This was a randomized, open-label, parallel-group, multicenter study comparing one cycle of treatment with Menopur® SC or Repronex® SC at a dose of 75 to 450 IU/day administered as a single, daily injection for up to 12 days in infertile women undergoing COH for IVF. Each subject participated in only one cycle of IVF. Fifteen centers participated in the study, each of which obtained institutional review board approval. Written informed consent was obtained from all participants prior to screening and study enrollment.
Subjects had to meet the following eligibility criteria to participate in the study: nonsmoking, 18 to 39 years of age with regular ovulatory cycles (24 to 35 days); have a diagnosis of unexplained infertility or infertility due to tubal factor; stage I or II endometriosis; normal ovaries and uterus on transvaginal ultrasonography; normal serum levels of estradiol (E2), prolactin, LH, FSH, testosterone, dehydroepiandrosterone sulfate, and thyroid-stimulating hormone; and have a body mass index of ≤ 34. In addition, all subjects were seronegative for hepatitis B and C and HIV and had a negative pregnancy test prior to initiating treatment. A semen analysis performed on a sample from either the subject's partner or the designated donor had to be normal according to the criteria established by the World Health Organization. A minimum of one menstrual cycle without IVF/assisted reproductive therapy (ART) treatment was required prior to screening. Subjects were excluded from participation if there was evidence of any clinically relevant systemic disease or any surgical or medical condition that could interfere with the absorption, metabolism, or excretion of gonadotropins. Subjects were not to have had a positive pregnancy test within three months of baseline screening and were also excluded from the study if they had undergone three or more prior ART cycles, had abnormal uterine bleeding, a history of substance abuse, a history of chemotherapy, were breast feeding, or if they had participated in any experimental drug study within 60 days of screening for this study.
Each eligible subject received daily injections of leuprolide acetate (LA; TAP Pharmaceuticals, Deerfield, IL; 0.5 mg/d SC) beginning 7 days prior to the anticipated onset of menses until the day before administration of human chorionic gonadotropin (hCG)(Novarel™, Ferring Pharmaceuticals Inc., Suffern, NY). LA was continued until there was evidence of down-regulation as indicated by a serum E2 concentration of ≤ 45 pg/mL and an endometrial lining ≤ 7 mm on transvaginal ultrasound. If the E2 level was ≥ 45 pg/ml, the endometrial lining was > 7 mm, or menses did not occur within 20 days after beginning LA, the subject was withdrawn from the study.
Subjects who met the down-regulation criteria listed above were randomized to receive single, daily doses of Menopur® SC or Repronex® SC. They were instructed to self-administer hMG SC, alternating their injections between the right and left lower abdomen at approximately the same time every afternoon. Subjects were also instructed to record injection site pain each day using a 0- to 10-point scale, with 0 representing no pain and 10 representing extreme pain. In addition, subjects recorded all adverse events (AEs) experienced during the study, including those associated with injection site reactions. Subjects received 225 IU for 4 days and on day 5, subjects returned to the study centers for transvaginal ultrasound and determination of E2 levels. Based on these findings, the investigators adjusted the daily dose of hMG by 75 to 150 IU up to a maximum of 450 IU per day. Serum E2 levels and ultrasound measurements were taken prior to each dose escalation and a maximum of 12 days total hMG treatment was allowed. Investigators were permitted to decrease the hMG dose at any time based on clinical judgment and safety concerns, and could discontinue hMG and/or withhold hCG administration if they believed the subject was at risk for development of ovarian hyperstimulation syndrome (OHSS). When at least 3 follicles reached a diameter of ≥ 16 mm as measured by transvaginal ultrasound and E2 levels were appropriate for the number of follicles observed based on the investigator's clinical judgment, hMG was discontinued and hCG (Novarel™, Ferring Pharmaceuticals, Inc.) was administered IM at a dose of 10,000 USP units. Oocytes were retrieved 34 to 36 hours later. Standard center-specific IVF culture conditions were allowed, however intracytoplasmic sperm injection (ICSI) and assisted hatching were not. Study centers were permitted to use coculture with homologous cells if it was standard practice and routinely used in all subjects undergoing IVF at that center. A maximum of four embryos could be transferred. Progesterone (Crinone™ 8% gel, 90 mg qd, Serono Laboratories, Inc., Randolph, MA) was self-administered beginning on day 2 or day 3 after oocyte retrieval for luteal phase support, and continued until there was fetal heart motion in an intrauterine pregnancy or there was a negative serum pregnancy test (β-hCG).
Throughout the study, investigators recorded the presence and nature of any AEs. Within 3 weeks of the initial β-hCG quantitative serum pregnancy test or discontinuation from study, subjects returned to the study center for an exit physical examination. Subject reports of AEs were recorded on the case report form and tabulated using Coding Symbols for Thesaurus of Adverse Reaction Terms (COSTART) terminology. Subjects' daily diary evaluations of injection site pain were tabulated on a 0- to 10-point scale.
The primary efficacy of this study was oocytes retrieved and therefore power calculations were done with 80% power to detect an among group difference of 30% in the number of oocytes retrieved. This required 59 patients per group.
A chi-square test was used to make between group comparisons on the percentage of subjects with at least one AE and at least one mild to moderate AE while a Fisher exact test was used to make comparisons on the percentage of subjects with at least one severe AE and at least one serious AE. A chi-square test was used to test for differences in the percentage of subjects with abnormal findings recorded at the study exit physical examination, while the Fisher exact test was used to test for differences in the percentage of subjects with clinically significant abnormal findings. The initial analysis of injection site pain on each treatment day compared the two treatment groups using a one-way ANOVA. A linear mixed model was then used to make treatment comparisons of injection site pain throughout the study. This model allowed the analysis of continuous correlated data to account for within subject variation.