Prednisolone Administration in Patients With Unexplained REcurrent MIscarriages — PREMI  

Fertility Disorders Clinical Trial

Official title: Prednisolone Administration in Patients With Unexplained REcurrent MIscarriages, PREMI Trial

Status Recruiting

Clinical Trial Summary

Recurrent miscarriages (RM) affects 3% of all fertile couples, but remains unexplained in most cases, limiting therapeutic options. Possibly the maternal immune system plays a role in recurrent miscarriage. Prednisolone suppresses the immune system and might enable development of normal pregnancy.

In this randomized controlled clinical trial the investigators will study the effect of prednisolone on the live birth rate in patients with RM. Secondary, the tolerability and safety for mother and child and the cost-effectiveness is investigated.

In the study one group of pregnant women with RM and gestational age <7 weeks will receive prednisolone, the other group will receive a placebo. Total use of the medicine during this study is 8 weeks, further care during the study is routinely antenatal care. Subjects will be asked to fill in 4 short questionnaires and will have contact with a research nurse at different time points to gain information on the course of the pregnancy and possible side effects.

Results of the study will be implemented in (inter) national guidelines, to effect everyday practice.

Clinical Trial Description

Rationale:

Recurrent miscarriage (RM) is defined as 2 or more spontaneous miscarriages. It affects 3% of all fertile couples and in less than 50% an underlying cause may be identified. Thus far, none of the therapies tested in women with unexplained RM showed improvement of the live birth rate (LBR).

As the fetus is a semi-allograft, which escapes maternal immune rejection in normal pregnancy, many studies proposed the involvement of immunological mechanism in RM.

Glucocorticoids could have an effect on these mechanisms. Indeed, a recent meta-analysis has shown a beneficial effect on live birth rate for treatment with prednisolone therapy (RR 1.58, 95% CI 1.23-2.02). The included trials however were inadequately powered, differed in inclusion criteria or contained co-intervention with heparin and aspirin. In addition, most patients were selected based on the natural killer cell density in prior uterine biopsy, though this has not yet proven to be a valid biomarker.

Objectives:

To assess the effectiveness of prednisolone administration, as compared to placebo, on the LBR in an unselected population of women with unexplained RM.

Secondary, the effectiveness of prednisolone on the LBR in various subgroups, the tolerability and safety of prednisolone, the cost-effectiveness and the effect on immune cell levels is studied.

Main study parameters/endpoints:

Primary outcome: live birth rate Secondary outcome: miscarriage rate, ongoing pregnancy rate, adverse events (including side effects and pregnancy complications), decidual immune cell level and direct costs.

Trial design:

Randomized double-blind, placebo controlled multi-center clinical trial. Follow up period ends 3 months after delivery (12 months after randomization).

Trial population:

Women with unexplained recurrent miscarriage, including at least 2 miscarriages, aged 18- 39 years are recruited in a new pregnancy with AD <7 weeks from 10 participating centers in the Netherlands (Coordinating center Leiden University Medical Centre, LUMC).

Diagnosis unexplained recurrent miscarriages is based on latest ESHRE guideline.

Intervention:

After a complete diagnostic work-up, eligible women will be asked to collect a sample of menstrual blood. Patients are then randomized for prednisolone or placebo in a subsequent pregnancy. Women are randomly assigned in a 1:1 ratio to prednisolone tablets (20 mg daily for 6 weeks, 10 mg daily for 1 week, 5 mg daily for 1 week) or identical placebo tablets.

The participants will then receive prenatal visits according to standard care with their own treating physician. All patients will be asked to fill in questionnaires at randomization, and 3, 6 and 12 months after randomization. In a subgroup of patients participating in the LUMC and Radboud MC, additional analyses will be performed, aimed at elucidating the effect of prednisolone on level of different immune cell populations in miscarriage tissue or placenta.

Ethical considerations relating to the clinical trial including the expected benefit to the individual subject or group of patients represented by the trial subjects as well as the nature and extent of burden and risks:

In the PREMI study the investigators will evaluate the effect of prednisolone on the live birth rate in patients with RM in a randomized, placebo-controlled trial. The risks and burden of participating in the trial are estimated as small. The risk of participation is the risk of prednisolone use; substantial evidence exists that prednisolone in this dosage and usage in first trimester is safe for mother and fetus.

Patients may however experience barriers for participation in this study, due to the possible assignment to the placebo-arm (with a possible nil effect on pregnancy outcome), as well as potential side effects. Considering the latter, in a previous feasibility trial no side effects were severe enough for women to stop taking medication. Moreover, to establish the most valid results as possible, there is no other solid manner to answer this research question than by conducting a well-designed double blinded placebo-controlled RCT. ;

Related Conditions & MeSH terms

• Abortion, Habitual
• Abortion, Spontaneous
• Fertility Disorders
• Habitual Abortion
• Miscarriage
• Recurrence
• Recurrent Miscarriage
• Recurrent Pregnancy Loss

• NCT number: NCT05725512
• Study type: Interventional
• Source: Leiden University Medical Center
• Contact: Eileen Lashley, PhD
• Phone: 0031-715263362
• Email: e.e.l.o.lashley@lumc.nl
• Status: Recruiting
• Phase: Phase 4
• Start date: January 29, 2024
• Completion date: July 29, 2027