The two-shot protocol. A randomized controlled trial of a novel two-injection ovarian stimulation strategy.
Valeria Donno, Noemie Sachs-Guedj, Marta Devesa et al.
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In 30 seconds
This phase III, single-centre randomised non-inferiority trial compared two sequential corifollitropin alfa (CFA) injections with conventional CFA followed by recombinant FSH in women undergoing elective fertility preservation. Among 194 participants, mean mature (MII) oocyte counts were 6.14 ± 4.59 and 7.19 ± 5.67, respectively (MD -1.04 [95% CI: -2.27; 0.18]). Although the difference was not statistically significant, non-inferiority was not demonstrated because the confidence interval crossed the prespecified margin of -1.5 MII oocytes.
Key findings
- Mean MII oocyte counts were 6.14 ± 4.59 with two-shot CFA and 7.19 ± 5.67 with conventional stimulation (MD -1.04 [95% CI: -2.27; 0.18]).
- Non-inferiority was not established: the lower confidence bound of -2.27 exceeded the prespecified non-inferiority margin of -1.5 MII oocytes.
- Stimulation duration was comparable: 10.27 ± 1.69 vs 10.19 ± 1.47 days (MD 0.09 [95% CI -0.39; 0.56]).
- FSH concentrations were higher with the two-shot protocol on Day 8 and on trigger day: 53.43 ± 13.28 vs 24.60 ± 8.33 IU/l and 31.28 ± 9.50 vs 24.46 ± 5.01 IU/l, respectively.
Why it matters
Reducing injection burden is a potential advantage in ovarian stimulation, particularly for elective fertility preservation. This trial provides a direct comparison of a two-injection strategy with a conventional regimen, but the failure to demonstrate non-inferiority means similar average outcomes cannot be taken as evidence that the protocols are equivalent.
What to keep in mind
The study included only women undergoing elective fertility preservation, so embryological differences between protocols could not be assessed. It was powered for MII oocyte counts; secondary outcomes, including hormonal profiles, warrant caution.