Prednisolone Administration in Patients With Unexplained REcurrent MIscarriages, PREMI Trial
试验速览
- 阶段
- 4 期
- 状态
- 招募中
- 发起方
- 入组人数
- 490
- 试验地点
- 1
- 主要终点
- Live birth rate
研究概览
简要总结
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.
详细描述
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:
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
盲法说明
None of the personnel with patient contact will have knowledge to the patient's allocation to prednisolone or placebo group.
入排标准
- 年龄范围
- 18 Years 至 40 Years（Adult）
- 性别
- Female
- 接受健康志愿者
- 否
入选标准
- •In order to be eligible to participate in this study, a subject must meet all of the following criteria:
- •Unexplained recurrent pregnancy loss: defined as the loss of ≥2 pregnancies, without any known cause for RM (parental chromosomal abnormalities, uterine anomalies, acquired or hereditary thrombophilia, endocrine diseases (such as hypothyroidism or diabetes)).
- •The miscarriages include:
- •all consecutive or non-consecutive pregnancy losses before the 24th week of gestation verified by ultrasonography or uterine curettage and histology
- •non-visualized pregnancies (including biochemical pregnancy losses and/or resolved and treated pregnancies of unknown location), verified by positive urine or serum hCG Ectopic and molar pregnancies are not included
- •Age 18 - 39 years at randomization (likelihood of miscarriages due to chromosomal aberrations is higher when age > 39 years. Such miscarriages are unlikely to be pre-vented by prednisolone therapy)
- •Conception confirmed by urinary pregnancy test, with estimated gestational age ≤ 7weeks
- •Willing and able to give informed consent in English or Dutch (IC)
排除标准
- •A potential subject who meets any of the following criteria will be excluded from participation in this study:
- •Any of the following diagnosis for the recurrent miscarriages
- •Antiphospholipid syndrome (lupus anticoagulant and/ or anticardiolipin anti-bodies and/or beta-2 glycoprotein [IgG or IgM)
- •Congenital uterine abnormalities (as assessed by 2D or 3d ultrasound, hys-terosonography, hysterosalpingogram or hysteroscopy)
- •Abnormal parental karyotype
- •Instable or exacerbation of auto-immune diseases such as diabetes, thyroid disease, inflammatory bowel diseases or SLE
- •Inability to conceive within 1 year of recruitment
- •Current treatment with systemic prednisolone or other immune suppressive medication (for any indication)
- •Previous enrolment in the PREMI trial
- •Enrolment in any other trial that studies the effectiveness of an intervention on RM
- •Contraindications to prednisolone use:
- •Known allergy for prednisolone
- •Acute bacterial infection or parasite infection
- •Active COVID infection
- •Systemic sclerosis
- •Ulcus ventriculi or ulcus duodeni in medical history
- •Obesity with BMI >40
- •Some drugs are known to interact with Prednisolone, and thus women on the following drugs are not eligible to take part in the PREMI trial:
- •Enzyme inducers, such as carbamazepine, fenobarbital, fenytoïne and ri-fampicine
- •CYP3A inhibitors, such as Cobicistat or Ritonavir
- •Cyclosporine
- •Vaccination (with inactivated virus or bacteria) during prednisolone use is possibly less effective
研究组 & 干预措施
Prednisolone
Prednisolone tablets (20 mg daily for 6 weeks, 10 mg daily for 1 week, 5 mg daily for 1 week)
干预措施: Prednisolone (Drug)
Placebo
Identical placebo tablets for 8 weeks
干预措施: Placebo (Drug)
结局指标
主要结局
Live birth rate
时间窗: Within 24 months after eligibility
Birth of a living child beyond 24 weeks
次要结局
- Congenital abnormalities(At or short after birth, within 24 months after eligibility)
- Ongoing pregnancy(At +/- 12 weeks of pregnancy)
- Survival at 28 days of neonatal life(28 days postpartum)
- Adverse events(From start intervention until stop intervention (maximum of 7 weeks))
- Pregnancy complications(During pregnancy, maximum of 9 months)
- Productivity costs due to condition(6 and 12 months after randomisation)
- Anxiety and depression(Measurement at start of pregnancy (randomisation), 3, 6 and 12 months after start)
- Quality of life (Health state)(Measurement at start of pregnancy (randomisation), 3, 6 and 12 months after start)
- Birthweight(At birth, within 24 months after eligibility)
- Medical consumption(6 and 12 months after randomisation)
- Gestational age(After birth, within 24 months after eligibility)
- Direct and indirect costs(After intervention, after a maximum of 24 months)
研究者
E.E.L.O. Lashley, MD
Principle investigator
Leiden University Medical Center