Clinical Trial Details
— Status: Active, not recruiting
Administrative data
| NCT number |
NCT03727971 |
| Other study ID # |
2018-001137-41 |
| Secondary ID |
2018-001137-41H- |
| Status |
Active, not recruiting |
| Phase |
Phase 2
|
| First received |
|
| Last updated |
|
| Start date |
January 1, 2019 |
| Est. completion date |
December 31, 2029 |
Study information
| Verified date |
January 2024 |
| Source |
Rigshospitalet, Denmark |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial 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) 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.
Description:
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.
2. Background: Asthma is one of the most common chronic diseases among women of reproductive
age characterized by both local (in the airways) and systemic inflammation, reversible airway
obstruction and airway hyperresponsiveness (AHR). The disease has a global prevalence of
approximately 300 million patients . In the western society, asthma and infertility are among
the most frequent chronic diseases in young adults Several links have been established
between asthma and the female reproduction as uncontrolled asthma both seems to be associated
with decrease fertility and increase adverse perinatal outcomes.
It has recently been shown that women with asthma have prolonged time to pregnancy (TTP) and
a tendency towards a higher number of miscarriages. Furthermore a study, looking at asthma
patients who recently had given birth to a full born child (n=1000) and a control cohort
(n=3000), found that TTP was longer among asthmatics.
These findings, in infertile and asthma patients, suggest that asthmatics both have local and
systemic inflammation probably involving the reproductive organs. This may be the cause of
the reduced pregnancy´s success rate, as it is well known that changes in the inflammatory
environment both systemically and locally in the endometrium can affect the fertility
negatively. Maternal asthma has furthermore been associated with several pregnancy
complications, as gestational hypertension, preeclampsia, gestational diabetes and small for
gestational age. The hypothesis is, that better asthma control with biological treatment
reduces local and systemic inflammation which may improve adverse perinatal outcomes and
other known pregnancy complication.
The investor group propose that targeting both the local and systemic inflammation with
immune modifying therapy, such as biologic drugs, could improve fertility. An increase in
rate of pregnancy as well as reduction in TTP is important for the individual women and her
partner, as well as the society.
3. Minor real-life study: Treatment with oral steroid have been tried numerous times, but
have little or no effect on conception, whereas three out of five patients with asthma in IVF
therapy, treated with omalizumab became pregnant at the following ovulation after IVF
treatment.
4. Material and methods
4.1 Rationale: Asthma is the most common chronic disease among fertile females and
infertility is an increasing and widespread problem in women with asthma. Inflammation seems
to be a possible cause of the reduced fertility among asthma patients and is therefore the
target of the current treatment suggestion. Studies suggest that asthmatics have an altered
microbiota in the lungs as well as in the female reproduction organs, which could be targeted
with biological treatment. However, no studies have examined the effect on neither pregnancy
rate nor TTP of biologic treatment in asthma.
4.2 Hypothesis: The investor group propose, that the highest pregnancy rate and the shortest
TTP is seen in patients with a low degree of inflammation resulting from modifying treatment
with biological drugs, assessed in a randomized design.
4.3 Purpose:
1. To compare, pregnancy rate (positive in serum-Choriogonadotropins (s-hCG)) and ongoing
pregnancy confirmed by ultra sound in week 7 in asthma patients undergoing IVF when
treated with either omalizumab or placebo at 3 consecutive menstrual cycles followed to
birth or abortion.
2. To investigate whether biological treatment with omalizumab increase both local and
systemic inflammatory control (in the lungs)
3. To investigate the association between, pregnancy rate (positive s-hCG) and ongoing
pregnancy confirmed by ultra sound and different degrees and location of asthmatic
inflammation.
4. To investigate the association between, pregnancy rate (positive s-hCG) and ongoing
pregnancy confirmed by ultra sound in week 7 and changes in the microbiota in asthmatic
patients.
5. Study design The Investigational medicinal product (IMP) - omalizumab are manufactured and
marketed with indication for severe asthma since 2005 and chronic spontaneous urticaria, but
as the project will investigate infertility within female asthma patients and this is not as
of yet an indication for the IMP the project will be run as a phase 2a study, (proof of
concept study).
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.
The subjects will have 1-2 week of run-in (diagnosis of asthma) with collection of
questionnaire-based material from the time of enrollment. Pregnant subjects will be followed
up until birth or loss of pregnancy after 3 consecutive IVF.
Time schedule: Screening, run-in, Randomization, intervention and follow up.
5.1 Recruitment: Questionnaire (screening-first contact): As the patients come to their first
pre- IVF consultation, they will be given a form with 20 standardized screenings
questionnaire regarding asthma. If the patient answers yes to one or more questions they will
be contacted and screened for having asthma and possible inclusion in the project.
5.3 Timeline
1. First patient in: 1st Februar 2019
2. Last patient in: 1st December 2023
3. Last patient last treatment/visit: 31st December 2023
4. Last patients last follow-up: 31st December 2029 (5 years of follow-up, on children born
by mothers in study)
5. End of analysis: 1st June 2030
5.4 Asthma diagnoses Asthma is diagnosed based on either asthma symptoms and a positive
asthma test ((Mannitol (Provocative dose 15% ≤ 635 mg), methacholine (Provocative dose 20% ≤
8 μmol)), Eucapnic Voluntary Hyperpnea ≥ 10% on two points and reversibility (≥ 200 ml and ≥
12%), Peak-expiratory-flow during 2 weeks with at least 20% variation and 100 mL currently or
within the last 10 years. Or an earlier diagnosis by a doctor (5-10 years) using one of the
above methods or increase in Forced Expiratory Ventilation (FEV1) of 200 ml and > 12 %,
during treatment with inhaled steroid over time (> 8 weeks).
5.5 Asthma subjects to be included in the study This study will enroll females, 18 - 40 years
of age, inclusive. They should have stable asthma with an Asthma Control Questionnaire (ACQ)
≤ 1,5. The treatment at time of enrollment should be Global Initiative for Asthma (GINA)
guidelines, step 1 to step 4, which is short acting beta2-agonist (SABA) with or without
continuous treatment with inhaled corticosteroid (ICS), and lastly, additional second
controller with montelukast or long acting beta2-agonist (LABA), if needed (GINA 1-4). In
case of uncontrolled asthma (i.e ACQ > 1,5), inclusion should be postponed for 4 weeks, in
which period increased asthma treatment will be prescribed and the patient can be re-screened
for enrollment when ACQ ≤ 1,5 over the last 2 weeks.
Women to be enrolled are infertile due to tubal factor infertility or unexplained infertility
and / or the partner has male factor infertility. Couples who are infertile due to other
reasons (for example endometriosis) are not included
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.
In a group of asthma patients to test an omalizumab induced reduction in number of cycles of
fertility treatment to evaluate pregnancy rate per embryo transfer, when treated with
omalizumab indicated by 41% pregnancy rate (omalizumab) to 19% pregnancy rate (placebo) after
3 cycles of fertility treatment (s-hCG test after 2 weeks and ongoing pregnancy ultrasound
after 7 weeks) and followed for 1 year. Secondary outcome is Ultrasound confirmed clinical
pregnancies ongoing after 3 months and baby take home rate, rate of complication. With a
p-value of 0.05 and power of 0.8, a group of 72 patients with atopic asthma should be
included in each arm. Regulating for drop-out (20%), resulting in 90 atopic asthma patients
in each arm.
Stratification: Blood eosinophilic cell count with a cut off 0.3 mia/L, ensuring equal number
of eosinophilic and non-eosinophilic asthma patients in each group. It will also be stratify
for age, with a cut of >30 years, ensuring equal number of patients with high and low age in
each group. There will be stratified for low sperm count, so that it will be equal number og
women with a male partner with low sperm count in each group.
