PROTOCOL for the medical abortion trial Draft 16
Date 18 July, 2011
1. Trial title:
Routine follow-up versus self-assessment of complete abortion following medical abortion, effect on its success and acceptability: a randomized controlled trial.*
* ClinicalTrials registry number NCT01487213
· Trial sponsor
Kristina Gemzell-Danielsson. Sponsor’s Protocol Code Number:
· Principal investigator
Kristina Gemzell-Danielsson, MD Ph D
Department of Woman and Child Health,
Division of Obstetrics and Gynaecology,
Karolinska Institutet,
Karolinska University Hospital,
SE-17176 Stockholm, Sweden
telephone: + 46 8517 72128
telefax no.: +46 8517-74314
email:
· Main co-investigators
Christian Fiala, MD Ph D
GynMed Clinic,
Mariahilfergürtel 37,
1150 Vienna, Austria
telephone: + 43 699 15 97 31 90
telefax no.: +43 1 892 25 81
email:
Erik Qvigstad, Professor, MD Ph D
Faculty of Medicine, University of Oslo and Dept. of Gynaecology,
Women and Children's Division, Ullevål University Hospital,
Kirkeveien 166, N-0450 Oslo, Norway
telephone: + 47 22119800
email:
Oskari Heikinheimo, MD Ph D
Dept. Obstetrics and Gynaecology,
P.O. Box 610
Helsinki University Central Hospital
00029-HUS, Helsinki, Finland
telephone: +358 40 5871070
telefax no.: +358 9 471 65440
email:
Gilda Piaggio, MSc, PhD
Statistika Consultoria, São Paulo, Brazil and Divonne-les-Bains, France
1764 vie de l’Etraz
01220 Divonne-les-Bains
France
telephone: +41 78 928 5793
telefax no.: +33 4 5020 3148
email:
Kevin Sunde Oppegaard, MD Ph D
Dept. of Gynaecology, Helse Finnmark, Klinikk Hammerfest,
Sykehusveien 35,
N-9613 Hammerfest, Norway
telephone: + 47 78421000
telefax no.: + 47 78421505
email:
2. Goals
To optimize the routines for follow-up after medical abortion in order to give women more autonomy by reducing the number of consultations involved and to reduce the frequency of postabortal curettage.
To provide means for women for postabortal self-assessment with the use of a quantitative urinary hCG test.
3. Scientific background
Unsafe abortion is a public health problem worldwide. It is estimated that 50 million pregnancies are terminated annually. One way of reducing the number of unsafe procedures is to increase safe choices for pregnancy termination.[1][2][3][4][5][6] In the last decade, attempts to develop alternative abortion methods have largely focused on medical methods. Some authors think that medical abortion would reduce unsafe procedures in resource-poor settings and would decrease maternal morbidity and mortality in areas where abortion is illegal.[7]
There is no unequivocal protocol for follow up after medical abortion. Protocols for medical abortion typically include multiple consultations and follow-ups when compared to surgical abortion. A follow-up visit after termination of pregnancy in order to ascertain the outcome, for timely diagnosis of complications and to provide contraceptive services is being recommended by several national and international guidelines.[8]
Medical abortion can also result in surgical intervention; a recent Norwegian study reported an 8.3% rate of surgical evacuation after the medical method.[9] A similarly high failure rate (8% among women with a duration of pregnancy of up to 49 days) in a recent study performed in the US was justified as: ‘The success rate in this study was lower than that reported by other researchers. This may be related, in part, to the lack of experience with medical abortion in the US.’[10] Trials comparing surgical and medical abortion methods have been relatively small and so far there is inadequate evidence to comment on the acceptability and side-effects of medical compared to surgical first-trimester abortions.
A recent study comparing preference of medical versus surgical termination of pregnancy less than 14 weeks’ gestation in Newcastle, UK, concluded that medical termination of pregnancy was associated with more negative experiences of care and lower acceptability. [11] In contrast, recent studies from Sweden[12] and Norway8concluded that the acceptability for the medical method is high. Success rates of up to 98% have been reported from centres with extensive experience with the method. 6,11,[13] In addition, home self-administration of vaginal misoprostol for medical abortion at gestation of up to 63 days has shown to be safe and effective.
Previous studies have shown that the number of visits required to the clinic has a major influence on the acceptability of medical abortion.[14] Home-use of misoprostol has been shown to be acceptable to women and their partners and is rapidly increasing in settings where it is legally permitted.12,[15] A systematic review assessed the evidence regarding follow up after medical and surgical abortion.[16] No direct evidence for Follow up versus no Follow up was available. Post abortal complications such as heavy bleeding, infection, ectopic- or incomplete abortion prompt women, especially if adequately counselled, to seek care outside of a routine follow up visit. Thus the main reason for the routine follow up is to detect an on-going pregnancy and to provide contraceptive counselling. Most clinics already provide contraceptive counselling at the time of the first visit in order to make it possible for the woman to start postabortal contraception without delay.
The review by Grossman et al.,16 focused on the accuracy of follow up protocols to diagnose an on-going pregnancy following medical abortion. Based on analyse of nine studies whereof only one was a RCT it was concluded that women’s self-assessment has varying sensitivity to diagnose on-going pregnancy. Serum hCG testing was found to be an accurate modality to detect on going pregnancy but it added both visits and costs of the medical abortion. Therefore, urine pregnancy test (u-hCG) later than one week after the abortion using a low sensitivity, semi quantitative test, may offer an acceptable and safe alternative to existing protocols.
4. Objectives
The primary objective for efficacy is to assess, relative to routine follow-up, the effect of self-assessment of complete abortion following medical abortion on the percentage of women requiring surgical intervention among women requesting medical termination of pregnancy with home administration of misoprostol in pregnancies up to 63 days gestation.
The primary objective is thus to demonstrate the non-inferiority of self-assessment of complete abortion following medical abortion compared to routine follow-up in terms of the percentage of women requiring surgical abortion, within a margin of non-inferiority of 5%.
5. Hypothesis
Self-assessment of the complete abortion using a semi-quantitative u-hCG test will be as effective and safe as routine follow-up.
6. Design
Prospective randomised controlled trial stratified by centre.
7. Setting/Centres
1. The Department of Obstetrics and Gynaecology, Karolinska University Hospital/ Karolinska Institutet, Stockholm, Sweden.
2. The Department of Gynaecology, Ullevål University Hospital, Oslo, Norway.
3. The Department of Gynaecology, Helsinki University central Hospital, Helsinki, Finland.
4. GynMed Clinic, Vienna, Austria.
8. Participants
Women requesting medical termination of pregnancy with home administration of misoprostol, with pregnancies up to 63 days gestation (based on ultrasound).
9. Interventions
Women with an unwanted pregnancy, with no contraindication to medical abortion and self administration of misoprostol at home, of up to 63 days gestation, will be randomised into two groups:
Group 1) Mifepristone at outpatient clinic, to be continued with home administration of misoprostol at 24-48 hours later. Follow-up out patient review two–three weeks later by qualified practitioner to evaluate success of procedure using the clinic’s standard routine. The patient charts will be reviewed after three months in order to control for possible extra visits related to abortion-related complications.
Group 2) Mifepristone at outpatient clinic, to be continued with home administration of misoprostol at 24-48 hours later. Patient responsible for her own follow-up two-three weeks later by means of two-step urinary-hCG DUO test from Vedal Lab (Alençon, France). Follow-up with telephone consultation during the following week. The patient charts will be reviewed after three months in order to control for possible extra visits related to abortion-related complications.
All women will receive a Follow-up questionnaire after one year, evaluating the use of contraception and subject satisfaction.
10. Outcome measures
Primary outcome
The primary objective for efficacy is to assess, relative to routine follow-up, the effect of self-assessment on the rate of complete abortion. The percentage of women requiring surgical intervention, extra visits and administration of extra misoprostol will be used to monitor incomplete abortion.
Secondary outcomes
· Acceptability determined by responses to the following questions:
1. If you ever were to have another termination of pregnancy, would you opt for the same method of follow-up?
2. If you ever have another termination of pregnancy, would you prefer the follow-up at the healthcare facility or to be responsible for your own follow-up at home?
3. What was the worst aspect of your treatment?
4. What was the best aspect of your treatment?
5. If you’ve previously had an abortion, how would you compare your experience this time with your previous treatment?
· In addition, the following secondary outcomes will be monitored:
· Clinical effectiveness using unplanned/emergency admission for various adverse events/complications/continuing pregnancies.
· The use of contraception and rate of repeat abortion at follow-up questionnaire at one year.
· The frequency of genital infections of women requesting termination of pregnancy during the study period.
11. Eligibility criteria
Inclusion criteria: Women requesting termination of pregnancy by means of mifepristone followed by home administration of misoprostol at < /=63 days of gestation, with no contraindication to medical abortion and self administration of misoprostol at home, and who have given their informed consent will be eligible for study recruitment.
Exclusion criteria: Women who do not wish to participate, women who do not want home administration of misoprostol, women who are unable to communicate in Swedish, Norwegian, English, Finnish or German and women with symptoms and signs of ectopic pregnancy. Minors (i.e. women < 18 years of age) will not be enrolled for the study. Women seeking termination of pregnancy with no sign of a visible intrauterine pregnancy (i.e. visible intrauterine yolk sac) and who previously have been treated for an ectopic pregnancy will be excluded.
12. Trial process and data collection
The study protocol is designed according to the recommendations in the CONSORT statement. The study is a prospective randomised multi centre study performed at gynaecological outpatient departments of Finnish, Norwegian and Swedish central university hospitals, as well as at a private abortion clinic in Austria. The study flow is planned as follows:
Enrolment
All women with a pregnancy up to 63 days gestation requesting termination of pregnancy by medical methods and opting for home administration of misoprostol will be invited to be included in the study at the initial outpatient consultation. The women will receive detailed information regarding the study, as well as an informed consent form.
Allocation and treatment
Designated study nurses and doctors will be responsible for recruiting and examining study participants at the outpatient clinics. Eligible women with a pregnancy up to 63 days gestation who elect to participate in the study and who sign an informed consent form will be randomised into either
Group 1 (outpatient standard follow-up after two-three weeks) or Group 2 (home self-assessment at two-three weeks followed by telephone consultation). Study participants will be administered mifepristone and misoprostol according to local routines.
Randomization procedure
Women who volunteer to participate in the study will be assigned to either outpatient standard follow-up or home self-assessment by randomisation at a ratio of 1:1 using the randomisation plan generator, as described by G. Dallal. [17]The randomisation procedure is a third party concealed randomisation. Karolinska Institutet will perform block randomisation, 10 subjects to each block, and send numbered lists to each participating centre. Each participating centre will then create opaque, numbered, envelopes containing the randomisation group for each participant. Randomisation will occur upon opening the envelope after the participant has signed informed consent to participate.
Follow-up at one-year
Study participants who have given their informed consent will be offered a telephone questionnaire after one year. Two attempts will be made to contact them by telephone after a year.
Women will be asked to rate acceptability of follow-up at a health care facility or home follow-up on a scale from 1 to 4
1, completely acceptable;
2, fairly acceptable;
3, fairly unacceptable;
4, completely unacceptable.
The women will record pain experienced between the insertion of misoprostol and the expulsion on a scale score, ranging from
0 (no pain) to
10 (unbearable pain).
Complications and the number of women requiring surgical intervention (e.g. for on-going pregnancy, retained products of conception, ectopic pregnancy) will be recorded.
Discontinuation
After recruitment, women may withdraw from the trial if they do not wish to participate. Any woman with a pregnancy of unknown location who develops symptoms suspicious of an ectopic pregnancy will be followed-up and treated for ectopic pregnancy according to local protocols.
Registration and reporting of suspected adverse events
Any unexpected and serious side effects and suspected adverse reactions will be immediately reported to the project leader as well as the trial steering committee. The regional ethics committee will also be notified according to local regulations.
13. Trial start date
March 2011
Expected completion March 2012. The trial will be halted during the summer holiday period July-August 2011.
14. Statistical analysis plan; power calculations - sample size
Total sample size, assuming a non-inferiority hypothesis with a margin of 5%, power 80%, 2-sided CI of 95% (alpha=0.025 for the non-inferiority hypothesis):
P (%) / Margin of non-inferiority5%
90 / 1131
92 / 925
Sample size
To establish the noninferiority of self-assessment of complete abortion following medical abortion compared to routine follow-up in terms of the percentage of women requiring surgical abortion, within a margin of non-inferiority of 5%, with a two-sided 95% CI (or a one-sided 97.5% CI) for the difference in the percentage of women requiring surgical abortion, a total of 925 women are needed. This calculation assumes a percentage of women requiring surgical treatment after surgical abortion of 8% with routine follow-up. Considering that 20% of women will be lost to follow-up, a total of about 1200 women have to be recruited.8,[18],[19]
The data will be analysed using the intention-to-treat principle, including all women in the groups as randomized. Numbers and proportions of women having surgical intervention will be calculated by intervention. Both interventions will be compared using both absolute and relative measures with 95% confidence intervals. The results will be also analysed using logistic regression to take into account the centre as stratifying variable and to test the homogeneity across centres.