Phase IV, open-label, randomized study of low-dose recombinant human follicle-stimulating hormone protocols for ovulation induction

Abstract

Background: This Phase IV, open-label, multicentre, randomized study (MEnTOR) compared two low-dose recombinant human follicle-stimulating hormone (r-hFSH) protocols for ovulation induction.

Methods: This study was conducted in six Middle Eastern countries between March 2009 and March 2011. Eligible women (18-37 years), with World Health Organization Group II anovulatory infertility, were randomized to receive r-hFSH (starting daily dose: 75 IU) as a chronic low-dose (CLD) (37.5 IU dose increase on Day 14) or low-dose (LD) (37.5 IU dose increase on Day 7) protocol if no follicles were ≥ 10 mm. The maximum r-hFSH daily dose permitted was 225 IU/day. The total length of ovarian stimulation could not exceed 35 days, unless ultrasound assessment suggested imminent follicular growth and maturation. Patients underwent only one treatment cycle. Primary endpoint: incidence of mono-follicular development. Secondary endpoints included: stimulation duration and rates of bi-follicular development; human chorionic gonadotrophin administration rate; clinical pregnancy; and cycle cancellation (owing to inadequate response). Adverse events (AEs) were recorded. The primary efficacy analysis was performed using data from all patients who received at least one dose of correct study medication, had at least one efficacy assessment, and no protocol violations at treatment start (CLD group, n=122; LD group, n=125).

Results: Mono-follicular development rates (primary endpoint) were similar in both groups (CLD: 56.6% [69/122] versus LD: 55.2% [69/125], p=0.93; primary efficacy analysis population). Similarly, there were no significant differences between groups in bi-follicular development, clinical pregnancy or cycle cancellation (inadequate response) rates. In patients who received human chorionic gonadotrophin injections, the mean duration of stimulation was 13.7 days in the CLD group and 12.9 days in the LD group. Clinical pregnancy rates for those patients who received an hCG injection were similar in both groups (CLD: 20.2% [19/94] versus LD: 19.8% [18/91], p=0.94; primary efficacy analysis population). Most AEs were mild in severity. Only one case of ovarian hyperstimulation syndrome was reported (mild; CLD group).

Conclusions: Efficacy and safety outcomes were similar for the two protocols.

Trial registration: ClinicalTrials.gov NCT01081626.

Figures

Figure 1

Treatment protocols. aWhen the leading follicle reached ≥17 mm and no more than two follicles had reached >14 mm, a single dose of hCG was injected to trigger ovulation. bDuration of ovarian stimulation could not exceed 35 days, unless ultrasound assessment suggested imminent follicular growth and maturation. The maximum permitted daily dose of r-hFSH was 225 IU. Ovarian response was monitored by TVUS every 7 days until a follicle of ≥10 mm was observed, and then scheduled according to local practice. hCG = human chorionic gonadotrophin; IU, international units; r-hFSH = recombinant human follicle-stimulating hormone; TVUS, trans-vaginal ultrasound.

Figure 2

Patient disposition. Patients were considered to have had an under-response if there was failure to develop at least one follicle of 10–12 mm in diameter after 35 days of r-hFSH stimulation. Patients were considered to have had an over-response if they developed more than three follicles of >14 mm in diameter and/or their E2 levels were >900 pg/mL after 35 days of r-hFSH stimulation. AFC = antral follicle count; BMI = body mass index; CLD = chronic low-dose; E2 = oestradiol; hCG = human chorionic gonadotrophin; LD = low-dose; PP = per-protocol; PRL = prolactin; r-hFSH = recombinant human follicle-stimulating hormone.