Use of Omalizumab Will Increase the Pregnancy Rate, Proof of Concept Study, Where Women With Asthma and Infertility Will be Treated Three Times With Weight and IgE Balanced Dosis at the First Day of Their Period Bleeding
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 66
- 试验地点
- 1
- 主要终点
- Pregnancy rate
研究概览
简要总结
The investigators have previously confirmed a clinical hunch that women with asthma have difficulties in becoming pregnant. The investigators found increased time to pregnancy (TTP) in women with asthma compared to non-asthmatic women (55 vs 33 months, p<0.001), furthermore, women with asthma had less successful pregnancies following fertility treatment (39.6 vs 60.4%, p=0.002). Treatment with omalizumab stabilizes the eosinophilic disease, through the systemic and most likely the anti-inflammatory pathways, which indicate a promising possibility to increase pregnancy rate. In a small real-life study in 2017, 5 patients with eosinophilic asthma who underwent in vitro fertilization (IVF), were treated with omalizumab prior to embryo transplantation; three out of the five women became pregnant. Lastly, the two remaining patients had several treatments with omalizumab, but did not become pregnant. This real-life study calls for further investigation. By targeting systemic inflammation with omalizumab treatment the aim is to increase asthma control before and during pregnancy. A treatment strategy aiming at improving overall inflammatory control may increase fertility, but also reduce well known maternal and perinatal adverse pregnancy outcomes such as pregnancy loss, preeclampsia, gestational diabetes, low-birth weight, small for gestational age (SGA), preterm delivery.
Study design:
A randomized control trial with omalizumab and placebo, stratified for blood eosinophil count, is therefore needed. A randomized, double blinded, parallel group, study to evaluate the difference between omalizumab (O) and placebo (P) on pregnancy rate in patients with atopic asthma.Treatment schedule: After collection of material (blood samples, sputum) 6th day (±1 day) of the menstrual cycle, the patients will be randomized in either the omalizumab group or the placebo group. No collection of material will be done at the time of enrollment, as this will be on different time of the female cycles. The treatment is initiated with one injection with weight and serum-immunglobulin E balanced omalizumab or one injection placebo. After omalizumab treatment at ovulation it will again be collected material (blood samples, sputum). If no pregnancy has occurred after first IVF cycle, this will be repeated for 3 consecutive IVF cycles in total or until pregnancy has occurred.
Outcome:
The primary out-come is efficacy of omalizumab, compared to placebo, in increasing pregnancy rate in females with asthma. Secondary out-comes are changes in the inflammation in lungs/systemic, pregnancy loss, asthma control and biomarkers in the blood/lungs.
详细描述
The investigators have previously investigated fertility in patients with asthma (Lundbeck 2011-9502), and found increased time to pregnancy (TTP) in women with asthma compared with non-asthmatic women (55 vs 33 months, p<0.001) and women with asthma had fewer successful pregnancies during fertility treatment (39.6 vs 60.4%, p=0.002). This study supported the clinical hunch that women with asthma have difficulties in becoming pregnant.
In eosinophilic severe asthma with immunglobulin E (IgE) related disease, treatment with omalizumab reduce the number of exacerbations and stabilize the all-over score of the disease, using the tool called Global evaluation of treatment effectiveness (GETE). However, chronic hives, with or without elevated IgE can also be treated successfully with omalizumab. Indicating a biologic class effect, beside IgE. The treatments stabilize the eosinophilic disease, through the systemic and most likely the anti-inflammatory pathways, which indicate a promising possibility to reduce time to pregnancy (TTP) and increase pregnancy rate. In a small real-life study (2017), 5 patients were treated with omalizumab that had eosinophilic atopic asthma, was infertile and underwent in vitro fertilization (IVF). The patients received treatment two weeks prior to embryo implantation in their IVF cycle. Three out of the five women became pregnant at the following IVF treatment, supporting the systemic effect of omalizumab. Lastly, the two remaining patients had several treatments with omalizumab, but did not become pregnant. This real-life study calls for further investigation.
By targeting systemic inflammation with biological treatment the aim is to progress from relieving to treating asthma and thereby increasing asthma control before and during pregnancy. An improved treatment strategy may increase fertility and reduce well known maternal and perinatal adverse pregnancy outcomes such as preeclampsia, gestational diabetes, low-birth weight, small for gestational age (SGA) infants, preterm and cesarean delivery. Fertility treatment is an advanced treatment, which is both expensive and stressful both psychologically and socially for the couples. Infertility is as common as 10-15% of couples in the reproductive age are affected. In Denmark 9 % of the annual birth cohort is born after fertility treatment, and among these, 30% are unexplained infertile. The prevalence of asthma is about 8-10 %. The true prevalence infertility among asthma patients is unknown as this population is largely under diagnosed and therefore probably larger then expected, but in a recent larger register-based study of 5000 asthmatic females, support that a significant number asthma patients have prolonged time to pregnancy. Furthermore, it is unexplored if a well-treated asthma improves fertility by increasing pregnancy rate and by lowering time to pregnancy.
A randomized control trial with omalizumab and placebo, stratified for blood eosinophil count, is therefore needed.
Safety issues: Pregnancy studies are not available, but omalizumab is a biologic drug with no former investigations showing teratogenic effect in real-life studies.
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
- Triple (Participant, Investigator, Outcomes Assessor)
盲法说明
All packaging and labeling of the biological drugs and placebo will be done in a way that ensures blinding for the investigator site staff. Glostrup pharmacy, the hospital pharmacy at the Capital region, will manage randomization and blinding.
Participants will be randomized in two equally big groups, one receiving omalizumab and one receiving placebo, by a computer based program, blinded to investigator. It will be randomized to blocks of 10, in total 16 blocks. It will be automated random assignment of subject numbers to randomization numbers. These randomization numbers are linked to the different treatment arms, which in turn are linked to medication numbers.
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
- •* Informed consent
- •Diagnosis of asthma
- •Infertility due to male factor infertility, tubal factor infertility or unexplained infertility.
- •Referred to IVF treatment with or without ICSI
- •Willingness to receive treatment with biologic drugs during menstruation period
- •Controlled disease with an ACQ ≤ 1.5
- •Exclusion criteria:
- •Other respiratory diseases than asthma
- •Other inflammatory disease or a disease that affects fertility.
- •Allergy to the investigational drugs
- •Respiratory infections requiring antibiotics or anti-viral treatment within 30 days
- •TESA / TESE, endometriosis
- •Infertility due to other reasons than male factor, tubal factor or unexplained infertility
排除标准
- 未提供
研究组 & 干预措施
omalizumab arm
The treatment is initiated with one injection with weight and serum-Immunoglobulin E balanced omalizumab one time per cyclus
干预措施: Omalizumab Injection (Drug)
placebo arm
Participants will be administered placebo (NaCl), one time per cyclus
干预措施: NaCl (Drug)
结局指标
主要结局
Pregnancy rate
时间窗: 7 weeks
To explore differences in pregnancy rate between asthmatic women receiving biological treatment vs. asthmatic women receiving normal asthma treatment and placebo. Pregnancy rate is defined as positive serum- Choriogonadotropin (in week 2) and ongoing pregnancy confirmed with ultra sound in week 7, after 3 consecutive IVF cycles. End of study measured as birth of life born infant or unsuccessful pregnancy
次要结局
- Differens in time to pregnancy between the two groups(12 months)
- Number of perinatal deaths.(12 months)
- Number of children born with small for gestational age(9 months)
- Number of malformation(5 years)
- Inflammation - degree of inflammation in sputum and blod before and after intervention(12 months)
- Rate of miscarriages in both groups.(9 months)
- Change in Immunoglobulin E concentration before and after intervention(6 months)
- Number of preeclampsia during pregnancy(9 months)
- Change in C-reactive-protein concentration before and after intervention(6 months)
- Number of children born preterm(9 months)
- Birth weight(9 months)
研究者
Vibeke Backer
Professor
Rigshospitalet, Denmark