyzer (Liatest D-Di, Liatest vWF, Liatest ATIII, Diagnostica Stago, Parsippany, NJ) with coefficients of variation (CVs) of 3.0%, 3.85%, and 4.0-8.0% respectively. Factor VIII was determined by measuring the clotting time of the sample in factor VIII deficient plasma (STA-Deficient VIII; Diagnostica Stago, Parsippany, NJ) with a CV of 3.5%. Free and total protein S were measured by immunoassay (Asserachrom Free and Total Protein S, Diagnostica Stago, Parsippany, NJ) with CVs of 14.0% and 4.0% respectively. Fibrinogen and C-reactive protein were measured by immunonephelometry using the BNII instrument (N Antiserum to Human Fibrinogen, N High Sensitivity CRP, Dade-Behring, Deerfield, IL) with CVs of 2.3-4% and 2.6% respectively.
The normalized activated protein C sensitivity ratio (nAPCsr) was measured using two thrombin generation assays. In the first assay, coagulation was triggered in defibrinated plasma with tissue factor in the presence and absence of activated protein C and the amount of thrombin captured in complex with a2-macroglobulin over 30 minutes was taken as a measure for thrombin generation and used to calculate the nAPCsr (nAPCsr α2M-IIa).14 In the second assay, the nAPCsr (nAPCsr CAT) was determined by measuring thrombin generation in the presence and absence of activated protein C in full plasma in real-time with a fluorogenic thrombin substrate using calibrated automated thrombinography (CAT).19 The CV's of the nAPCsr α2M-IIa and nAPCsr CAT were 3.5% and 7%, respectively.
Repeated measures analyses of variance corresponding to a cross-over design incorporating both baseline and washout periods were used to determine the significance associated with differences between the hormonal contraceptive treatments for each of the biomarkers tested. Pre-planned contrasts were used to test for differences between the pre-treatment periods corresponding to oral and transdermal active treatments. Contrasts were also used to test for changes from pre-treatment to active treatment within each treatment and to determine whether these changes were parallel across the two active treatments. Biomarkers that had non-normal distributions based on residual plots were log transformed prior to analysis. Based on the analyses of variance results, there was no evidence of any significant order effects for any of the biomarkers. Analyses were performed using SAS Version 8.2 (SAS Institute, Cary, NC). Statistical significance was determined based on a=.05
Please refer to this study by its ClinicalTrials.gov identifier: NCT00554632
|Principal Investigator:||Julia V Johnson, MD||Fletcher Allen Health Care & University of Vermont|