NRN 


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                    

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

Site

Dept.

Takenobu Koizumi

Gunma Prefectural Children’s Pediatric Center

Neonatology

Sadao Yamanami

Kawaguchi City Medical Center

Neonatal Intensive Care

Tsutomu Ohno

Saitama Prefectural Children’s Medical Center

Neonatal Intensive Care

Yoshikazu Kida

Matsudo City Hospital

Neonatology

Yasushi Itani

Kanagawa Prefectural Children’s Medical Center

Neonatology

Masanori Tamura

Nagano Prefectural Children’s Medical Center

Neonatology

Satoshi Kusuda

Osaka City Comprehensive Medical Center

Neonatology

Yutaka Sumida

Osaka Med. Center for MCH

Neonatology

Hideto Nakao

Hyogo Prefectural Children’s Hospital

Neonatology

Yuichi Kondoh

Kumamoto City Hospital

Neonatology

Masato Kajiwara

Oita Prefecture Hospital

Neonatology

Harumi Otsuka

Chiba City Kaihin Hospital

Neonatology

Takeshi Fujimori

Kokuho Asahi Chuo Hosp.

Neonatology

Yoko Homma

Jichi National Medical School H.

Pediatrics

Yunosuke Ogawa

Saitama Medical College

Pediatrics

Isao Hasegawa

Kyoto Prefectural U. of Med

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

Osaka Medical Center for MCH.

Coordinator

 

Clinical Coordinator

Shinya Hirano

Osaka University Faculty of Medicine, Pediatrics


 

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  symptomatic patent ductus arteriosus.  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.  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.  Thus, it has not been widely used in actual clinical practice.  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 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.

 

²        Meet the inclusion criteria

²        Do not fall into the exclusion criteria

²        Guardian’s informed consent is obtained.

 

2.      All infants weighing less than 1000 g at birth will be registered first.  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 weeksday at birth.

(3)       Birth weight standard deviation ³ -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:  To be conducted within 6 hours of birth before randomization.  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 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.

3rd:             Gestational weeks according to Ballard measurement.

 

Via Internet

       Input data of the patients.

 

       Confirm the input data on the “patient data confirmation screen”.  The patient is automatically stratified immediately after inputting “confirm”.

 

       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.

 

   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), (³ 26w)

 

 

A table of random numbers is used for randomization.

 

VIII. Test Items (to be completed)

 

1.Echosonographic Study

Hours, days

 of age

0-5 hr

24hr

48hr

3DAY

7DAY

14DAY

21DAY

EDC

(40w)

IVH

PVL

PDA

×

 

 

²        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.  When the two members make the same judgment, it will be adapted.  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.

       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,

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.

 

 


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 Pediatric Center

Neonatology

 

 

 

 

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 Hospital

Neonatology

 

 

 

 

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 H.

Pediatrics

 

 

 

 

17.

Yunosuke Ogawa

Saitama Medical College

Pediatrics

 

 

 

 

18.

Isao Hasegawa

Kyoto Prefectural U. of Med

Pediatrics

 

 

 

 

 

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

 


 

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.