Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT03196882 |
| Other study ID # |
IJG-FER-2012 |
| Secondary ID |
2012-005480-28PI |
| Status |
Completed |
| Phase |
Phase 4
|
| First received |
June 15, 2017 |
| Last updated |
June 22, 2017 |
| Start date |
July 10, 2013 |
| Est. completion date |
January 30, 2017 |
Study information
| Verified date |
June 2017 |
| Source |
Jordi Gol i Gurina Foundation |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
Currently, there is no consensus regarding iron supplementation dose that is most beneficial
for maternal and offspring health during gestation. This deficit, or excess, of iron
prejudices the mother-child wellbeing. Therefore the hypotheses are that an iron
supplementation adapted to values of hemoglobin at the start of the pregnancy will would be
more effective in preventing iron deficiency, without increasing the risk of
hemoconcentration by the end of pregnancy. This would be helped optimize mother-child health
status.
The aims of the study are to determine the highest level of effectiveness of iron
supplementation adapted to hemoglobin (Hb) levels in early pregnancy, which would be optimum
for mother-child health.
To accomplish this objective a Randomized Clinical Trial (RCT) triple-blinded was designed.
The study is structured as a RCT with 2 strata, depending on the Hb levels before week 12 of
gestation.
Stratum 1: If Hb from 110 to 130 g/L, randomly assigned at week 12 to receive iron
supplement of 40 or 80 mg/d.
Stratum 2: If Hb >130 g/L, randomly assigned at week 12 to receive iron supplement of 40 or
20 mg/d.
This study will be conducted in non-anemic pregnant women at early gestation stage, and
their subsequent newborns. The data recollected to mothers will be: socio-economic data,
clinical history, food item frequency, lifestyle and emotional state, and adherence to iron
supplement prescription. In addition, biochemical measured will be Hemoglobin, serum
ferritin, C reactive protein, cortisol, and alterations in the HFE gene (C282Y, H63D). In
children, the data collected will be: ultrasound fetal biometry, anthropometric
measurements, and temperament development
Should conclusive outcomes be reached, the study would indicate the optimal iron
supplementation dose required to promote maternal and infant health. These results would
contribute towards developing guidelines for good clinical practice.
Description:
The study will be conducted in 2 Primary Care Centers (PCC) from Tarragona and Reus of the
Catalunya Sexual and Reproductive Healthcare Service [Atención a la Salud Sexual y
Reproductiva (ASSIR)] of the Catalan Institute of Health [Instituto Catalán de la Salud
(ICS)]. The specialist health-care workers include gynecologists and midwives. The
participating reproductive health-care services (RHS) provide cover for urban, suburban, and
rural PCCs.
The clinical follow-up of the pregnancy in the PCC will be according to the program set by
RHS. This includes a clinical visit at recruitment into the present study, a visit every
trimester, and one at 40 days post-partum.
In the recruitment visit before week 12 of the pregnancy, the inclusion criteria will be
assessed (except the Hb levels and the number of fetuses) as well as the exclusion criteria.
Informed consent will be solicited. A clinical history will be recorded, which include date
of birth, socioeconomic status, parity, date of last menstruation, corrected date of last
menstruation, estimated date of partum, risk factors during pregnancy, pregnancy planning,
previous use of contraceptives, clinical antecedents, surgery and personal obstetric data,
toxic habits, blood pressure, height, weight of the mother (self-reported at the recruitment
visit and measured objectively at each clinical follow-up visit). Similar data from the
father will be solicited.
Moreover, a questionnaire regarding the ingestion of iron supplements, multi-vitamins, or
other treatments and, if a smoker, the Fagerstrom test for tobacco dependency. A blood
sample for standard biochemical analyses (including hemoglobin) will be sent for processing
in the centralized laboratory.
At visit 1, around the 12th week of gestation, Hb levels will be evaluated as will be the
number of fetuses (using echography) to confirm that the inclusion criteria are fulfilled.
If fulfilled, the individuals will be retained in the study and, if not, will be transferred
out of the study, and considered a screening failure. The remaining women will be assigned
to Stratum 1 or Stratum 2 of the study and will be randomized with respect to iron
supplement prescription. Clinical history will be taken, including the use of multi-vitamins
and iron supplements and the questionnaires filled-in about food consumption, physical
activity, anxiety status and tobacco dependency. ). A physical examination will be performed
to measure weight and blood pressure. The ultrasound data on the fetus will be recorded to
assess Crown Rump Length (CRL). A physical examination will be performed to measure weight
and blood pressure. Venous blood will be taken for analyses, the results of which will be
reviewed in the next clinical visit. The iron supplementation that will be needed at the
next visit will be prepared for distribution. Adverse events occurring since the previous
visit will be recorded.
At visit 2, around week 24 of gestation, clinical history will be taken, and will include
questionnaire about use of multi-vitamins and iron supplements which, from this visit
onwards, includes the adherence to the iron supplementation prescribed. The questionnaires
about food consumption, physical activity, anxiety status and tobacco dependency are
filled-in. A physical examination will be performed to measure weight and blood pressure.
The fetal ultrasound data will be registered to assess status of fetus and estimated fetal
weight. The biochemical analyses/results will be reviewed and a further blood sample taken
for analysis, the results of which will be reviewed at the next clinical visit. The iron
supplementation that will be needed at the next visit will be prepared for distribution.
Adverse events occurring since the previous visit will be recorded.
At visit 3, around week 36 of gestation, the clinical history will be taken, the
questionnaire about use of multi-vitamins and iron supplements as well as the questionnaires
about food consumption, physical activity, anxiety status and tobacco dependency will be
filled-in. A physical examination will be performed to measure weight and blood pressure.
The fetal ultrasound data will be recorded to assess status of fetus and estimated fetal
weight and the biochemical results will be evaluated. A further blood sample will be taken
for analyses, the results of which will be discussed at the next clinical visit. The iron
supplementation that will be needed at the next visit will be prepared for distribution.
Adverse events occurring since the previous visit will be recorded.
At visit 4 (40 days post-partum), the clinical history will be taken, the questionnaire
about use of multi-vitamins and iron supplements as well as the questionnaires about food
consumption, physical activity, anxiety status and tobacco dependency will be filled-in. A
questionnaire on post-partum depression and the Parenting Stress Index will be applied. The
standard laboratory analyses results will be discussed. A further blood sample will be taken
for analyses. Data on birth (type of delivery) and the newborn will be recorded (weight and
height). Clinical history of the baby will be recorded, including: gender, status of
newborn, Apgar score, anthropometric data (weight, height, head circumference),
breastfeeding and levels of vitamin D. Cognitive development will be assessed, as well as
behavioral and temperament. Adverse events occurring since the previous visit will be
recorded.
Sample size:
To achieve the study's main objective, sample size is calculated in accordance with the
following parameters: an alpha risk of 0.05 and a beta risk of 0.20 in a two tailed test of
comparison. A drop-out rate or lack of data of 35% is factored-in.
To calculate the sample size, previous data from the research group of investigators were
consulted (Aranda, 2011, Hernández-Martínez, 2011, Ribot, 2012). A prevalence of 23.5% of
iron deficiency anemia was observed in the 3rd trimester in pregnant women with Hb levels of
110-130 g/L in the first trimester and a prevalence of risk of hemoconcentration of 14.7% in
the 3rd trimester of pregnant women who started pregnancy with Hb levels of 130-150 g/L.
- In Stratum 1, to reduce the frequency of anemia ferropenic from 23.5% to 11.5% in the
intervention group supplemented with 80mg/day of iron with respect to the group
supplemented with 40mg/day, will be necessary to include 236 women in each group
- In Stratum 2, to reduce the frequency of hemocontration from 14.7% to 2.7% in the
intervention group supplemented with 20mg/day of iron with respect to the group
supplemented with 40mg/day, will be necessary to include 116 women in each group
Intervention assignment: Allocation
The pregnant women are assigned to Stratum 1 or Stratum 2 as a function of the hemoglobin
values in the baseline analysis of the study. They are, then, randomly assigned to 2
treatment groups to receive different iron supplements.
Stratum 1: If Hb from 110 to 130 g/L, randomly assigned at week 12 to receive iron
supplement of 40 or 80 mg/d.
Stratum 2: If Hb >130 g/L, randomly assigned at week 12 to receive iron supplement of 40 or
20 mg/d.
The randomization is performed using centralized computer software, which is automatic and
masked and applies to the electronic data collection forms, as well. The procedure for
randomization is independent for each Stratum.
Blinding The study will be triple blind: the participant, the health-care professional, and
the statistician. The treatment drug will be administered "blind" i.e. the doses are not
identifiable since the packaging has the same format, presentation, and visual
characteristics. The laboratory of MEIJI TEDEC FARMA, SA will be responsible for
manufacturing, packaging and labeling the study medications.
Only MEIJI TEDEC FARMA, SA and the Clinical Pharmacology Service of the Vall d'Hebron
Hospital in Barcelona will know the distribution codes and the composition of each of the
treatments.
There would be no need for un-blinding except if an unexpected serious adverse event occurs.
In which case, the pharmaco-vigilance staff of TEDEC-MEIJI FARMA S.A. will take
responsibility for un-blinding and communicating the adverse event to the appropriate health
authorities. TEDEC-Meiji Farma SA will not reveal the treatment codes until the end of the
trial, when these data and the documents generated will be made available to the Principal
Investigator (VA) and the Promoter (Institut d'investigació en Atenció Primària, IDIAP,
Jordi Gol i Gurina ).
Statistical methods The description of the variables studied will be performed using
conventional techniques. Variables with non-normal distribution will be transformed as
necessary for normalization of distribution of values. The Kolmogorov-Smirnov and the
Shapiro-Wilks test will be used to verify normality of distributions.
Analysis of the primary outcome The effects of iron dose supplement in each RCT on the
biochemical iron status and mother-child health will be compared using regression models
adjusted for those variables that can influence the relationship. Logistic regression or Cox
models will be applied for qualitative variables such as, for example, the percentage of
anemia or hemoconcentration at the end of pregnancy. Linear multiple regression models will
be applied for dependent quantitative variables. The models will be adjusted for those
variables that biologically affect the relationships studied, such as the serum ferritin
levels, presence of alterations in the HFE gene, age of the mother, gestational age, parity,
anthropometric indices, diet, and lifestyle, and the interactions between these variables.
Initially included in the model will be all those variables that form part of the
theoretical model and, in a second phase, the variables for entry into the model will be
selected step by step (forward and backward) to achieve the most reduced stable models.
Conditions for the application of models will be verified using standard techniques that are
based, essentially, on residuals analysis. The bilateral null hypothesis of normality, no
difference, and non-significance of the regression coefficients, will be rejected when their
Monitoring To ensure correct conduct and security of the RCT according to the requirements
of good clinical practice, external services will be contracted to perform the tasks of
monitoring of the participating centers according to the requirements of the Spanish Agency
of Medicines and Health Products [Agencia Española de Medicamentos y Productos Sanitarios;
AEMPS].
