Micronised Vaginal Progesterone Luteal‑Phase Support vs Placebo for Live Birth in Women with Unexplained Infertility Expectant Management: Randomized Trial

The primary objective is to determine whether progesterone luteal phase support administered during expectant management improves live birth rates in women diagnosed with unexplained infertility, compared with placebo. Demonstrating an increase in live birth would provide evidence for a therapeutic strategy that could enhance reproductive outcomes without resorting to assisted reproductive technologies.

Secondary objectives include:

• Evaluation of the total budget impact of adding luteal phase support from both healthcare and societal perspectives.
• Assessment of safety and feasibility, encompassing adverse events, effects on quality‑of‑life measures, and pregnancy and neonatal outcome parameters.

The trial enrolled adult women with unexplained infertility who were managed expectantly for at least six months according to Dutch NVOG guidelines. The sponsor did not provide the total number of participants. Eligible participants were required to be ≥18 years old, have a body‑mass index < 45 kg/m², and demonstrate a regular menstrual cycle of 21–35 days. Additional criteria included a Hunault prognostic score ≥ 30 %, primary or secondary infertility persisting ≥1 year, a total motile sperm count ≥ 10 million/ml, and no evidence of tubal pathology unless confirmed absent by patency testing. Women meeting these conditions were classified as patients and considered a vulnerable population. No specific lifestyle requirements such as diet or physical activity were stipulated in the available information.

The PLUIM study is a randomized, double-blind, placebo-controlled interventional trial evaluating whether luteal‑phase progesterone support increases live birth rates in couples with unexplained infertility managed expectantly. Eligible women meeting inclusion criteria are screened during a baseline visit, after which they are allocated 1:1 to receive either 600 mg micronised progesterone vaginal capsules nightly for up to six months or a matching placebo. Follow‑up visits occur at month 1, month 3, month 6 (end of treatment), and at month 12 and month 18 for safety, compliance, and quality‑of‑life assessments. The primary efficacy assessment is pregnancy leading to live birth within six months after randomisation; secondary outcomes are recorded through the 18‑month follow‑up. Participant involvement therefore extends from the screening visit through the final 18‑month visit, approximately 18 months total. Early discontinuation may occur if a serious adverse event related to the study medication arises, if the participant withdraws consent, if protocol non‑compliance is identified, or if pregnancy occurs outside the predefined treatment window.

The investigational product is Utrogestan 300 mg soft vaginal capsules, containing micronised progesterone as the active substance. Each capsule is a soft gelatin formulation intended for vaginal use. Participants in the active arm receive a total daily dose of 600 mg, administered as two 300 mg capsules inserted vaginally once daily during the luteal phase of the cycle.

The comparator is a matching placebo soft vaginal capsule, identical in appearance to the active product (oblong, slightly yellow, containing an oily solution). The placebo contains no progesterone and incorporates compensating quantities of excipients to maintain blinding. The placebo is administered using the same route, dosage form, and frequency as the active medication.

Administration is scheduled to begin after ovulation confirmation and continue until the end of the luteal phase or until pregnancy is confirmed. Compliance is monitored through participant‑maintained dosing diaries, capsule count at each study visit, and verification of proper insertion technique as documented by study staff.

Efficacy will be evaluated primarily by the occurrence of a live birth within six months after randomisation. Secondary efficacy parameters include rates of clinical pregnancy, ongoing pregnancy, biochemical pregnancy loss, and miscarriage within the same six‑month period. Additional pregnancy‑related outcomes such as multiple pregnancy rate, time to pregnancy, pregnancy loss, pregnancy complications, perinatal outcomes, type of delivery, and overall pregnancy outcomes will be recorded for all pregnancies achieved within six months of randomisation.

Safety and tolerability will be monitored through side‑effect reporting and compliance assessment using a medication diary and a questionnaire administered six months after randomisation. The number of adverse events and serious adverse events will be captured throughout the treatment phase.

Health‑related quality of life will be assessed with the FertiQoL questionnaire at three time points: at randomisation, at six months, and at eighteen months post‑randomisation. Progression to assisted reproductive techniques (MOH‑IUI, IVF, ICSI) within six months, as well as the use of ART and any ongoing pregnancy achieved after the six‑month study period and during a twelve‑month follow‑up, will be documented.

Economic evaluation will be performed by analysing budget impact and cost‑effectiveness using live birth rates and associated costs. All efficacy data will be collected according to the predefined schedule, entered into the trial database, and analysed using appropriate statistical methods to compare the progesterone luteal support arm with the placebo arm.