Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT04284696 |
| Other study ID # |
1949-2019 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
N/A
|
| First received |
|
| Last updated |
|
| Start date |
February 11, 2020 |
| Est. completion date |
June 1, 2022 |
Study information
| Verified date |
June 2024 |
| Source |
Medical University of Vienna |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
Nausea and vomiting is a common complication of pregnancy and occurs in 70-80% of all
pregnancies. The symptoms usually start 2-4 weeks after fertilization and peak between the
9th and 16th week of gestation. In the 22nd week of pregnancy, the symptoms usually resolve.
In up to 10% of all pregnancies nausea and vomiting may persist until delivery, which is
called emesis gravidarum. In 0.3-2% of all pregnancies, nausea and vomiting occur with a
pathological intensity called hyperemesis gravidarum. The cause of nausea and vomiting during
pregnancy is unknown, but it is believed that the stimulus is the placenta and not the fetus.
Antihistamines have proven to be an effective therapy. Histamine is increasingly produced
during pregnancy by mast cells in the endometrium and myometrium, but also by mast cells in
the placenta and in the decidua. High expression of the histamine-producing enzyme
histamine-decarboxylase (HDC) in the placenta and many histamine receptors at the
feto-maternal transition in the decidua indicate a physiological role of the histamine during
pregnancy. The antidote is diamine oxidase (DAO), which is produced in the decidua and
trophoblast and breaks down histamine. DAO acts as a barrier to prevent excessive passage of
histamine into the maternal and fetal circulation. DAO levels increase exponentially in the
first 20 weeks of pregnancy to 1000 times the baseline before pregnancy. It has been shown
that intravenous vitamin C significantly reduces blood histamine levels in both allergic and
non-allergic disorders. Another study with the German Navy also proved that oral vitamin C
administration can reduce nausea in seasickness. In an Australian study in 2016, it was shown
that chewing gum was not inferior to ondansetron therapy in patients with postoperative
nausea and vomiting (PONV). From the available literature, we conclude that high maternal
histamine concentrations in early pregnancy may be a cause of nausea and vomiting, whereas
DAO is not sufficiently expressed by the transfer of histamine from the decidua and
trophoblast into the maternal circulation prevent. Vitamin C has been identified in
controlled clinical trials as a way to lower blood histamine levels. Furthermore, chewing gum
was already described as a treatment option for nausea and vomiting. The aim of this study is
therefore to test whether chewing gum containing vitamin C in pregnant women with emesis
gravidarum has the potential to reduce nausea and vomiting and to evaluate a possible
association between maternal human chorionic gonadotropin (hCG) or histamine levels and the
severity of nausea and vomiting in early pregnancy as well as the influence of other factors
such as thyroxine and pyridoxine.
Description:
The following 3 groups of patients should be compared: (1) patients with emesis gravidarum
who take a chewing gum with vitamin C (verum) "ad libitum" several times daily for 2 weeks;
(2.) patients with emesis gravidarum who take chewing gum without vitamin C (placebo) "ad
libitum" several times daily for 2 weeks; (3.) patients with emesis gravidarum who do not use
chewing gum during the study phase. The enrollment will take place at the Department of
Obstetrics and Gynecology, Division of Obstetrics and Feto-Maternal Medicine, at the Medical
University of Vienna. All pregnant women in the first trimester, who present for triage and
birth registration between 6 to 9 gestational weeks, complaining of nausea and meeting the
inclusion criteria, will be offered to participate in the study. If they agree to
participate, patients will be randomized to one of the 3 study groups. In case of enrollment,
patients are not allowed to take any other nausea therapy during the study period, otherwise
the results could be distorted. Both the vitamin C-containing chewing gums (verum) and the
non-vitamin C-containing chewing gums (placebo) are manufactured by the company Frey AG
(Migros-Genossenschafts-Bund, 8031 Zurich, CH). Both chewing gums are not distinguishable
from each other in taste. The only difference between verum and placebo is the proportion of
150mg vitamin C per chewing gum (for verum) or no vitamin C (for placebo). The other
ingredients are as follows: sweeteners isomalt, sorbitol, maltisirup, sucralose, acesulfame
K, chewing gum (with antioxidant E306), sodium L-ascorbate, flavorings, acidifier (apple and
citric acid), thickener gum arabic, dye E171, humectant E422 and E1518, coating agents E903
and E553b. The randomization takes place by means of the GCP-compliant web-based randomizer
of the Institute of Medical Informatics, Statistics and Documentation (IMI) of the Medical
University of Graz (license Meduni Vienna). The ratio of the allocation to the 3 groups is
1:1:1. Furthermore, as co-variable nicotine abuse is included in the randomization, since
smoking with a lower risk correlates with suffering from hyperemesis gravidarum. Study
patients are asked to complete a validated questionnaire (modified PUQE-Score) on their
condition. In addition, there is a blood sampling for the determination of human chorionic
gonadotropin (hCG), diamine oxidase (DAO), thyroxine, pyridoxine and the histamine
concentration in the blood of the patient. Patients are subsequently evaluated at two further
follow-up appointments, one in the course of routine retesting for cervical crease
measurement (between 11-14 weeks of gestation) and 2nd time during routine organ screening
(between 20-24 weeks of gestation). At these appointments, the same blood sampling is
repeated and the evaluation of well-being using the Modified PUQE questionnaire are carried
out again. With the second control appointment the supervision ends within the study. The
study phase is thus completed at the latest at the time of the organ screening at the
Department of Obstetrics and Gynecology, at the latest until the 24th week of pregnancy. For
the determination of DAO, hCG, thyroxine, pyridoxine and histamine, the following tubes (a
total of 32mL blood) are necessary: 3 serum tube of 8mL with separating gel (DAO, hCG,
thyroxine, pyridoxine) + 1 EDTA tube of 8mL (histamine). In addition, it is planned to store
the material that has not been used for the determination of blood concentrations in order to
answer future questions in the field of biomedical research in the MedUni Vienna Biobank. The
legal basis for this can be found in the Research Organization Act 2018 §2d. For each
additional project that uses samples and / or data from this study, a separate report will be
sent to the Ethics Committee of the Medical University of Vienna. The analysis of the DAO
levels takes place in the Allergy Center Floridsdorf, which has many years of experience in
the measurement of DAO and is considered a reliable partner. The samples are pseudonymized
and stored at -80°C. The measurement of of the other blood levels is carried out by the
Clinical Institute for Laboratory Medicine at the Medical University of Vienna. The samples
are taken directly after acceptance by means of a cooled transport container on site for
analysis (coordinated preanalytics). The design of the planned study is prospective,
randomized, double-blind, placebo-controlled. Blinding is provided between verum and placebo
chewing gum (groups 1-2). The taste of verum and placebo chewing gum is identical. The
non-inferiority of chewing gum chewing against doing nothing should also be proved. In
addition to the course of objective parameters such as DAO, hCG and histamine, the personal
condition of the affected patient should be assessed on the basis of the modified PUQE score.
The number of ingested chewing gum is determined by means of the number of used packs on the
1st inspection date. In addition, maternal characteristics are collected, which should be
descriptive and should be included in the multivariate model: age, pregnancy, parity,
gestational age at diagnosis, comorbidities, long-term medication, complications in this or
previous pregnancies, previous hyperemesis gravidarum, nicotine abuse, educational level. In
addition, the pregnancy outcome is retrospectively assessed in order to evaluate any
influence of the chewing gum containing vitamin C on the pregnancy outcome. The primary
endpoint is the modified PUQE score for the 1st control appointment. Secondary endpoints are
the PUQE score at the 2nd control appointment, as well as DAO and histamine concentrations
for the 1st and 2nd control appointment. About the statistical methods: Based on the work of
Birkeland E et al., a standard deviation of 3 points or less can be assumed for each Modified
PUQE score group. Power analysis was conducted in preparation of the study, thereby a
caseload of 111 patients was calculated to find differences between the groups with a power
of >80%. Descriptive statistics (number, mean, standard deviation, median, minimum and
maximum) should be given separately for the 3 target variables Modified PUQE score, DAO and
histamine values for the 3 measurement times. The data is also displayed graphically using
box plots and trajectories. Further metric variables are also described by mean, standard
deviation, median, minimum and maximum, categorical variables are described by absolute and
relative frequencies. As a primary analysis, a mean value comparison of the Modified PUQE
scores is performed between the 3 groups for the measurements at the 2nd control date. For
this, an ANCOVA model is calculated, to which the respective initial values at birth
registration and the week in which the second measurement takes place are considered as
covariates. From the ANCOVA model, the null hypothesis that there are no group differences on
average is tested with an F-test at the 5% significance level. If this global null hypothesis
is discarded, all pairwise group comparisons are performed by T tests for the corresponding
model coefficients of the ANCOVA model at the 5% significance level. This test procedure does
not require any further correction for multiple testing when comparing 3 groups. In another
exploratory model, the maternal characteristics listed in the preceding section are
additionally included as covariates to investigate the potential influence of these variables
on the Modified PUQE score and to calculate adjusted group differences. The secondary
endpoints are compared to the primary endpoint using ANCOVA models between the three groups.
As a further analysis, the Spearman correlations between the Modified PUQE scores, hCG, DAO,
thyroxine, pyridoxine and histamine levels at the three different time points will be
determined.
