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Pregnancy Rate, Asthma, Infertility, Omalizumab (PRO_ART)

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ClinicalTrials.gov Identifier: NCT03727971
Recruitment Status : Recruiting
First Posted : November 1, 2018
Last Update Posted : January 29, 2019
Sponsor:
Collaborator:
Novartis
Information provided by (Responsible Party):
Vibeke Backer, Bispebjerg Hospital

Brief Summary:

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, secretion of the vagina, secretion of the rectum, microbiota) 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, secretion of the vagina, secretion of the rectum, secretion of the uterus, microbiota). 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/uterus, change in microbiota in the uterus and lungs, pregnancy loss, asthma control and biomarkers in the blood/lungs/uterus.


Condition or disease Intervention/treatment Phase
Asthma Infertility, Female Drug: Omalizumab Injection Drug: NaCl Phase 2

  Show Detailed Description

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 180 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: A randomized, double blinded, parallel group, study
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Masking Description:

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.

Primary Purpose: Treatment
Official Title: 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
Actual Study Start Date : January 1, 2019
Estimated Primary Completion Date : February 1, 2021
Estimated Study Completion Date : April 1, 2021

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Asthma Infertility
Drug Information available for: Omalizumab

Arm Intervention/treatment
Active Comparator: omalizumab arm
The treatment is initiated with one injection with weight and serum-Immunoglobulin E balanced omalizumab one time per cyclus
Drug: Omalizumab Injection
The treatment is initiated with one injection with weight and serum-immunoglobulin E balanced omalizumab. After omalizumab treatment at ovulation it will again be collected material (blood samples, sputum, secretion of the vagina, secretion of the rectum, secretion of the uterus, microbiota). 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.

Placebo Comparator: placebo arm
Participants will be administered placebo (NaCl), one time per cyclus
Drug: NaCl
The treatment is initiated with one injection with placebo. After placebo injection treatment at ovulation it will again be collected material (blood samples, sputum, secretion of the vagina, secretion of the rectum, secretion of the uterus, microbiota). 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.




Primary Outcome Measures :
  1. Pregnancy rate [ Time Frame: 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


Secondary Outcome Measures :
  1. Inflammation - degree of inflammation in sputum and blod before and after intervention [ Time Frame: 12 months ]
    Change in Sputum and blood Eosinophilic cell count (before treatment and after treatment)

  2. Change in Vascular Endothelial Growth Factor concentration before and after intervention [ Time Frame: 12 months ]
    Change in Vascular Endothelial Growth Factor,in blood, sputum and uterus secretion (before treatment, and after treatment).

  3. Microbiome [ Time Frame: 12 months ]
    Changes in the microbiota in sputum, the vagina, the uterus and the rectum (before treatment and after treatment).

  4. Rate of miscarriages in both groups. [ Time Frame: 9 months ]
    Difference in rate miscarriages between the groups.

  5. Differens in time to pregnancy between the two groups [ Time Frame: 12 months ]
    Total time from first attempt at conceiving to first treatment day, adjusted time to pregnancy.

  6. Change in C-reactive-protein concentration before and after intervention [ Time Frame: 6 months ]
    Change in C-reactive-protein, in blood, sputum and uterus secretion (before treatment, and after treatment).

  7. Change in interleukin-6 concentration before and after intervention [ Time Frame: 6 months ]
    Change in interleukin-6, in blood, sputum and uterus secretion (before treatment, and after treatment).

  8. Change in interleukin-8 concentration before and after intervention [ Time Frame: 6 months ]
    Change in interleukin-8, in blood, sputum and uterus secretion (before treatment, and after treatment).

  9. Change in Immunoglobulin E concentration before and after intervention [ Time Frame: 6 months ]
    Change in Immunoglobulin E, in blood, sputum and uterus secretion (before treatment, and after treatment).

  10. Change in Tumor-necrosis factor A concentration before and after intervention [ Time Frame: 6 months ]
    Change in Tumor-necrosis factor A, in blood, sputum and uterus secretion (before treatment, and after treatment).

  11. Change in eosinophil cationic protein concentration before and after intervention. [ Time Frame: 6 months ]
    Change in eosinophil cationic protein, in blood, sputum and uterus secretion (before treatment, and after treatment).

  12. Number of malformation [ Time Frame: 9 months ]
    Number of malformation in both groups

  13. Number of children born preterm [ Time Frame: 9 months ]
    Number of children born preterm in both groups

  14. Number of preeclampsia during pregnancy [ Time Frame: 9 months ]
    Number of preeclampsia during pregnancy in both groups

  15. Number of perinatal deaths. [ Time Frame: 12 months ]
    Number of perinatal death in both groups

  16. Number of children born with small for gestational age [ Time Frame: 9 months ]
    Number of children born with small for gestational age in both groups

  17. Birth weight [ Time Frame: 9 months ]
    Difference in birth weight between the two groups



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 40 Years   (Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

* 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
  • Current smokers and tobacco consumption more than 10 pack years.
  • TESA / TESE, PCOS, endometriosis
  • Infertility due to other reasons than male factor, tubal factor or unexplained infertility

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03727971


Locations
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Denmark
Bispebjerg Hospital Recruiting
Copenhagen, Denmark, DK-2400
Contact: Vibeke Backer, Professor    +45 3531 6579    backer@dadlnet.dk   
Contact: Casper Tidemandsen, Research Assistent    +4523497817    casper.tidemandsen.01@regionh.dk   
Principal Investigator: Vibeke Backer, Professor, D.MSc., Physcian         
Principal Investigator: Casper Tidemandsen, MD         
Sponsors and Collaborators
Bispebjerg Hospital
Novartis

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Responsible Party: Vibeke Backer, Professor, Bispebjerg Hospital
ClinicalTrials.gov Identifier: NCT03727971     History of Changes
Other Study ID Numbers: 2018-001137-41
2018-001137-41 ( EudraCT Number )
H-18016605 ( Other Identifier: Etics comitee )
First Posted: November 1, 2018    Key Record Dates
Last Update Posted: January 29, 2019
Last Verified: January 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided
Plan Description: Plan to share data for relevant research purposes

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No

Additional relevant MeSH terms:
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Asthma
Infertility
Infertility, Female
Bronchial Diseases
Respiratory Tract Diseases
Lung Diseases, Obstructive
Lung Diseases
Respiratory Hypersensitivity
Hypersensitivity, Immediate
Hypersensitivity
Immune System Diseases
Genital Diseases, Male
Genital Diseases, Female
Omalizumab
Anti-Allergic Agents
Anti-Asthmatic Agents
Respiratory System Agents