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Microsoft word - metexprotocolmec.doc
The METEX study
IN WOMEN WITH ECTOPIC PREGNANCY
PARTICIPATING CENTERS Academic Medical Center, University of Amsterdam
PO Box 22700
1100 DE Amsterdam
Coordinators: P.J. Hajenius, MD, PhD
W.M. Ankum, MD, PhD B.W. Mol, MD, PhD F. van der Veen, MD, PhD
Onze Lieve Vrouwe Gasthuis
PO Box 95500
1090 HM Amsterdam
Coordinator: H.R. Verhoeve, MD
PO Box 37610
1030 BD Amsterdam
Coordinator: A.B. Dijkman, MD
Maxima Medical Center
PO Box 7777
5500 MB Veldhoven
Coordinator: B.W. Mol, MD, PhD
3.1 Participating centers
3.2 Inclusion criteria
6.1 Primary outcome measure
6.2 Secondary outcome measures
In industrialized countries the incidence of ectopic pregnancy is approximately 1-2% of all
pregnancies (1-4). The diagnosis of ectopic pregnancy is usually made by non-invasive methods,
i.e. sensitive pregnancy tests (in urine and serum) and high resolution transvaginal sonography
(TVS), which have been integrated in reliable diagnostic algorithms. These algorithms, in
combination with the increased awareness and knowledge of risk factors among both clinicians
and patients, have enabled an early and accurate diagnosis of ectopic pregnancy (5-7).
As a consequence, the clinical presentation of ectopic pregnancy has changed from a life
threatening disease, necessitating emergency surgery, to a more benign condition in sometimes
even asymptomatic patients for which non-surgical treatment options are available, i.e. medical
treatment with systemic methotrexate or expectant management. In contrast to surgical
treatment, the ectopic pregnancy is not removed and as a consequence there is a remaining risk
of tubal rupture. Close serum human chorionic gonadotrophin (hCG) monitoring is therefore
mandatory to detect impending treatment failure and/or inadequately declining serum hCG
concentrations (8,9). The risk of tubal rupture combined with the need for scrupulous follow-up
is likely to cause distress in the patient because of uncertainty about treatment outcome (10).
Non-surgical treatment modalities may therefore have a negative impact on the patients' health
related quality of life.
Methotrexate is a folic acid antagonist which inhibits de novo
synthesis of purines and
pyrimidines, thereby interfering with DNA synthesis and cell proliferation. Secondary to its
effect on highly proliferative tissues, e.g. trophoblast, methotrexate has a strong dose related
potential for toxicity. Side effects include stomatitis, conjunctivitis, gastritis-enteritis, impaired
liver function, bone marrow depression, and photosensitivity. Methotrexate has been shown to
be safe with virtually no adverse effects reported on reproductive outcome (11).
Methotrexate can be administered systemically in a multiple dose
regimen or in a single dose
. The multiple dose regimen involves the administration of a total of four intramuscular
methotrexate injections every other day at a dose of 1.0 mg/kg body weight alternated with
folinic acid 0.1 mg/kg body weight on the day following each methotrexate injection (12). The
administration of folinic acid decreases the side effects of the drug. A single dose
regimen – one
single intramuscular injection of methotrexate 1.0 mg/kg body weight or 50 mg/m2 body surface
area- was introduced to minimize side effects and to improve patients' compliance and to reduce
overall costs (13).
Data provided by randomised controlled trials indicate that systemic methotrexate
treatment should only be used in selected patients with ectopic pregnancy. Important selection
criteria are the ectopic pregnancy size, absence of fetal cardiac activity on TVS, and maximum
hCG concentrations (14, 15).
Expectant management has been practiced based on the acknowledgement that the
natural course of many early ectopic pregnancies is a self limiting process, ultimately resulting in
tubal abortion or reabsorption. Selection criteria in uncontrolled studies are the ectopic
pregnancy size, absence of fetal cardiac activity on TVS and various upper limits of serum hCG
concentrations that continue to decline, and/or a low serum progesterone concentration. Success
rates vary between 42 and 100% (16). Data provided by randomised controlled trials is scarce.
To date, only two randomised placebo controlled trials are available comparing expectant
management with other treatment options. In one trial, 30 patients with a small tubal pregnancy
and no fetal cardiac activity and a serum hCG concentration < 5,000 IU/l were randomly
allocated to oral methotrexate while another 30 patients were managed expectantly (17). The oral
route of administration and the low dosage of methotrexate, namely 2.5 mg/day orally during
five days, are uncommon and likely to fail. This trial virtually represents a comparison between
two placebo treatments as demonstrated by similar success rates of 77% in both treatment
groups and is therefore not informative from a clinical viewpoint. The other trial, comparing
prostaglandins versus expectant management, involving 23 women with an ectopic pregnancy
and an initial serum hCG concentration < 2,500 IU/l, was stopped prematurely after the first
interim analysis, showing that prostaglandin therapy was significantly better than expectant
management (18). However, in view of a non-surgical management of ectopic pregnancy this
trial is not informative. Prostaglandins were administered locally in the ectopic pregnancy under
laparoscopic guidance combined with systemic prostaglandin injection twice daily during three
In some women presenting with suspected ectopic pregnancy, the pregnancy can not be
identified on TVS (19,20). These women with a so called pregnancy of unknown location (PUL)
can be managed expectantly with monitoring of serum hCG to identify whether a PUL turns out
to be an intra uterine pregnancy, an ectopic pregnancy, a failing PUL (with an uneventful serum
hCG decline to undetectable levels) or a persisting PUL (with plateauing serum hCG
concentrations) (21). Women with a persisting PUL and women with a visible ectopic pregnancy
but with low and plateauing serum hCG concentrations have thus far been offered medical
treatment with methotrexate (20,22). However, there is no evidence on the effects of treatment
in this particular subgroup of women, which represents about 10% of women presenting with
suspected ectopic pregnancy.
To study whether in women with an ectopic pregnancy with low but plateauing serum hCG
concentrations treatment with systemic methotrexate in a single dose intramuscular regimen is
superior over expectant management in terms of tubal rupture, future pregnancy, health related
quality of life and costs.
3. STUDY DESIGN
3.1 Participating centers
This study is a multicenter randomised controlled trial with four participating centers in The
1. Academic Medical Center Amsterdam (coordinator P.J. Hajenius, MD, PhD),
2. Onze Lieve Vrouwe Gasthuis Amsterdam (coordinator H.V. Verhoeve, MD),
3. BovenIJ Hospital Amsterdam (coordinator A.B. Dijkman, MD) and
4. Máxima Medical Center Veldhoven (coordinator B.W. Mol, MD, PhD).
Other clinics in The Netherlands, predominately those already participating in the European
Surgery in Ectopic Pregnancy (ESEP) study (ISRCTN37002267), are being contacted for
participation in the present study.
3.2 Inclusion criteria
All hemodynamically stable patients ≥ 18 years with either an ectopic pregnancy (a visible
ectopic pregnancy or an ectopic mass on TVS) and a plateauing serum hCG concentration <
1,500 IU/L or with a PUL and a plateauing serum hCG concentration < 2,000 IU/L (persisting
PUL) will be eligible for the trial. The difference in serum hCG cut-off levels for these two
entities is based on our earlier work (7).
Patients with a viable ectopic pregnancy, signs of tubal rupture or active intra abdominal
bleeding, and/or abnormalities in liver or renal function or in full blood count will not be
included. In patients fulfilling the inclusion criteria, written informed consent will be obtained
before randomisation is carried out. Those women refusing participation will be registered.
Randomisation will be performed by a web based randomisation program, using a computer
program with stratification for hospital, serum hCG concentration (< 1,000 IU/l versus 1,000-2,000
IU/l), TVS findings (visible ectopic pregnancy/mass or PUL). In each centre, a back-up procedure
with sealed envelopes will be available in case the central randomisation procedure fails.
The following treatment options will be compared: systemic methotrexate in a single dose
intramuscular regimen (1 mg/kg body weight) versus expectant management. Women who are
Rhesus negative will receive 375 IE anti D intramuscularly. Pain relief, if necessary, is given with
Paracetamol. Patients are advised to refrain from sexual intercourse. Treatment and follow up
will be carried out in the outpatient clinic.
5. FOLLOW UP
5.1 Short term
Complications will be registered in the Case Record Form. In both groups weekly serum
hCG measurements will be performed until serum hCG is no longer detectable. Serum hCG
concentrations will be expressed in IU/L (conversion factor to SI unit, 1.00 according to the
World Health Organization Third International Standard 75/537). Seven days after a
methotrexate injection liver and renal function and full blood count will be checked as well.
In patients treated with methotrexate, a second methotrexate injection is given in case the
serum hCG concentration on day 7 has declined < 15% of the initial value on day 1 (start of
treatment) (11). If the serum hCG concentration fails to fall by at least 15% during any
successive week of follow-up, this also results in repeat administration of methotrexate with a
maximum of a total of three injections (23). In case of hemodynamic instability and/or signs of
tubal rupture (i.e. increasing abdominal pain in combination with falling haemoglobin level and
signs of intra abdominal haemorrhage on TVS) or whenever more than three methotrexate
injections are required, surgical treatment will be installed.
In patients treated expectantly, treatment (systemic methotrexate or surgery) will be
started whenever at any of the weekly follow up visits the serum hCG concentration has risen >
15% of the prior value. If the serum hCG concentration falls by > 15% of the prior value,
expectant management is continued. In case of a persistent plateauing serum hCG concentration
(i.e. < 15% fall or < 15% rise), the serum hCG concentration is assessed after 48 hours to ensure
it is not increasing. If it is increasing as described above, treatment (systemic methotrexate or
surgery) is installed (24). Whenever hemodynamic instability and/or clinical signs of tubal
rupture (i.e. increasing abdominal pain in combination with falling haemoglobin level and signs
of intra abdominal haemorrhage on TVS) occur, surgical treatment will be installed.
5.2 Long term
Women treated with methotrexate are advised not to get pregnant within three months after
treatment (21). To assess fertility in both treatment arms, patients will be contacted by means of a
questionnaire, every six months for a period of 24 months. Questions will focus on the desire for
pregnancy, unprotected sexual intercourse with a chance of spontaneous conception, contraceptive
use, infertility treatment, and the occurrence of any pregnancies and their outcome.
6. OUTCOME MEASURES
6.1 Primary outcome measure
The primary outcome measure is an uneventful decline of serum hCG to an undetectable level (<
2 IU/l) by primary treatment, i.e. single dose systemic methotrexate or expectant management.
6.2 Secondary outcome measures
Secondary outcomes are number of (re)interventions (additional methotrexate injections or
surgical procedures for persistent trophoblast and/or clinical signs), treatment complications,
future fertility, health related quality of life, financial costs, and patients preferences.
Future fertility is defined as time to the occurrence of a spontaneous vital intra uterine
pregnancy. A vital intra uterine pregnancy is defined as a viable pregnancy visible at ultrasound at a
gestational age of ≥ 12 weeks, or the delivery of a child. If an intra uterine pregnancy does not
occur, follow-up ends on the day of the last consultation. In addition to intra uterine
pregnancies, repeat ectopic pregnancies are also assessed. The date of occurrence of an ectopic
pregnancy will be determined from the first day of the last menstrual period.
Health related quality of life will be assessed by standard self administered psychometric
questionnaires with established viability and reliability at different time points; before
randomisation, after one week, four weeks and three months.
Costs will be assessed in direct costs with data on costs and used resources in the
Patients' preferences will be assessed in an interview on the basis of written descriptions
of both interventions using a treatment trade-off technique and will be compared with a control
group, recruited among women visiting the infertility clinics of the participating hospitals.
Inclusion METEX study:
EP and plateauing serum hCG < 1,500 IU/l
PUL and plateauing serum hCG < 2,000 IU/l
• Signs of shock
• Signs of tubal rupture/abdominal bleeding
• Vital ectopic pregnancy •
Contraindications for MTX
Single dose MTX im
• Serum hCG clearance time
• Additional interventions
• Health related quality of life
Follow-up 6, 12, 18, 24 months after index ectopic pregnancy
• Spontanous intra uterine pregnancy
Health realted quality of life
Data analysis will be according to the intention to treat
Short term outcome measures are compared in relative risks and their 95% confidence
intervals. Future fertility is assessed by life table analysis. Kaplan-Meier curves are constructed,
estimating the cumulative probability of spontaneous intra uterine pregnancy and repeat ectopic
pregnancy over time. In case a spontaneous viable intra uterine pregnancy does not occur, follow up
ends at the last date of consultation, or at the moment when either in vitro
fertilisation (IVF) or tubal
surgery will be performed. Spontaneous conceptions that occur after failed IVF treatment will be
registered, but they will not be considered as endpoint in the analysis. The log-rank test is used to test
differences between the Kaplan-Meier curves for statistical significance. The differences between
both treatment modalities are expressed as a fecundity rate ratio with 95% confidence interval,
calculated through Cox proportional hazard analysis.
Changes in health related quality of life over time, and differences between the two
groups will be measured using analysis of variance.
Depending on differences of equivalence between the strategies, the economic evaluation
will be a cost-effectiveness analysis or a cost-minimisation analysis.
Patient's preferences will be analysed by differences in trade-off.
9. POWER CALCULATION
Assuming an uneventful decline of serum hCG of 90% in the methotrexate group and of 60% in
the expectant management group, and assuming a power of 80% and a significance level of 5%,
36 patients in each group are needed (6,15,16,25,26).
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Contemporary Clinical Trials 30 (2009) 256–268 Contents lists available at Contemporary Clinical Trials Early anti-pseudomonal acquisition in young patients with cystic ﬁbrosis:Rationale and design of the EPIC clinical trial and observational study Miriam M. Treggiari Margaret Rosenfeld Nicole Mayer-Hamblett , George Retsch-Bogart Ronald L. Gibson Judy Williams Julia Emerson Richard A . Kronmal Bonnie W. Ramsey
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