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PROTOCOL
Assessment of Perinatal Outcome after Sustained Tocolysis
in Early Labour
APOSTEL II STUDY
(April 2009)
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PROTOCOL TITLE ‘Assessment of Perinatal Outcome after Sustained Tocolysis for Early
Labour’
Protocol ID
APOSTEL II
Short title
APOSTEL studie
Version
1.1
Date
19-4-2009
Coordinating investigator/project
Prof. dr. J.A.M. van der Post, AMC Amsterdam
leader
Principal investigator(s) (in Dutch:
Prof. dr. F.K. Lotgering, UMC St Radboud Nijmegen
hoofdonderzoeker/uitvoerder)
Drs. Carolien Roos, UMC St. Radboud Nijmegen
Multicenter research: per site
Dr. M.E.A. Spaanderman, UMC St Radboud Nijmegen
Dr. K.W. Bloemenkamp LUMC Leiden
Dr. H.C. Scheepers, AZM Maastricht
Dr. J. van Eyck, Isala Klinieken Zwolle
Dr. A. Bolte, VuMC Amsterdam
Dr. M. Porath, Máxima MC Veldhoven
Dr. D.N.M. Papatsonis, Amphia Ziekenhuis Breda
Mw. K.M. Sollie-Szarynska, UMCG Groningen
Dr. J.M.J. Cornette, Erasmus MC Rotterdam
Dr. A. Kwee, UMCU Utrecht
Prof. dr. J.H. Kok, neonatologie AMC Amsterdam
Methodology:
Dr. B.C. Opmeer, AMC Amsterdam
Dr. B.W. Mol, AMC Amsterdam
Sponsor (in Dutch:
ZonMW, grant number: 80-82310-98-08210
verrichter/opdrachtgever)
Independent physician(s)
Prof. dr. M.J. Heineman, AMC, Department of
Gynaecology and Obstetrics
Pharmacy
Apotheek Haagse ziekenhuizen, Den Haag
Mw. dr. S. Samavati, productie apotheker
Trial registration
PROTOCOL SIGNATURE SHEET
NTR 1336, Dutch Trial Register, www.ntr.nl
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1-4-2009
Name
Head of Department Gynaecology and
Obstetrics:
Prof. dr. M.J. Heineman
Coordinating Investigator/Project leader:
Prof. dr. J.A.M. van der Post,
Gynaecologist
Apostel Study
Signature
Date
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TABLE OF CONTENTS
1.
2.
3.
4.
INTRODUCTION AND RATIONALE .............................................................................. 8
OBJECTIVES ................................................................................................................10
STUDY DESIGN ...........................................................................................................11
STUDY POPULATION ..................................................................................................12
4.1
Inclusion criteria: ...................................................................................................12
4.2
Exclusion criteria: ..................................................................................................12
4.3
Sample size calculation:........................................................................................12
5. TREATMENT OF SUBJECTS .......................................................................................13
5.1
Investigational product/treatment ..........................................................................13
5.2
Use of co-intervention ...........................................................................................13
6. INVESTIGATIONAL MEDICINAL PRODUCT ................................................................14
6.1
Name and description of investigational medicinal product ...................................14
6.2
Summary of findings from non-clinical studies.......................................................14
6.3
Summary of findings from clinical studies..............................................................14
6.4
Summary of known and potential risks and benefits ..............................................15
6.5
Description and justification of route of administration and dosage .......................15
6.6
Dosages, dosage modifications and method of administration ..............................15
6.7
Preparation and labelling of Investigational Medicinal Product ..............................15
7. METHODS ....................................................................................................................16
7.1
Study parameters/endpoints .................................................................................16
7.1.1 Main study parameter/endpoint .........................................................................16
7.1.2 Secondary study parameters/endpoints ............................................................16
7.2
Randomisation, blinding and treatment allocation .................................................16
7.3
Study procedures ..................................................................................................16
7.4
Withdrawal of individual patients ...........................................................................17
7.4.1 Specific criteria for withdrawal ...........................................................................17
7.5
Follow-up of subjects withdrawn from treatment....................................................17
7.6
Premature termination of the study .......................................................................17
8. SAFETY REPORTING ..................................................................................................18
8.1
Section 10 WMO event .........................................................................................18
8.2
Adverse and serious adverse events ....................................................................18
8.2.1 Suspected unexpected serious adverse reactions (SUSAR) .............................18
8.2.2 Annual safety report ..........................................................................................19
8.3
Follow-up of adverse events .................................................................................19
8.4
Data Safety Monitoring Board (DSMB) ..................................................................19
9. STATISTICAL ANALYSIS .............................................................................................20
9.1
Interim analysis (if applicable) ...............................................................................20
10.
ETHICAL CONSIDERATIONS ..................................................................................21
10.1 Regulation statement ............................................................................................21
10.2 Recruitment and consent ......................................................................................21
10.3 Benefits and risks assessment, group relatedness ................................................21
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10.4 Compensation for injury ........................................................................................21
11.
ADMINISTRATIVE ASPECTS AND PUBLICATION .................................................22
11.1 Handling and storage of data and documents .......................................................22
11.2 Annual progress report..........................................................................................22
11.3 End of study report ................................................................................................22
11.4 Public disclosure and publication policy ................................................................23
12.
REFERENCES .........................................................................................................24
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LIST OF ABBREVIATIONS AND RELEVANT DEFINITIONS
ABR
ABR form (General Assessment and Registration form) is the application form
that is required for submission to the accredited Ethics Committee (ABR =
Algemene Beoordeling en Registratie)
AE
Adverse Event
AR
Adverse Reaction
CA
Competent Authority
CCMO
Central Committee on Research Involving Human Subjects
CL
Cervical length
CV
Curriculum Vitae
DSMB
Data Safety Monitoring Board
EU
European Union
EudraCT European drug regulatory affairs Clinical Trials GCP Good Clinical Practice
FN
Fibronectin
IB
Investigator’s Brochure
IC
Informed Consent
IMP
Investigational Medicinal Product
IMPD
Investigational Medicinal Product Dossier
METC
Medical research ethics committee (MREC); in Dutch: medisch ethische
toetsingscommissie (METC)
NICU
Neonatal Intensive Care Unit
(S)AE
Serious Adverse Event
SPC
Summary of Product Characteristics (in Dutch: officiële productinformatie IB1tekst)
Sponsor
The sponsor is the party that commissions the organisation or performance of the
research, for example a pharmaceutical company, academic hospital, scientific
organisation or investigator. A party that provides funding for a study but does not
commission it is not regarded as the sponsor, but referred to as a subsidising
party.
SUSAR
Suspected Unexpected Serious Adverse Reaction
TMT
Tocolytic maintenance therapy
Wbp
Personal Data Protection Act (in Dutch: Wet Bescherming Persoonsgegevens)
WMO
Medical Research Involving Human Subjects Act (Wet Medisch-wetenschappelijk
Onderzoek met Mensen
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SUMMARY
Rationale: At present, women with threatening preterm labour before 32 weeks are
transferred to a neonatal centre, treated with corticosteroids (to improve lung maturity) and
tocolytics (to delay labour). It is questionable whether treatment with tocolytics should be
maintained after 48 hours.
Objective: This study will answer the question if sustained (> 48 hours) tocolysis improves
perinatal outcome.
Study design: randomized placebo controlled trial.
Study population: 400 women with threatening preterm labour between 26 and 32+2 weeks
gestational age after 48 hours with tocolytic treatment and steroids.
Intervention: random allocation to nifedipine (intervention) or placebo (control) for twelve
days.
Main study parameters/endpoints: Primary outcome is composite neonatal morbidity
status, i.e. severe morbidity and death at 6 months. Secondary outcomes are gestational age
at delivery, number of days in neonatal intensive care and total days in hospital.
Sample size calculation: The study will be evaluated according to intention to
treat. To exclude a 10% difference in adverse neonatal outcome 400 women have to be
randomised (two sided test, ß 0.2 at alpha 0.05). Intention to treat analysis.
Nature and extent of the burden and risks associated with participation, benefit and
group relatedness: As we compare two strategies that are already applied in current
practice, no additional risks or burden are expected from the study.
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1. INTRODUCTION AND RATIONALE
Problem definition
HEALTH CARE PROBLEM: Preterm birth is the most common cause of neonatal morbidity
and death worldwide (1). Two thirds of the preterm births occur as a result of spontaneous
labour or preterm rupture of membranes. Preterm birth is responsible for approximately 75%
of all neonatal deaths and 50% of childhood neurological morbidities (2). It is also associated
with high immediate and long-term costs after discharge from the hospital (3). These include
costs for special education services, institutionalised care for physically and mentally
handicapped infants (4). The prevalence of adverse neonatal outcome is strongly related to
gestational age at delivery and declines from 77% at 24-27 weeks to less then 2% at 34
weeks and more (5).
Perinatal death and morbidity are not only strongly related to early gestational age but also to
whether or not steroids are administrated antenatally and whether a preterm infant is
transferred to a tertiary care centre in- or ex-utero (6). Therefore, postponing delivery for 48
hours with tocolytics in order to allow maximal effect of maternal parenteral steroid
administration and transportation of the mother to a centre with NICU facilities is the standard
treatment of choice in women with the diagnosis of threatening preterm delivery between 24
and 32 weeks gestational age, 24 weeks being considered the limit of viability (7).
Approximately 75% of women with a diagnosis of threatening preterm labour are still
pregnant after the first 48 hours of tocolytic therapy. After this 48 hour period the risk of
preterm delivery persists and in daily obstetrical practice two weeks after treatment for
preterm labour 60% of women has delivered a child (16).
In national and international guidelines, a uniform treatment of threatening preterm birth after
48 hours of tocolytic therapy has not yet been developed. As a consequence, some
obstetricians maintain tocolytic therapy until term, 37 weeks gestational age, others stop
tocolytics after 48 hours irrespective of gestational age or continue until for example 28
weeks gestational age. Maintenance treatment with several tocolytic agents is being carried
out in daily practice including betamimetics (9,10), magnesium sulphate (11), indomethacin
(12) and calcium channel blockers (13) to achieve further prolongation of pregnancy and
prevent adverse neonatal outcome. However, so far no beneficial effect has been
established of this prolonged treatment and it is not clear whether prolonged treatment is
effective (14). On the one hand, tocolytic maintenance therapy with calcium channel blockers
might be beneficial due to its positive effect on gestational age. On the other hand, its use of
tocolytics is related to severe side effects for mother and child (15, 16). Moreover,
prolongation of pregnancy might also increase the chance for perinatal complications (17)
such as infection.
After 32 weeks gestational age, survival statistics are equal to term. Neither two systematic
reviews included in DARE (18, 19) nor a Cochrane systematic review on maintenance
tocolysis with terbutaline demonstrated a beneficial effect of tocolytic maintenance therapy
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(TMT). A trial of maintenance tocolysis with nifedipine was underpowered to rule out an
effect on prolonging gestation (20).
In summary, preterm delivery is an important health care problem. Whereas it is evident that
tocolysis with administration of corticosteroids is effective for 48 hours, there is insufficient
evidence for a rational policy after these 48 hours. In this randomised clinical trial we will
study the effect of maintenance therapy compared to no treatment. The data collected can
be used to compare several strategies, including measurement of cervical length and
fibronectin prior to the decision for sustained tocolysis.
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2. OBJECTIVES
Primary objective
To evaluate the effectiveness of tocolytic maintenance therapy for postponing delivery after
initial standard tocolytic therapy in women with threatening preterm birth from 26-32+2 weeks
gestational age in terms of:
Neonatal mortality
Composite neonatal morbidity
Chronic Lung disease
Severe intraventricular haemorrhage more than grade 2
Periventricular leucomalacia more than grade 1
Proven sepsis
Necrotising enterocolitis
Secondary objective
Gestational age at delivery
Birth weight
Number of days on additional oxygen
Number of days on supported ventilation
Number of days in intensive care
Total days in hospital until 3 months corrected age
Costs
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3.
STUDY DESIGN
Multicenter randomised placebo-controlled clinical trial
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4.
STUDY POPULATION
The trial will study 400 pregnant patients after 48 hours of standard treatment with tocolytics
for threatening preterm labour. The randomised clinical trial will be performed in perinatal
centres that are collaborating, as well as their affiliated hospitals if suited.
4.1 Inclusion criteria:
All women with a gestational age between 26+0 and 32+2 weeks who are spontaneously in
labour, and for whom the clinician has decided that preterm birth is likely and consequently
have been treated accordingly with tocolytics and steroids for 48 hours, are eligible for the
trial.
4.2 Exclusion criteria:
Women having signs of intra uterine infection, with placenta praevia, women whose child has
signs of fetal distress (abnormal CTG, abnormal biophysical profile) or women with any
contraindication for the use of nifedipine or having a maternal disease (hypertension, HELLP
syndrome, preeclampsia or other) as reason for delivery.
4.3 Sample size calculation:
A difference in reduction of compound morbidity from 25% to 15%, with a beta of 0,2 at alpha
of 0.05 can be detected if 400 patients can be analysed (200 in each arm).
During an earlier trial in two perinatal centres (VUMC, AMC) concerning acute tocolysis 40
patients were randomised per centre per year. Assuming that 75% is undelivered after 48
hrs, it means that 30 patients per centre per year can be randomized. For the participating
centres this means 300 patients can potentially be randomised each year, thus indicating
that 400 patients in two years is a reasonable objective.
Estimated is an incidence of compound morbidity of 30% for the whole group based on the
earlier trial and historical data extracted from the electronic registry from the AMC. The initial
analysis will be according to the intention to treat principle. In a second analysis, we will
assess the effectiveness of TMT in those women in whom the treatment could be applied
according to plan.
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5. TREATMENT OF SUBJECTS
Prior to randomisation, all patients will undergo an examination of the cervix with a speculum,
at which time a swab will be placed in the posterior vaginal fornix for 10 seconds to absorb
cervicovaginal secretions. Fibronectin measurement will not be performed in women with
ruptured membranes, > 3cm dilatation or vaginal bleeding. The swab will be stored, and
fibronectin will be measured after the patient has completed the study. Moreover, in all
women cervical length will be measured transvaginally.
5.1 Investigational product/treatment
Tocolysis with nifedipine in a maximum dosage of 80 mg/24 hours versus placebo. In case
the patient is still undelivered at 10 days after randomisation, study medication will be
discontinued according to a predefined scheme. Patients allocated to nifedipine will take 60
mg/24 hours at day 10, 40 mg/24 hours at day 11, and 20 mg/24 hours at day 12, to
discontinue study medication at day 13. Patients allocated to placebo will receive placebo
medication in a similar form. When the clinical condition of the patient allows it, the patient
can be discharged prior to ending study medication. If a patient starts study medication at a
gestational age of 31+1 weeks or later, she will continue study medication after 32+2. In case
of renewed threatening preterm labour, patients will restart study medication according to the
allocation they had.
5.2 Use of co-intervention
Prophylactic treatment with antibiotics is the decision of the attending physician.
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6. INVESTIGATIONAL MEDICINAL PRODUCT
6.1 Name and description of investigational medicinal product
Nifedipine retard CF 20 mg, tablets
6.2 Summary of findings from non-clinical studies
Calcium channel blockers or calcium antagonists are non-specific smooth muscle relaxants,
predominantly used for the treatment of hypertension in adults. They exert their tocolytic
effect by preventing the influx of extracellular calcium ions into the myometrial cell.
Concerns arose from animal studies (Harake 1987) that nifedipine may have adverse effects
on the fetal and placental circulation. Subsequent studies failed to confirm this (Meyer 1990).
6.3 Summary of findings from clinical studies
Calcium channel blockers are entirely non-specific for uterine as distinct from other smooth
muscle cells, but have been demonstrated in vitro to have potent relaxant effect on human
myometrium (Saade 1994). The most widely used and studied calcium channel blocker is
nifedipine which (like nicardipine) belongs to the dihydropiridine group. Nifedipine was first
reported in 1980 in an observational study to be an effective tocolytic agent with minimal side
effects (Ulmsten 1980). Two apparently significant drug interactions have been reported
when nifedipine and IV magnesium sulphate were used concurrently (Snyder 1989,
Waisman 1988).
A prospective, multicenter cohort study of 78 women (81 outcomes; 3 sets of twins) who had
1st-trimester exposure to calcium channel blockers, including 44% to nifidipine, was reported
in 1996 (Magee et al.). Compared with controls, no increase in the risk of major congenital
malformations was found.
A Cochrane systematic review of randomised trials shows that calcium antagonists improve
neonatal outcome and delay delivery more effectively than -agonists (Papatsonis et al 28),
while Baysian interpretation of several trials comparing -agonists versus placebo are
consistent with tocolytics reducing perinatal mortality and neurological damage (Fisk et al
29).
The use of nifedipine is recommended by the Dutch Society for Obstetrics an Gynaecology
(NVOG) as a tocolytic agent of first choice for tocolysis in women with threatened preterm
labour (Richtlijn “dreigende vroeggeboorte”, http://www.nvog-documenten.nl/). Many clinics
in The Netherlands use it at present as tocolytic drug of first choice.
A recent report on nifedipine from a single centre (Free University Amsterdam) of 7 cases of
temporary pulmonary oedema (Lenglet et al 2007), but other investigators could not confirm
this (Oei and Van de Water 2007). One case of fetal death due to hypotension after the use
of nifedipine has been described (Van Veen et al 2005). In this case, nifedipine had been
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administered as 10mg chew tablet every 15 minutes. Hypotension occurred after
administration of the second chew tablet. In the present study, we only use the slow release
form.
A large prospective cohort study registering serious maternal and neonatal side effects of
tocolytics had just finished recruiting. Preliminary data show that, among >1000 women using
nifedipine, the incidence of hypotension after the use of nifedipine leading to discontinuation
of treatment occurred in less than 0.5% of the patients (Mol and Visser were investigators in
that study, personal communication). Women with multiple pregnancies were not at
increased risk. Neither mothers nor children suffered permanent damage. Long-term follow
up of children exposed in utero to nifedipine for a median period of 7 days showed no
adverse effects (Houtzager 2006).
6.4 Summary of known and potential risks and benefits
Nifedipine is considered safe and its use is associated with little side-effects. It is
recommended as one of the tocolytic drugs of first choice by the Nederlandse Vereniging
voor Obstetrie en Gynaecologie.
6.5 Description and justification of route of administration and dosage
The active medication will be Nifedipine retard 20 mg produced by Centrafarm. Nifedipine is
available as oral medication, and is in this form recommended in the guideline of the Dutch
Society of Obstetrics an Gynaecology. A large cohort study in The Netherlands and Belgium
showed the incidence of hypotension leading to discontinuation of treatment to be below
0.5%. The only case of fetal death that has been described was reported after the use of
nifedipine as chew tablet. No such reports are known after the use of nifedipine slow retard.
6.6 Dosages, dosage modifications and method of administration
Tocolysis with nifedipine in a maximum dosage of 80 mg/24 hours versus placebo (4 tablets,
20 mg, oral use). In case the patient is still undelivered at 10 days after randomisation, study
medication will be discontinued according to a predefined scheme. Patients allocated to
nifedipine will take 60 mg/24 hours at day 10, 40 mg/24 hours at day 11, and 20 mg/24 hours
at day 12, to discontinue study medication at day 13 of the study. Patients allocated to
placebo will receive placebo medication in a similar form. In case of renewed threatening
preterm labour, patients will restart study medication according to the allocation they had.
6.7 Preparation and labelling of Investigational Medicinal Product
The active medication will be Nifedipine retard 20 mg produced by Centrafarm. Placebo
medication will be made by the Apotheek Haagse ziekenhuizen in The Hague
(mw. dr. S. Samavati, productie apotheker). This pharmacy will also label the medication. It
will then be delivered to the pharmacies of the ten participating hospitals, who will be
responsible for local distribution.
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7. METHODS
7.1 Study parameters/endpoints
7.1.1 Main study parameter/endpoint
The main outcome measure will be a composite poor neonatal outcome, including
chronic lung disease, PVL, IVH grade 2, NEC, proven sepsis and perinatal death.
7.1.2 Secondary study parameters/endpoints
Secondary outcomes will be gestational age at delivery, number of days on
ventilation support, in NICU and total days in hospital. In case of a not optimal
maternal or neonatal condition at 6 weeks post partum, the mother and/or her child
will be followed until 12 months.
Moreover, we register maternal morbidity or complications that might be related to
the prolonged use of tocolytics during the study. A panel with experts will
subsequently judge whether the complication is due to the use of tocolytics or not.
Additional application for long term follow up of children (2 and 5 years) and
mothers will be performed.
7.2 Randomisation, blinding and treatment allocation
Randomization, stratified for centre, parity and singleton or multiple gestation, will
be performed after baseline data have been entered in a web-based database
system, using a central randomization system.
Treatment allocation will only be known to the pharmacy that prepares the placebo
medication. A sealed list with the codes of the study medication will be available to
the principal investigator. In case a patient is suspected of having side effects that
might be due to nifedipine, the local clinician responsible for the patient can contact
the principal investigator and the code for study medication can be unblended.
7.3 Study procedures
Patients will be treated according to local protocol, but for the intervention under
study.
In case a patient has signs of repeated threatened preterm labour after the study
medication has been completed, i.e. at more than 12 days after study entry, and if
the gestational age is below 30+0 weeks, the patient can start with repeated
tocolysis for 48 hours and repeated administration of tocolytics. In case the patient
remains undelivered at 48 hours after the start of repeated tocolysis, she will again
have study medication for 12 days, i.e. nifedipine 80mg per day, with a decrease of
the dose at days 10, 11 and 12, or placebo.
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7.4 Withdrawal of individual patients
Patients can leave the study at any time for any reason if they wish to do so without
any consequences. The investigator can decide to withdraw a subject from the
study for urgent medical reasons.
7.4.1 Specific criteria for withdrawal
In patients with signs of intra-uterine infections (maternal temperature > 38o C, fetal
tachycardia) or signs of fetal distress (abnormal CTG, meconium stained amniotic
fluid), the study medication will be discontinued. Further management will be left to
the expertise of the responsible clinician. The responsible clinician can contact a
responsible person from the project group in case of suspected side effects or other
medical problems. If necessary, treatment allocation will be unblinded.
7.5 Follow-up of subjects withdrawn from treatment
As the statistical analysis is planned according to intention to treat principle,
patients that discontinue study medication will be analysed in the group that they
were allocated to.
7.6 Premature termination of the study
An interim analysis is planned after the follow up data of the first 200 women that
have been included is obtained (see paragraph 9.1).
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8. SAFETY REPORTING
8.1 Section 10 WMO event
In accordance to section 10, subsection 1, of the WMO, the investigator will inform the
subjects and the reviewing accredited METC if anything occurs, on the basis of which it
appears that the disadvantages of participation may be significantly greater than was
foreseen in the research proposal. The study will be suspended pending further review
by the accredited METC, except insofar as suspension would jeopardise the subjects’
health. The investigator will take care that all subjects are kept informed.
8.2 Adverse and serious adverse events
All observed or volunteered adverse events, regardless of treatment group or suspected
causal relationship to study drug, will be recorded.
An adverse event is defined as an event after which treatment with the study medication
has to be stopped. Reasons for discontinuation are liver function abnormalities,
dyspnoea, lung oedema, hypotension leading to CTG abnormalities, myocardial
infarction, anaphylactic shock, admission to intensive care, fetal asphyxia, fetal death or
maternal death.
A SAE is defined as the fetal or maternal death or maternal illness necessitating IC or
CCU treatment. All SAEs will be reported to the accredited METC that approved the
protocol, according to the requirements of that METC.
8.2.1
Suspected unexpected serious adverse reactions (SUSAR)
All observed or volunteered SUSARs, regardless of treatment group or suspected causal
relationship to study drug, will be recorded. In case of an emergency, the principal
investigator will notify the pharmacist who will break the code for reporting of the SUSAR
to the authorities.
The principal investigator will report expedited the following SUSARs to the METC:
The expedited reporting will occur not later than 15 days after the principal investigator
has first knowledge of the adverse reactions. For fatal or life threatening cases the term
will be maximal 7 days for a preliminary report with another 8 days for completion of the
report.
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Annual safety report
In addition to the expedited reporting of SUSARs, the principal investigator will submit,
once a year throughout the clinical trial, a safety report to the accredited METC.
This safety report consists of:

a list of all suspected (unexpected or expected) serious adverse reactions, along with
an aggregated summary table of all reported serious adverse reactions, ordered by organ
system, per study;

a report concerning the safety of the subjects, consisting of a complete safety
analysis and an evaluation of the balance between the efficacy and the harmfulness of
the medicine under investigation.
8.3 Follow-up of adverse events
All adverse events will be followed until they have abated, or until a stable situation has
been reached. Depending on the event, follow up may require additional tests or medical
procedures as indicated, and/or referral to the general physician or a medical specialist.
8.4 Data Safety Monitoring Board (DSMB)
A DSMB will be established prior to start of the trial. We are planning to ask
Prof. dr. F.M. Helmerhorst (gynaecologist, Leiden University Medical Centre),
Prof. dr. M. Offringa (neonatologist, Academic Medical Centre, Amsterdam) and
Prof. dr. J.G.P. Tijssen (clinical epidemiologist, Academic Medical Centre, Amsterdam),
as members of the DSMB. Prior to the start of the trial the DSMB will define criteria to
terminate the trial prematurely.
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9. STATISTICAL ANALYSIS
DATA-ANALYSIS AND PRESENTATION The analysis of the randomised clinical trial will
be by intention to treat. First, the nifedipine and placebo group will be compared. Relative
risks and 95% confidence intervals will be calculated for the relevant outcome measures.
The analysis will be stratified for whether or not membranes are ruptured and gestational
ages of 24-28 and 28-32 weeks.
In case of equivalence between outcomes, the analysis will be repeated on a par protocol
basis. Subsequently, planned subgroup analysis will be done for cervical fibronectin
status as well as cervical length at study entry. We will then use decision analysis to
evaluate whether measurement of cervical fibronectin and/or cervical length is helpful in
the triage of women undergoing tocolytic maintenance or not.
We will compare three strategies
I.
no treatment after 48 hours of tocolytic therapy has been completed
II.
maintenance tocolytic therapy for all patients
III.
testing with vaginal examination, fibronectin and/or sonography, and subsequent
tailored maintenance of tocolytic therapy.
9.1 Interim analysis (if applicable)
An interim analysis is planned after the follow up data of the first 200 women that have
been included is obtained. If there is a significant difference in the primary outcome,
i.e. a poor neonatal outcome, at p < .005 (2-sided), the trial will be stopped.
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10. ETHICAL CONSIDERATIONS
10.1 Regulation statement
The study will be conducted according to the principles of the Declaration of Helsinki
(WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI Ethical Principles for
Medical Research Involving Human Subjects Version Edinburgh, Scotland, October 2000,
with Note of Clarification on Paragraph 29 added by the WMA General Assembly,
Washington 2002 end Note of Clarification on Paragraph 30 added by the WMA General
Assembly, Tokyo 2004 and in accordance with the Medical Research Involving Human
Subjects Act (WMO) and other guidelines, regulations and Acts.
10.2 Recruitment and consent
Eligible patients will be informed shortly about the study by the supervising gynaecologist
or by the attending resident. Subsequently, a trained research nurse will inform the
patient in detail. The patient will also obtained written information about the study from the
research nurse. This process of information has to take place in the first 24 hours of
tocolysis. Subsequently, the patient can think about participation and discuss the study
with her family. After this period of consideration, i.e. 48 hours after start of the initial
tocolysis, the patient has to decide about participation. In case of participation, the
informed consent form should be signed prior to randomisation. This process is handled
by the research nurse.
10.3 Benefits and risks assessment, group relatedness
Whereas it is evident that tocolysis with administration of corticosteroids is effective for 48
hours, there is insufficient evidence for a rational policy after these 48 hours. The
potential benefit of tocolytic maintenance would be a longer duration of the pregnancy,
and therefore a better development of the child. The potential harm would be the
complications of tocolytic maintenance, of which intrauterine infection and hypoperfusion
of the placenta will be the most obvious ones. At present, there is no evidence on which a
rational choice between the two strategies can be based.
10.4 Compensation for injury
There will be an insurance which is in accordance with the legal requirements in the
Netherlands (Article 7 WMO and the Measure regarding Compulsory Insurance for
Clinical Research in Humans of 23rd June 2003). This insurance provides cover for
damage to research subjects through injury or death caused by the study.
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1. € 450.000,-- (i.e. four hundred and fifty thousand Euro) for death or injury for each
subject who participates in the Research;
2. € 3.500.000,-- (i.e. three million five hundred thousand Euro) for death or injury for
all subjects who participate in the Research;
3. € 5.000.000,-- (i.e. five million Euro) for the total damage incurred by the
organisation for all damage disclosed by scientific research for the Sponsor as
‘verrichter’ in the meaning of said Act in each year of insurance coverage.
The insurance applies to the damage that becomes apparent during the study or within 4
years after the end of the study.
11. ADMINISTRATIVE ASPECTS AND PUBLICATION
11.1 Handling and storage of data and documents
Data will be collected using a website dedicated to studies in the Dutch consortium for
obstetric studies. Similar website oriented database have already been developed.
Data monitoring will be done by research nurses in each of the participating centres. A
substantial part of these research nurses is already working for the above mentioned
consortium.
Data handling will be done anonymously, with the patient code only available to the local
investigator and the research nurse working in the local centre. Patients will be asked for
informed consent for follow up of their children using the Child Behaviour Checklist
(CBCL) at 2 years of age, as well as follow-up in their later life.
11.2 Annual progress report
The principal investigator will submit a summary of the progress of the trial to the
accredited METC once a year. Information will be provided on the date of inclusion of the
first subject, numbers of subjects included and numbers of subjects that have completed
the trial, serious adverse events/ serious adverse reactions, other problems, and
amendments.
11.3 End of study report
The principal investigator will notify the accredited METC and the competent authority of
the end of the study within a period of 90 days. The end of the study is defined as the last
patient’s last visit.
In case the study is ended prematurely, the principal investigator will notify the accredited
METC within 15 days, including the reasons for the premature termination.
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Within one year after the end of the study, the principal investigator will submit a final
study report with the results of the study, including any publications/abstracts of the study,
to the accredited METC.
11.4 Public disclosure and publication policy
No specific arrangements will be made between ZonMW and the investigator concerning
the public disclosure and publication of the research data. The principle investigator will
publish the results of the study as soon as appropriate.
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12. REFERENCES
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
Berkowitz GS, Papiernik E. Epidemiology of preterm birth. Epidemiol Rev 1993; 15
(1993):414-443.
Hack M, Fanaroff AA. Outcomes of children of extremely low birthweight and
gestational age in the 1990's. Early Hum Dev 1999; 53(3):193-218.
Petrou S. Economic consequences of preterm birth and low birthweight. BJOG 2003;
110 Suppl 20:17-23.
Petrou S. The economic consequences of preterm birth during the first 10 years of life.
BJOG: An International Journal of Obstetrics and Gynaecology 2005; 112(s1):10-15.
Landelijke Neonatale Registratie 2003. Dutch Neonatal Database 2002. Prismant 2002.
Crowley P. Prophylactic corticosteroids for preterm birth (Cochrane Review). The
Cochrane Library 2004;(3).
NVOG Richtlijn No 3: “Dreigende Vroeggeboorte” 2004. (Guideline No3 Dutch Society
of Obstetrics and Gynaecology: Threatening preterm labour November 2004).
Stichting Perinatale Registratie Nederland ”Perinatale Zorg in Nederland 2001”,
Bilthoven 2005. (Dutch National Perinatal Registry).
Nanda K, Cook LA, Gallo MF, Grimes DA. Terbutaline pump maintenance therapy after
threatened preterm labour for preventing preterm birth. Cochrane Database Syst Rev
2002;(4):CD003933.
Dodd J.M., Crowther C.A. Oral betamimetics for maintenance therapy after threatened
preterm labour (Protocol for a Cochrane Review). The Cochrane Library, Issue 4, 2002.
Oxford: Updated Software. 2002.
Crowther CA, Hiller JE, Doyle LW. Magnesium sulphate for preventing preterm birth in
threatened preterm labour (Cochrane Review). The Cochrane Library 2004;(4).
King J, Flenady V, Cole S, Thornton S. Cyclo-oxygenase (COX) inhibitors for treating
preterm labour. Cochrane Database Syst Rev 2005;(2):CD001992.
Gaunekar NN, Crowther CA. Maintenance therapy with calcium channel blockers for
preventing preterm birth after threatened preterm labour. Cochrane Database Syst Rev
2004;(3):CD004071.
Thornton JG. Maintenance tocolysis. BJOG: An International Journal of Obstetrics and
Gynaecology 2005; 112(s1):118-121.
Finnstrom O, Olausson PO, Sedin G, Serenius F, Svenningsen N, Thiringer K et al.
The Swedish national prospective study on extremely low birth weight (ELBW) infants.
Incidence, mortality, morbidity and survival in relation to level of care. Acta Paediatr
1997; 86(5):503-511.
Papatsonis DNM et al Nifedipine and ritodrine in the management of preterm labour: a
randomized controlled trial Obst Gynecol 1997;90:230-34.
van Veen AJ et al. Severe hypotension and fetal death due to tocolysis with nifedipine.
BJOG. 2005 Apr;112(4):509-10.
Meirowitz NB, Ananth CV, Smulian JC, Vintzileos AM. Value of maintenance therapy
with oral tocolytics: a systematic review. J Matern Fetal Med 1999;8:177-183.
24 of 25
Versie 1.0
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
25-10-2007
Apostel Study
Sanchez-Ramos L et al. Efficacy of maintenance therapy with oral tocolytics: a metaanalysis. Am J Obst Gynecol 1999;181:484-90.
Carr DB, Clark AL, Kernek K, Spinnato JA. Maintenance oral nifedipine for preterm
labour: a randomised clinical trial. Am J Obstet Gynecol 1999;181:822-827
King JF et al Calcium channel blockers for inhibiting preterm labour. Cochrane
database syst rev 2002;2:CD002255
NM Fisk, J Chan. The case for tocolysis in threatened preterm labour. BJOG
2005;112:98-102.
Papatsonis DNM et al. Calcium channel blockers in the management of preterm labour
and hypertension in pregnancy. Eur J Obs Gyn 2001;97:122-40.
Read MD, Wellby DE. The use of a calcium antagonist (nifedipine) to suppress preterm
labour. Br J Obstet Gynaecol 1986;93:933-7.
Snyder SW, Cardwell MS. Neuromuscular blockade with magnesium sulfate and
nifedipine. Am J Obstet Gynecol 1989;161:35-6.
Waisman GD, Mayorga LM, Camera MI, Vignolo CA, Martinotti A. Magnesium plus
nifedipine: potentiation of hypotensive effect in preeclampsia? Am J Obstet Gynecol
1988;159:308-9.
Magee LA, Schick B, Donnenfeld AE, Sage SR, Conover B, Cook L, McElhatton PR,
Schmidt MA, Koren G. The safety of calcium channel blockers in human pregnancy: a
prospective, multicenter cohort study. Am J. Obstet Gynecol 1996;174:823-8.
Houtzager BA, Hogendoorn SM, Papatsonis DN, Samson JF, van Geijn HPF et al.
Long-term follow up of children exposed in utero to nifedipine or ritrodrine for the
management of preterm labour. BJOG 2006 Mar; 113(3):324-31.
Saade GR, Taskin O, Belfort MA, Erturan B, Moise KJ Jr. In vitro comparison of four
tocolytic agents, alone and in combination. Obstetrics and Gynecology 1994;84:374-8.
Ulmsten U, Andersson KE, Wingerup L. Treatment of premature labor with the calcium
antagonist nifedipine. Archives of Gynecology 1980;229:1-5
Oei SG, Van de Water M. Indications for respiratory complications during the use of
oral nifedipine as a tocolytic agent, especially in patients with multiple pregnancies .
Ned Tijdschr Geneesk. 2007;151:1100
Van Veen AJ, Pelinck MJ, Van Pampus MG, Erwich JJ. Severe hypothension and fetal
death due to tocolysis with nifedipine. BJOG 2005;112:509-510
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