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Indian Pediatr 2009;46: 1063-1069 |
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Gemfibrozil in Late Preterm and Term Neonates
with Moderate Jaundice: A Randomized Controlled Trial |
Jaikrishan, Praveen Kumar and Anil Narang
From the Neonatal unit, Department of Pediatrics, Post
Graduate Institute of Medical Education and Research, Chandigarh, India.
Correspondence to: Dr Praveen Kumar, Additional
Professor, Department of Pediatrics, PGIMER, Chandigarh 160 012, India.
[email protected]
Received: June 24, 2008;
Initial review: September 5, 2008;
Accepted: September 18, 2008
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Abstract
Objective: To determine, if oral Gemfibrozil is
effective in decreasing the duration of phototherapy by at least 24
hours in neonates >34 weeks gestation with non-hemolytic jaundice, as
compared to placebo.
Design: Double blind placebo controlled
randomized controlled trial.
Setting: Tertiary care neonatal unit in north
India.
Subjects: Ninety seven neonates >34 weeks
gestation with non-hemolytic jaundice within first 7 days of life
requiring phototherapy.
Intervention: Two doses of Gemfibrozil (60
mg/kg/dose) or placebo, 12 hours apart. Babies were treated with single
surface special blue light phototherapy. Serum total bilirubin (STB) was
measured 8 hourly. Phototherapy was stopped if two consecutive STB
values were below phototherapy zone.
Primary outcome measure: Duration of
phototherapy.
Results: The median (IQR) duration of
phototherapy was 40 (30, 60) hours in Gemfibrozil and 36 (19, 55) hours
in the placebo group (P=0.13). The peak STB levels were 16.8 ±
2.7 mg/dL and 16.3 ± 2.3 mg/dL in Gemfibrozil and placebo groups,
respectively. No side effect of the drug or placebo was noticed.
Conclusion: Two doses of gemfibrozil
(60mg/kg/dose) given 12 hours apart were not able to reduce the duration
of phototherapy, or peak bilirubin level in babies > 34 weeks gestation
with non-hemolytic jaundice in the first week of life. Gemfibrozil was
not associated with any side effects.
Key words: Fibric acid, Gemfibrozil, Jaundice, Neonate,
Phototherapy.
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P hototherapy and exchange
transfusion are the standard therapies for neonatal hyperbilirubinemia.
However, both have
their drawbacks(1,2). The enzymatic pathways of bilirubin production and
elimination are well understood and many pharmacological interventions to
prevent or treat hyperbilirubinemia have been tried but with limited
success. Clofibrate has been shown to be an efficient inducer of bilirubin
glucuronyl transferase enzyme and z-transport protein(3,4). This drug is
however associated with side effects and there are concerns about its
carcinogenic potential(5).
Gemfibrozil, a newer fibric acid derivative, has
chemical, pharmacological and clinical similarities with Clofibrate. It
acts on peroxisome proliferator activated receptor
a
(PPAR
a).
The UDP glucuronyl transferase enzyme 1A1, which leads to glucuronidation
of bilirubin is a PPAR
a
target gene(6-8). Thus gemfibrozil induces glucuroni-dation of bilirubin.
Its safety profile is much better than clofibrate and has been used in
children with hyperlipidemia due to persistent nephrotic syndrome and HIV,
and no side effects were reported(9,10). The purpose of this clinical
trial was to determine, if oral Gemfibrozil would decrease the duration of
phototherapy by at least 24 hours in late preterm and term neonates with
non-hemolytic jaundice, as compared to placebo.
Methods
This was a double blind, randomized, placebo controlled
trial (RCT), conducted in the neonatal unit of a tertiary care center in
North India, from January 2005 to December 2005. The study was approved by
the Institute Ethics Committee and a written informed consent from one of
the parents was taken before inclusion into the study.
Subjects
Inborn neonates more than 34 weeks of gestation, with
neonatal jaundice requiring phototherapy within first seven days of life,
were eligible. Phototherapy was started as per Cockington charts(11).
Babies were excluded if they had kernicterus, evidence of hemolysis, serum
total bilirubin in exchange zone at enrollment, major congenital
malformation, severe birth asphyxia, large internal/external blood
collections, necrotizing enterocolitis or dehydration. Those babies who
underwent exchange or partial exchange transfusion before enrollment and
whose mothers received phenobarbitone in antenatal period were also
excluded.
Sample size
In our institution, previous data showed that the mean
duration of phototherapy was 75.13±41.4 hours in babies >34 weeks with
non-hemolytic jaundice. To detect a difference of 24 hours, with 80% power
and 2 tailed a
error of 5%, 46 babies were required in each group. It was planned to
enroll 5 babies extra, to take care of attrition.
Intervention
Babies were randomized to Gemfibrozil or placebo group
using a web based random number generator(12) by a person not involved in
the study. Gemfibrozil and placebo were packed in sachets made of aluminum
foil and sealed to prevent entry of any moisture. These opaque sealed
sachets were numbered serially. Caregivers and those who measured the
outcome were blinded to the allocated intervention. The sachets of
gemfibrozil were prepared from capsule Lopid,
manufactured by Parke Davis (Michigan, USA), which was in the form of
white powder. For accurate dose titration, liquid form of the drug was
prepared. As Gemfibrozil is insoluble in water or milk, the contents of 2
capsules of Lopid (600 mg) were suspended in 10 mL of a vehicle. The
vehicle solution was made 3 monthly with help from National Institute of
Pharmaceutical Education and Research (NIPER), Mohali, India. It contained
xanthum gum (0.5%w/v), glycerol (5%w/v), sodium methyl paraben (0.2%w/v),
sodium propyl paraben (0.2% w/v) and demineralised water q.s. These
constituents of vehicle are innocuous and used frequently in eatables and
medicines as preservatives. The vehicle solution was stored at 4şC. Each
placebo sachet contained 600 mg of microcrystalline cellulose, which was
dispersed in 10 mL of the same vehicle. Whenever babies were enrolled, the
sachets were opened serially and the contents suspended in 10 mL vehicle
solution and mixed thoroughly by one of the investigators (JK). The
solution contained 60 mg/mL of gemfibrozil or placebo and dose was 1 mL/kg.
The first dose was given within 60 minutes of enrollment and the second,
after 12 hours.
Outcome variables
The duration of phototherapy was the primary outcome
parameter. Peak serum total bilirubin (STB), age at peak bilirubin, rate
of exchange transfusion and time difference between onset of jaundice and
peak STB were secondary outcome measures.
Data collection and monitoring
STB was measured every 8 hourly using a dual wavelength
direct spectrophotometer (BIL-100, Cosmo Medical Co. Ltd, Korea).
Bilirubinometer was calibrated against bilirubin standards at 3 monthly
intervals. Babies were treated with single surface special blue light
phototherapy. The irradiance of these phototherapy units was measured
daily at the baby’s level by Minolta Airshields radiometer. Irradiance was
maintained at >12 µW/cm 2/nm,
throughout the study period. Exchange transfusion was done when STB
exceeded 20 mg/dL or threshold limit as per Cockington charts. Every baby
underwent blood grouping, direct Coombs test, reticulocyte count and
peripheral blood film examination and glucose 6 phosphate dehydrogenase
(G6PD) estimation. All babies were breast fed and formula milk was added
wherever there was inadequate breast milk output. Conjugated fraction of
bilirubin was checked once after enrolling. SGOT and SGPT levels were
measured 24 hours after administration of first dose. Babies under
phototherapy were examined daily for any rash.
Statistical analysis
Intention to treat analysis was done in a blinded
manner, using the statistical software package SPSS version 10.0. The code
was broken only after complete analysis. Comparison between control and
treatment groups for duration of phototherapy and peak STB was performed
with Student’s t test for equality of means while the rate for
exchange transfusions was compared by Chi square test. It was decided a
priori that oral gemfibrozil will be considered an efficient treatment
modality if there is at least 24 hours reduction in duration of
phototherapy, without any serious adverse effects.
Results
A total of 178 inborn babies >34 weeks gestation and <7
days of age developed neonatal jaundice requiring phototherapy during the
study period. Of these, 97 were enrolled into the study. Forty nine babies
were allocated to Gemfibrozil group and forty eight to placebo; 48 babies
in Gemfibrozil group and 45 in placebo group completed the study (Fig.
1). The mean gestation, weight and age at enrollment of the study
population were 36.9±1.6 weeks, 2461± 658 grams and 78±29 hours,
respectively. The gestation, birth weight, sex distribution and G6PD
deficiency status of those not randomized was similar to that of
randomized infants. The basic demographic profile of the studied babies
was similar in Gemfibrozil and placebo groups (Table I). The
factors at enrollment which could affect subsequent serum bilirubin levels
were not different between Gemfibrozil and placebo groups, except G6PD
deficiency, which was more prevalent in gemfibrozil group (Table
II). Table III shows the primary and secondary outcomes
of the study. The duration of phototherapy (Fig. 2), number
of babies undergoing exchange transfusion, peak STB and age at peak STB
were not different between the treatment and control groups. A Kaplan
Meier survival curve did not demonstrate any difference in the probability
of babies remaining under phototherapy at different ages between the two
groups (log rank test: P = 0.48) (Fig. 3). The
results were not different when late preterm and term infants were
analyzed separately (data not shown).
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Fig.1 Flow of study patients. |
TABLE I
Description of Study Population
Characteristic |
Gemfibrozil |
Placebo |
|
(n= 49) |
(n= 48) |
Males (%) |
27 (55) |
28 (58) |
SGA < 2SD (%) |
4 (8) |
5 (10) |
LGA (%) |
0 (0) |
4 (8) |
Mode of delivery (%) |
Normal vaginal delivery |
25 (51) |
34 (71) |
Cesarean section |
18 (37) |
11 (23) |
Outlet forceps delivery |
6 (12) |
3 (6) |
Gestation (weeks) (mean ± SD) |
36.9 ± 1.7 |
36.8± 1.6 |
Birth weight (g) (mean ± SD) |
2431 ± 592 |
2494 ± 727 |
Difference between the two groups was not significant (P>0.05).
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TABLE II
Baseline Variables Affecting Serum Total Bilirubin
Characteristic |
Gemfibrozil |
Placebo |
|
(n= 49) |
(n= 48) |
Weight loss (% of birth weight) (mean ±SD) |
5.55 ± 2.9 |
5.57 ± 3.7 |
Oxytocin use in mother (%) |
25 (51) |
18 (37) |
Age at enrollment (h) (mean ± SD) |
80 ± 28 |
77 ± 31 |
STB at enrollment (mg/dL) (mean ± SD) |
15.7 ± 2.7 |
15.6 ± 3.1 |
Irradiance (µwatt/cm2/nm) (mean ± SD) |
13.0 ± 3.3 |
12.8 ± 3.1 |
G6PD deficiency* (%) |
26 (53) |
12 (25) |
ABO setting (%) |
9 (18) |
8 (17) |
* P= 0.01, All other P values >0.05.
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TABLE III
Primary and Secondary Outcomes
Outcome |
Gemfibrozil |
Placebo |
|
(n= 49) |
(n= 48) |
Duration of phototherapy (h)* |
Mean ± SD |
50.4 ± 38.8 |
41.6 ± 26.6 |
Median (IQR) |
40 (30, 60) |
36 (19, 55) |
Exchange transfusion (%) |
1 (2) |
2 (4) |
Peak STB (mg/dL) (mean ± SD) |
16.8 ± 2.7 |
16.3 ± 2.3 |
Time between onset of jaundice and peak STB (h) |
Mean ± SD |
8.9 ± 12.2 |
7.3 ± 10.7 |
Median (IQR) |
3.5 (0, 15) |
0 (0, 12) |
Age at peak STB (h) (mean ± SD) |
88.5 ± 27.7 |
85.0 ± 30.7 |
SGOT >30 IU/L (%) |
3(6) |
1(2) |
SGPT >30 IU/L (%) |
3(6) |
3 (6) |
*The data of babies who underwent exchange
transfusion were excluded from the analysis of duration of
phototherapy. All P values >0.05. |
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Fig.2 Box and whisker plot of duration of
phototherapy. |
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Fig.3 Kaplan-Meier survival plot showing
the probability of babies remaining under phototherapy at different
ages. |
Interaction of G6PD deficiency and Gemfibrozil: A
total of 38 babies were G6PD deficient, 12 in placebo and 26 in
Gemfibrozil group. The duration of phototherapy was 50.7±46.3 hours in
Gemfibrozil G6PD deficient subgroup in comparison with 53.4± 35.9 hours in
placebo G6PD deficient subgroup (P >0.05). The peak bilirubin level
and rate of exchange transfusion were also not different between the two
groups. A logistic regression analysis was done with Gemfibrozil/placebo,
G6PD deficiency and gesta-tion as independent variables and phototherapy
duration as dependent variable. After adjusting for G6PD deficiency, there
was no significant difference in phototherapy duration between Gemfibrozil
and Placebo group.
Side effects: No rash was noted in
either Gemfibrozil or Placebo groups. The mean SGOT and SGPT levels were
similar in both groups. Three babies in Gemfibrozil and one in Placebo
group had SGOT levels >30 units/L, while 3 babies in each group had SGPT
level >30 units/L (Table III). None of the babies developed
cholestasis in either group. No other untoward side effects were noted.
Discussion
Oral drug treatment of neonatal jaundice, if effective
and safe, is a more attractive option as compared to phototherapy and
exchange transfusion. Clofibrate, a fibric acid derivative increases the
hepatic clearance of bilirubin by 100% within 6 hours in rats(13). Studies
from France and Iran have shown that it decreases the intensity and
duration of neonatal jaundice (3,4,14). Gemfibrozil, is a newer drug of
the same class with similar effect on PPAR a
but an improved safety profile.
We were able to ensure effective blinding of the
investigators, caregivers, laboratory and the statistician. The duration
of phototherapy was chosen as primary outcome and a difference of 24 hours
as clinically relevant because that would translate into lesser duration
of hospital stay and cost of treatment. However there was no significant
difference in the duration of phototherapy between Gemfibrozil and placebo
groups. There were more number of babies with G6PD deficiency in the
Gemfibrozil group which may have potentially masked the benefits of
Gemfibrozil. It has been documented that phototherapy is less effective in
G6PD deficient babies(15,16). The duration of phototherapy in our study
was however not different between Gemfibrozil and placebo groups even when
analyzed for the sub-group of G6PD deficient babies. This was also
corroborated by a regression analysis. The initial two randomized
controlled trials of clofibrate from France were reported in 1981 and
1985(3,4). In the initial study in term babies, from the 16th hour after
clofibrate administration, the treated group had a significantly lower
bilirubin level compared with placebo. The intensity and duration of the
jaundice was lower and less intensive phototherapy was needed. In the
second study by the same authors(4), clofibrate given to preterm neonates
(31-36 weeks gestation) at 24 and 48 hours reduced the bilirubin levels,
number of bilirubin estimations and phototherapy duration. The one
recently published controlled trial of clofibrate by Mohammadzadeh, et
al.(14) was not blinded and no placebo was used. Most of the babies
were enrolled beyond one week of life, which doesn’t represent the normal
pattern of neonatal jaundice.
Induction of bilirubin-conjugating UGT1A1 enzyme by
fibric acid derivatives in microsomes from liver has been shown in
rats(17). However finofibrates do not increase bilirubin glucuroni-dation
in mice, underscoring the species specificity(18,19). There is a
possibility of racial variations in the UGT1A1 gene in humans which may
make certain populations more responsive to fibrates. There is no
pharmacokinetic data available on Gemfibrozil in infants. We chose the
dose and schedule by extrapolating adult data and did not measure serum
Gemfibrozil levels. Food may also affect the rate and extent of
Gemfibrozil absorption. In neonates, who are fed very frequently, drug
absorption might be erratic and not reach the therapeutic concentrations.
We enrolled the babies when the STB levels reached phototherapy zone at a
mean age of 80 hours. Induction of UGT1A1 genes by Gemfibrozil in humans
may take more time than shown in animals. Hence, starting the drug earlier
may be more effective. Lindenbaum, et al.(4), in 1985,
studied the prophylactic role of clofibrate in newborns of 31-36 weeks of
gestation by giving the drug at 24 and 48 hours. Those babies who received
prophylactic clofibrate had lesser bilirubin level, lesser need for
bilirubin determination and less duration of phototherapy. However this
approach would imply unnecessary administration of the drug to many
babies. The sample size calculation was based on mean phototherapy
duration (75.13 ± 41.43 hours) among the same kind of babies in last year
in our unit. However, the average duration of phototherapy during the
study period (46.1±33.6 hours) was much lesser, probably due to better
phototherapy lights and closer monitoring of irradiance. As a result, the
study was underpowered to detect a 24 hours difference; to detect that,
one would need to enroll 71 babies in each group.
To conclude, two doses of gemfibrozil (60mg/kg/dose)
given 12 hours apart were not able to reduce the duration of phototherapy
in late preterm and term babies presenting with moderate non-hemolytic
jaundice in the first week of life. Gemfibrozil was however well tolerated
and was not associated with any side effects. Whether Gemfibrozil given
earlier, from first day of life, or in different therapeutic doses will be
effective is an area for further investigation.
Acknowledgment
We are grateful to Dr Arvind Bansal, Department of
Formulations, National Institute of Pharmaceutical Education and Research,
Mohali, India for his kind help in preparing the vehicle solution.
Contributors: JK recruited subjects, collected and
analyzed data and wrote the manuscript, PK designed the study, checked the
data and edited the manuscript, AN helped in planning the study and edited
the manuscript.
Funding: None.
Competing interests: None stated.
What is Already Known?
• Gemfibrozil, a newer fibric acid derivative
induces glucuronidation of bilirubin.
What this Study Adds?
• Two doses of Gemfibrozil (60mg/kg/dose) given
12 hours apart were not able to reduce the duration of phototherapy
in late preterm and term babies presenting with moderate
non-hemolytic jaundice in the first week of life.
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