Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT00288600 |
| Other study ID # |
ivig01 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
Phase 4
|
| First received |
February 6, 2006 |
| Last updated |
December 2, 2015 |
| Start date |
October 2006 |
| Est. completion date |
August 2010 |
Study information
| Verified date |
December 2015 |
| Source |
Oswaldo Cruz Foundation |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
Brazil: National Committee of Ethics in Research |
| Study type |
Interventional
|
Clinical Trial Summary
The use of intravenous immunoglobulin G (IVIG) therapy has been reported in
hyperbilirubinemia of Rh hemolytic disease but we don't have enough evidences for it. Human
Immunoglobulin is considered an alternative to delay the hemolytic process and consequently
reduce the number of exchange transfusions and transfusions of red cells concentrate, thus
diminishing the risk of transmitting transfusional therapies-related diseases. OBJECTIVE: To
determine the effect of IVIG in decreasing the incidence and severity of neonatal immune
hemolytic jaundice due to Rh hemolytic disease reducing the need for exchange transfusion as
a primary goal in these babies. METHODS: This will be a randomized, double blind, clinical
trial involving all newborns with risk of significant hyperbilirubinemia due to direct
Coombs-positive Rh hemolytic disease. The primary goal will be need for exchange transfusion
and others are: incidence of late anemia, kernicterus and deafness Babies were randomly
assigned into two groups: group 1 (study group) received phototherapy plus IVIG (500 mg/kg);
and group 2 (control group) received phototherapy and normal saline solution (10 ml/Kg) in
the first 6 hours of life. Exchange transfusion was carried out in any group if at any time
the bilirubin level reached 340 micromol/l (20 mg/dl) or more, or rose by 8.5 micromol/l per
h (0.5 mg/dl per h). Adverse effects will be related in two groups. Parents informed consent
will be asked in pre-natal time.
Description:
The Hemolytic Anemia due to Rh alloimmunization is characterized by the hemolysis of Rh (D)
fetal red cells caused by the action of anti Rh (D) maternal antibodies in the fetal
circulation.
The perinatal hemolytic disease due to Rh alloimmunization is almost extinct all over the
world. The administration of Specific Human Immunoglobulin prevents the sensitization
process and when introduced in the perinatal care of pregnant women, it reduces the
incidence of cases of Rh alloimmunization.
Unfortunately Brazil does not have effective policies geared to reducing the perinatal
hemolytic disease and its consequences and thus the incidence of this condition continues to
be high.
The conventional treatment includes phototherapy and exchange transfusion. The advantages of
the exchange transfusion in the Rh hemolytic disease are well defined but its risks remain
high and the mortality rates related to the procedure range around 2% and the morbimortality
(thrombocytopenia, thrombosis of the portal vein, necrotizing enterocolitis, metabolic
disorders and infection) reach 12%. The procedure requires the availability of compatible
blood, a team with appropriate training in the procedure and a neonatal ICU infrastructure
prepared to prevent the admission of newborns whose mothers did not go through prophylaxis.
The use of immunoglobulin associated to phototherapy may reduce the need for exchange
transfusion, thus allowing for more sensitized newborns to receive treatment and therefore
avoiding neurological damages associated with the hemolytic disease.
If the high incidence of the disease, the difficulties and the risks involved in an exchange
transfusion, the difficulties in obtaining Rh negative blood are taken into consideration,
it becomes clear that it is important conducting studies to prove the effectiveness of the
immunoglobulin in such cases.
General Objective To determine the effect of IVIG in decreasing the incidence and severity
of neonatal immune hemolytic jaundice due to Rh hemolytic disease reducing the need for
exchange transfusion as a primary goal in these babies.
Specific Objectives
1. To asses if the administration of immunoglobulin in newborns with hyperbilirubinemia
caused by alloimmunization Rh(D) hemolytic anemia:
1. Reduces the need for phototherapy
2. Reduces the length of the phototherapy treatment
3. Reduces the need or number of exchange transfusion
4. Reduces the time of hospitalization
2. To evaluate the risk for those patients that received immunoglobulin and the side
effects during its administration.
3. To evaluate the incidence of late anemia and the sequelae of hyperbilirubinemia
(deafness, development retardation, cholestasis and kernicterus) during the first year
of life.
4. To evaluate the Ig-G subclasses and the presence of anti-HLA antibodies of paternal
blood cells in the groups of newborns studied and their relation with the clinical
response to immunoglobulin.
Methodology This will be a randomized and double-blind clinical trial essay . The mothers
will be approached during the prenatal treatment, after being diagnosed as carriers of
hemolytic disease due to Rh alloimmunization. The research will be presented and the
mother/family will be invited to participate in the study. The informed consent term will be
presented to the mother/family and they will be allowed some time to decide. If they are
accepted in the study they will receive a questionnaire on the issues related to the
possible reasons of sensitization.
After obtaining the free and informed consent from the parents, the sensitized newborns will
be randomized in 2 groups, in a 1:1 proportion. The study group will receive Human
Immunoglobulin (Immunoglobulin® - 50mg/ml) with a dose of 500mg/kg, equivalent to 10ml/kg
during the initial 6hours of life, through intravenous infusion for 2 hours; the control
group will receive the same volume in saline solution at 0.09%.
All newborns included in the study will be granted with conventional supplementary treatment
that includes the indication of exchange transfusion and of phototherapy, according to
specific criteria recommended by the American Academy of Pediatrics in 2004. The criteria
apply equally to both groups. The study will be monitored individually and it will be
allowed to be interrupted it if any important side effect occurs such as anaphylactic
reaction or if the results of a given group are significantly better than those of the other
before the inclusion of new subjects in the research, according to the size of the sample or
in case the drug does not yield the desired beneficial effects.
An independent neonatologist, previously chosen, will check the undesirable side effects and
will partially monitor the results of the study. The report on undesirable effects will be
conducted for each case; two intermediate evaluations on the results of the research are to
be conducted. The Committee on Ethics on Research will be informed of every non-expected or
undesired effect related to the medication under study or of the need to interrupt the
research.
Sample Size :
The calculated size of the sample, considering a reduction of 30% on the indication of
exchange transfusion, with a statistical significance of 95% and test power of 80% was 90
newborns. An investigator will approach all pregnant women and/or parent/responsible for the
babies potentially eligible for the study and he will deliver them a consent term.
Randomization and blinding The randomization will be performed by drawing blocks of
different sizes. In order to avoid that the health professionals in the nursery know which
product is being infused into the newborns (Immunoglobulin or Saline Solution 0.9%) the
syringes with the required volumes will be prepared in the pharmacy and wrapped in aluminum
foil. The color of the products is similar. The newborns will be monitored and clinically
followed-up before, during and after the two groups equally receive the infusion. All
clinical changes such as cardiac and respiratory frequency and hemoglobin saturation will be
recorded before and after the infusion in the two groups. All newborns, before and after the
procedure, will be submitted to Glucose dosages by screening method (Blood sugar test).
Complementary treatment
The complementary treatment will be administered and secured to all newborns admitted into
the study and will follow the protocols below:
Indication for exchange transfusion
The babies to whom an exchange transfusion at birth would be indicated will be excluded from
the study. The indications for exchange transfusion at birth are:
- Bilirubin on the umbilical cord superior or equal to 4 mg%
- Fetal hydrops or congestive heart failure due to serious anemia.
The exchange transfusion will be indicated to the following newborns after birth, according
to the existing literature and presenting the following features:
- Bilirubin level is rising over 0.5mg/dl per hour despite phototherapy or
- Hyperbilirubinemia, according to APP directives.
Indication of Phototherapy
All newborns will receive phototherapy beginning in the first 6 hours of life The procedure
adopted will be the triple phototherapy placed 50cms away from the newborns; the irradiance
of the device will be measured every day.
Indication for blood transfusion:
The newborns that present the conditions mentioned below will be indicated to receive reed
blood transfusion at the volume of 15ml/kg, according to criteria below:
1. Hematocrit level under 25% with positive direct or indirect Coombs Hematocrit level
under 21%, with negative direct and indirect Coombs
2. Reticulocytes - less than 1%
3. Hematocrit level under 30% accompanied by clinical signs of severe anemic. Auditory
Evoked Potential All newborns involved in the study will undergo a non-invasive hearing
test, at the occasion of hospital discharge or at the first time they go to the
ambulatory for follow-up. The application of the hearing evoked potential is indicated
to all isoimmunized newborns and is routinely performed at the local where the study is
taking place.
Follow-up after hospital discharge All newborns will be followed-up at the Follow-Up
Ambulatory until the first year of life, during which the laboratorial follow-up will be
conducted (Hematocrit/Coombs) as well as the complete physical and neurological examination.
The Bayley method will be used for neurological evaluation, to be performed by a trained
professional at the end of the first year of life. Every fact related to the clinical
evolution during the first year of life will be recorded: the presence of cholestasis,
nutritional situation (evaluation) through z-score at the time of hospital discharge, by the
6th month and at the end of the first year, regarding weight, height and head perimeter,
using NCHS as standard; hospital admittance for blood transfusion or other treatments,
presence of infection that might be related to the use of blood derivates (hepatitis B and C
, cytomegalovirus).
Laboratorial Tests The laboratorial exams will be performed based on maternal samples, drawn
during the pre-natal period and on samples of the newborn, drawn at birth (blood of the
umbilical cord) and through heel puncture and withdrawal of 2 capillary tubes. These
capillaries will be centrifuged and the total bilirubin will be measured by the Bilirubin
Meter B105, ERMA INC.). The technicians to perform the exams will not be aware of the
allocated group of the patient under examination.
1. Determination of ABO blood groups of the mother- direct and reversal proof- a technique
in the vial with BIOTEST reagents.
2. Determination of the ABO blood group of the newborn -
3. Determination of maternal and fetal Rho ( D) factor - Technique in vial using the
anti-D monoclonal saline solution and BIOTEST Rh control saline solution.
4. Research for irregular antibodies P.A I - in the phase of immediate reading, proteic
phase at 37º - technique in the vial with BIOTEST reagents and sensitized red cell-test
( Coombs control) by BIOTEST
5. Identification of Irregular Antibodies - technique performed with reagents in the
albuminous Coombs vial and a Panel of phenotyped red cells and sensitized red cells (
Combs Control) by BIOTEST
6. Dosage of irregular antibodies in the maternal serum with phenotyped red cells of the
newborn
7. Research for anti-A and anti-B IgG in the blood serum of the Rh negative alloimmunized,
blood type "O" positive mother.
8. Direct test of human immunoglobulin (Direct Coombs) in samples of the NB - technique
performed in a vial with BIOTEST reagents.
9. Classification of IgG subclasses - immunoenzymatic test (ELISA)
10. Research for anti-HLA antibodies against paternal blood cells.
Data analysis:
The data will be stored in the attached worksheet and analyzed using statistical methods to
compare the results of laboratorial exams and the presence or absence of exchange
transfusion during hospital stay among those children who were given intravenous
immunoglobulin and those that were not. These tests will take into consideration that the
sample has been randomized in blocks. The observations will also be conducted by stratifying
both groups, as follows: premature babies, non-premature babies, babies that underwent
intra-uterus transfusion and those that did not. The data will be examined by the
statistical program SPSS 13.0, using the appropriate tests for quantitative and binary
variables.
