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NEONATAL RESEARCH NETWORK
http://nrn.shiga-med.ac.jp/
NEONATAL RESEARCH NETWORK JAPAN
A NATION-WIDE NETWORK
TO CONDUCT MULTICENTER RANDOMIZED PLACEBO-CONTROLLED TRIALS IN
JAPAN
FOUNDED IN 1998
Funded with the research grant of the Department for Family and Children, Ministry of Health,
Japan
1998
3,000,000 yen
1999
3,000,000 yen
2000
3,000,000 yen
2001
3,000,000 yen
2002
3,000,000 yen
2003
3,000,000 yen
Funded with the research grant of the Department for Drug Safety, Ministry of Health and Labor,
Japan
2001
28,000,000 yen
2002
28,000,000 yen
2003
28,000,000 yen
I. Research Theme
1998-2003
Low dose indomethacin for the prevention of intraventricular hemorrhage in extremely low
birthweight infants.
Launched in November, 1999.
15 centers, 600 cases
placebo-controlled trial
present status:
Entry 200 cases in 20 months.
1999-2003
Early trophic feeding to prevent neonatal morbidities (sepsis, necrotizing enterocolitis) in very low
birthweight infants.
Launched in August, 2000.
23 centers, 400 cases
controlled trial
present status:
Entry 50 cases in 9 months.
2001-2003
Doxapram trial for apnea of prematurity
To be launched in April, 2002.
placebo-controlled trial
2002-2003
Beclomethasone inhalation for the prevention of chronic lung disease in extremely low birthweight
infants.
(under preparation)
controlled trial
II. Research Organization
Research Advisory Committee
Yunosuke Ogawa, Professor of Pediatrics, Saitama Medical College
Hiroshi Nishida, Professor of Neonatology, Tokyo Women’s Medical College.
Hajime Togari, Assistant Professor of Pediatrics, Nagoya City University Medical School.
Yoshiyuki Uetani,Assistant Professor of Pediatrics, Kobe National University Medical
School.
Masanori Fujimura, (Principal Investigator), President of Osaka Medical Center for MCH.
Protocol Committee
Masanori Fujimura, (The Principal Investigator), President of Osaka Medical Center for
MCH.
Satoshi Kusuda, Department of Neonatology, Osaka City General Hospital Medical Center.
Shinya Hirano, Department of Pediatrics, Osaka University.
Noriyuki Nakanishi, Department of Public Health, Osaka University Faculty of Medicine,
Registration Committee
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Hirofumi Aotani, Department of Pediatrics, Shiga U. of Medical Science
Shinya Hirano, Department of Pediatrics, Osaka University.
Data Center and Safety Committee
Noriyuki Nakanishi, Department of Public Health, Osaka University Faculty of Medicine,
Principal Investigator (In receipt of Research Grant)
Masanori Fujimura, Osaka Medical Center for MCH, Neonatology
Coodinating Centers and Committee
IVH trial
Co-Investigator
Takenobu Koizumi
Sadao Yamanami
Tsutomu Ohno
Yoshikazu Kida
Yasushi Itani
Masanori Tamura
Satoshi Kusuda
Yutaka Sumida
Hideto Nakao
Yuichi Kondoh
Masato Kajiwara
Harumi Otsuka
Takeshi Fujimori
Yoko Homma
Yunosuke Ogawa
Isao Hasegawa
Site
Gunma Prefectural Children’s
Pediatric Center
Kawaguchi City Medical Center
Saitama Prefectural Children’s
Medical Center
Matsudo City Hospital
Kanagawa Prefectural Children’s
Medical Center
Nagano Prefectural Children’s Medical
Center
Osaka City Comprehensive Medical
Center
Osaka Med. Center for MCH
Hyogo Prefectural Children’s Hospital
Kumamoto City Hospital
Oita Prefecture Hospital
Chiba City Kaihin Hospital
Kokuho Asahi Chuo Hosp.
Jichi National Medical School H.
Saitama Medical College
Kyoto Prefectural U. of Med
Dept.
Neonatology
Neonatal Intensive
Care
Neonatal Intensive
Care
Neonatology
Neonatology
Neonatology
Neonatology
Neonatology
Neonatology
Neonatology
Neonatology
Neonatology
Neonatology
Pediatrics
Pediatrics
Pediatrics
<Committees>
Indomethacin Specialist
Kazuo Itabashi, Urawa City H. Pediatrics
Ultrasound Image Committee
Masanori Nishikawa
Department of Radiology,
Osaka Medical Center for MCH.
Yutaka Sumida
Department of Neonatology
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Osaka Medical Center for MCH.
Coordinator
Clinical Coordinator
Shinya Hirano
Osaka University Faculty of Medicine, Pediatrics
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I. SIGNIFICANCE OF THE STUDY
Intraventricular hemorrhage is a serious disease which causes cerebral
disorder, and it is associated as much as 26% of extremely low birth weight
infants (survey of the 532 extremely low birth weight infants hospitalized
at the 18 sites in Neonatal Research Network (NRN) in 1997).
In particular,
serious hemorrhage having high risk of causing death or cerebral paralysis
and mental retardation accounts for 52% of the intraventricular hemorrhage,
and there are estimated 350 patients annually in Japan.
Indomethacin is known to be effective for treatment of
ductus arteriosus.
symptomatic patent
Recently, it has been reported that intraventricular
hemorrhage might be prevented by administering low dose of indomethacin
for a few days at an early stage of birth.
In order to establish the therapy,
the Network will conduct a multicenter, randomized, blind study.
Low dose
of indomethacin will be administered to infants at an early stage of birth
to examine its efficacy in preventing patent ductus arteriosus and
intraventricular hemorrhage.
If the treatment
is established by this
study, incidence of serious intraventricular hemorrhage in extremely low
birth weight infants is expected to be reduced by maximum 50%, hence
significantly reduces the mortality rate of newborn infants.
Intravenous indomethacin is an effective therapy for patent ductus
arteriosus, and no substitute iv drug is available in Japanese market.
On the other hand, this drug was known to have some adverse effects to
extremely low birth weight infants even before it was approved in 1994.
These include reduction of blood flow to brain, bowel and kidney, which
may induce cerebral hypoxia, necrotic enterocolitis, renal failure and
oliguria.
In addition, indomethacin has a potential risk of impairing
platelet aggregation and may affect hemostatic function.
Indomethacin
may also decrease blood sugar level and make infectious diseases inapparent,
which must be carefully observed.
Currently, intravenous indomethacin sodium is used only when its benefit
to the infants is expected to surpass the potential risk caused by the
adverse effects, i.e., when it is absolutely necessary for the infant to
close the patent ductus and the potential damage by the drug must be accepted.
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On the other hand, due to the potential risk of the adverse effects,
indomethacin has not been widely used for prevention of intraventricular
hemorrhage, despite of the reliable reports to show its efficacy.
As mentioned above, extremely low birth weight infants are at a very high
risk of having intraventricular hemorrhage.
In addition,
intraventricular hemorrhage is one of the most serious diseases among the
problems to disturb life and growth of extremely low birth weight infants.
However, to date, much of the prophylactic treatment for intraventricular
hemorrhage has been conservative.
That is, it has been expected that the
disease might be automatically reduced as a result of improvement in
perinatal care.
Although there are research reports on prophylactic use,
its efficacy has not been
confirmed.
in actual clinical practice.
Thus, it has not been widely used
Under such circumstances, intravenous
indomethacin is expected to be the most effective prophylactic medication
for intraventricular hemorrhage so far studied and reported.
This study stands at the same viewpoint as treatment of patent ductus
arteriosus, in that intravenous indomethacin will be administered for the
benefit of the infants.
However, in order to prevent the intraventricular
hemorrhage, intravenous indomethacin will be administered to all extremely
low birth weight infants who are at high risk of hemorrhage.
In this regard,
it is different from treatment of patent ductus arteriosus where intravenous
indomethacin will be administered only to the infants who have already
had the disease.
In other words, indomethacin will be administered to
all extremely low birth weight infants who are apparently at high risk
of intraventricular hemorrhage.
That is, infants with high risk, but not
necessarily experiencing intraventricular hemorrhage will receive
prophylactic indomethacin which apparently has some adverse effects.
In
this study, low dose of intravenous indomethacin will be administered
continuously to minimize the risk of the adverse events in an attempt to
prove the benefits of indomethacin in preventing intraventricular
hemorrhage.
Accomplishment of the initial objective of the study will
lead to the novel therapeutic approach for prevention of intraventricular
hemorrhage, thus it is expected to be beneficial to all extremely low birth
weight infants.
Two major comparative studies have been conducted in overseas relevant
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to this study.
A prophylactic study for preventing ICH with low dose iv
IM coordinated by the US NIH and published in 1994, showed that indomethacin
substantially reduced incidence of severe intraventricular hemorrhage and
at the same time substantially promoted the closure of patent ductus
arteriosus.
The study concluded the remedy is effective to extremely low
birth weight infants.
No adverse event was observed other than transient
decrease in urination.
The other study, conducted by Medical Research
Council, Canada, was started in 1995 and completed patient enrollment with
1,200 babies in April 1998, and is in the follow-up period.
This subject
was discussed in Cochrane Systematic Review, and they stated that (1) early
stage administration of indomethacin is effective to prevent severe
intraventricular hemorrhage, and (2) further comparative blinded study
is required to specify the subjects to be treated and dose regimen in more
detail.
In terms of adverse events, they stated that no serious side effect
was reported, and the renal disturbance was reversible and recovered after
administration.
Thus, it concluded that the initial objective was
accomplished in relatively safe manner.
II. Objectives
A multicenter, randomized blind study will be conducted to investigate
the prophylactic effect of low dose of intravenous indomethacin sodium
to prevent patent ductus arteriosus and intraventricular hemorrhage that
are the major factors affecting the prognosis of extremely low birth weight
infants.
III.
Inclusion Criteria
1. All infants who satisfy the following criteria will be the subjects
to be enrolled in this study.

Meet the inclusion criteria

Do not fall into the exclusion criteria

Guardian’s informed consent is obtained.
2. All infants weighing less than 1000 g at birth will be registered first.
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Infants who fall into the exclusion criteria and/or infants for whom
guardian’s consent is not obtained still have to be registered on the
internet NRC site, and then excluded from the study.
1) Inclusion Criteria:
Infants must satisfy all of the following five
conditions.
(1) Extremely low birth weight infants weighing more than 400 g
and
less than 1000 g at birth.
(2) Gestation above 22 weeks０day at birth.
(3) Birth weight standard deviation  -1.99 sd.
All infants born less
than 24 weeks 0 day is to be included.
(4) First dose to be given within 6 hours of birth.
(5) Informed consent to participate to the study is obtained from the
guardians.
2) Exclusion Criteria:
Subjects who are found to fall into the following
exclusion criteria at selection time will be excluded from the study subjects,
after being registered on the internet NRC site.
Subjects who are
instructed to be excluded from the study will receive usual treatment.
(1) Subjects diagnosed as grade 3 and 4 intraventricular hemorrhage.
(2) Subjects with patent ductus arteriosus which requires the usual
treatment.
(3) Subjects with hemorrhage tendency.
(4) Subjects with platelet count < 50,000/mm3.
(5) Subjects with necrotizing enterocolitis
(6) Subjects with significant birth defects.
(7) Subjects judged by the investigator to be inappropriate as study
subjects.
3. Cranial ultrasound test:
randomization.
To be conducted within 6 hours of birth before
Confirm the infant has not had grade 3 or 4
intraventricular hemorrhage and then move on to the next step.
IV. Approval of the Study Sites
This study will follow the standard procedures set by each site and will
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be conducted only upon approval by the site.
V. Informed Consent from the Guardians
After confirming that the patient meets the inclusion criteria and does
not fit to the exclusion criteria stated in the protocol, the process moves
on to explanation and obtaining consent.
Explanation to the subject’s guardian will be made by the practitioner
of the department in charge of the study or the nurse working as a coordinator,
using an explanatory form.
Depending on the circumstances, explanation
can be done before delivery.
VI. Enrollment with Use of Internet
1. All infants weighting less than 1,000 g when hospitalized to NICU shall
be registered on the internet NRC site.
2. Whether or not the informed consent is obtained shall also be registered.
3. By registration, the infants are automatically randomized to (1) study
subject, (2) not meeting the inclusion criteria, or (3) fitting to
exclusion criteria and notified.
4. Study drug number will not be given unless the infant is registered.
1) Determination of gestational age
Gestational age will be determined prior to registration.
For each subject,
if upper ranking method is not reliable, lower ranking method shall be
taken.
Reliability of the method will be judged by the obstetrician or
the neonatologist.
1st:
Gestational weeks based on fetal CRL by ultrasound taken at 8-11
weeks of pregnancy.
2nd:
Gestational weeks calculated from day 1 of the last menstrual period.
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3rd:
Gestational weeks according to Ballard measurement.
Via Internet
① Input data of the patients.
② Confirm the input data on the “patient data confirmation screen”.
The patient is automatically stratified immediately after inputting
“confirm”.
③ Put study drug number label on the back cover of the patient’s case
report.
Same number of the study drug must be administered in all the three
administrations.
Study drugs other than the specified number must not
be administered to the patient.
VII. Starting Administration (within 6 hours of birth)
1. Study Drug
Specific number of intravenous indomethacin sodium or
placebo (1 vial is equivalent to 1 mg of indomethacin).
Preparation: Dissolve the study drug in the vial in 1 ml of normal saline.
New vial of the same number will be used at the next administration.
2. Dose Regimen
(1) Administration should be started within 6 hours of birth.
(2) Method of administration: A dose of intravenous injection of 0.1 mg
/kg of the study drug will be given continuously in 6 hours.
Two
additional dose will be given in the same manner in every 24 hours.
Administration will be completed when the third administration is
completed.
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Administration will be discontinued when either of the
following symptoms occur.
Development of IVH-3, IVH-4
Tendency of hemorrhage
Platelet count < 50,000/mm3
Necrotizing enterocolitis
oliguria for 24 hours after administration (< 0.5
ml/kg/hr)
Deterioration of patent ductus arteriosus
1) Subjects who discontinued administration of the study drug will be
judged as drop-outs.
2) The drop-outs will be excluded from the analysis and will receive usual
therapy.
3) The drop-outs should be immediately registered in internet NRC site.
3. Stratification
When registered on the internet NRC site, patients will be stratified by
the following characteristics.
Block randomization for each coordination center
Apgar score (5 minutes): (0-7), (8-10)
Gestation:
(22w, 23w), (24w, 25w), ( 26w)
A table of random numbers is used for randomization.
VIII. Test Items (to be completed)
１．Echosonographic Study
Hours, days
0-5
24hr
of age
hr
48hr
3DAY
7DAY
14DAY
21DAY
EDC
(40w)
IVH
○
○
○
○
○
○
○
○
PVL
○
○
○
○
○
○
○
○
PDA
○
○
○
○
○
×
○
○
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
Determination of drug concentration in plasma:
Kitasato University
IX. Endpoint
Primary:
1) Incidence of grade 3, 4 intraventricular hemorrhage on day 6.
2) Mortality rate at 0-27 days after birth.
3) Incidence of patent ductus arteriosus on day 6.
4) Requirement of surgery for patent ductus arteriosus.
Secondary:
1) Developmental impairment at 1 and a half year old.
2) Developmental impairment at 3 years of age.
X. Judgment of Ultrasound Image
Diagnosis and grade of intraventricular hemorrhage and patent ductus
arteriosus will be determined by the two ultrasound image committee members,
using the judgment criteria and forms prepared in advance.
members make the same judgment, it will be adapted.
When the two
If the two members
make different judgment, they will discuss and adapt the agreed judgment.
If they do not reach agreement, they will ask for the judgment of the Steering
Committee.
XI.
Study Period
1. Starting time of the study:
April, 1999
Each site will start the study when preparation is completed.
Sites
where preparation is delayed will start the study after April.
2. Study Period:
2 years until March 2001.
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Target number of subjects: 500
3. Discontinuation of the study:
In case of the following, the study may be discontinued before the
end of the study period, upon decision by the Advisory Committee.
1) The study causes serious accident and/or side effects and is found
to be harmful.
2) It becomes apparent that neither of the primary endpoints of the
study can be proved.
4. Follow-up: 1 year and 6 months, 3 years at corrected age.
Method: The procedures established by The high-risk Infant Follow-up
Research Network.
Follow-up is scheduled to complete in March 2004.
X. Research Organization
1) Important decisions of this study such as planning, starting time
and discontinuation must be approved by the research Advisory
Committee organized by the following members.
Research Advisory Committee
Yunosuke Ogawa,
Professor of Pediatrics, Saitama Medical College
Hiroshi Nishida,
Professor of Neonatology, Tokyo Women’s Medical College.
Hajime Togari,
Assistant Professor of Pediatrics, Nagoya City University
Medical School.
Yoshiyuki Uetani
Assistant Professor of Pediatrics, Kobe National University
Medical School.
Masanori Fujimura
The Principal Investigator,
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Vice-president of Osaka Medical Center for MCH.
2) This study will be conducted upon approval of the research network
meeting.
It will be called Neonatal Research Network.
3) Decisions of the Neonatal Research Network will be made by majority
vote and validated upon approval of co-investigators.
4) Study sites shall decide whether to implement the study plans before
the start of the study.
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ORGANIZATION OF THE NEONATAL RESEARCH NETWORK
STUDY SITES, PRINCIPAL INVESTIGATOR IN CHARGE AND NRN COMMITTEE MEMBERS
Principal Investigator in charge: Masanori Fujimura, Osaka Medical Center
for MCH, Neonatology
Site
No.
Co-Investigator
Site
Dept.
1.
Takenobu Koizumi
Gunma Prefectural Children’s Neonatology
Pediatric Center
2.
Sadao Yamanami
Kawaguchi City Medical Center Neonatal
Intensive Care
3.
Tsutomu Ohno
Saitama Prefectural
Children’s Medical Center
Neonatal
Intensive Care
4.
Yoshikazu Kida
Matsudo City Hospital
Neonatology
5.
Hitoshi Ida
Japan Red Cross Medical Center Neonatology
6.
Yasushi Itani
Kanagawa Prefectural
Children’s Medical Center
Neonatology
7.
Masanori Tamura
Nagano Prefectural
Children’s Medical Center
Neonatology
8.
Koji Shimura
Shizuoka Prefectural
Children’s Hospital
Neonatology
9.
Satoshi Kusuda
Osaka City Comprehensive
Medical Center
Neonatology
10.
Yutaka Sumida
Osaka Med. Center for MCH
Neonatology
11.
Hideto Nakao
Hyogo Prefectural Children’s Neonatology
Hospital
12.
Yuichi Kondoh
Kumamoto City Hospital
Neonatology
13.
Masato Kajiwara
Oita Prefecture Hospital
Neonatology
14.
Harumi Otsuka
Chiba City Kaihin Hospital
Neonatology
15.
Takeshi Fujimori
Kokuho Asahi Chuo Hosp.
Neonatology
16.
Yoko Homma
Jichi National Medical School Pediatrics
H.
17.
Yunosuke Ogawa
Saitama Medical College
Pediatrics
18.
Isao Hasegawa
Kyoto Prefectural U. of Med
Pediatrics
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Reg. Committee
Hirofumi Aotani
Shiga U. of Medical Science, Pediatrics
Data Coordinator
Noriyuki Nakanishi
Osaka University Faculty of Medicine, Public Health
<Committees>
Indomethacin Specialist
Kazuo Itabashi, Urawa City H. Pediatrics
Ultrasound Image Committees
Masanori Nishikawa
Department of Radiology,
Osaka Medical Center for MCH.
Yutaka Sumida
Department of Neonatology
Osaka Medical Center for MCH.
Coordinator
Clinical Coordinator
Shinya Hirano
Osaka University Faculty of Medicine, Pediatrics
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1. Japanese Neonatal Research Network frame is established as follows;
Research Funding; Ministry of Health
Eighteen clinical centers
One specialist to develop an automatic internet patient registration system
One epidemiologist for data center activity(Assistant Professor of Public
Health, Osaka University)
Advisory Committee(four Professors of Neonatal Medicine)
The Principal Investigator of the Network: Masanori Fujimura, MD.
2.For the indomethacin trial
One pharmacologist who study alubumin binding
One neonatologist who did a study at the time of indomethacin labeling for
the newborn PDA
3.The first Network meeting of the study centers is to be scheduled on
November 16, 1998. Your materials are in good timing for me.
4.The preparatory survey of the study centers, IVH, and PDA incidences is
on the way
5. The randomized trial of indomethacin for the prevention of IVH and
PDA is to be stared in April 1999.
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