The PROMISE trial (coming to an end in October 2013)
What is it?
The PROMISE (progesterone in miscarriage treatment) trial is a major research study that aims to find out whether having progesterone supplements in the first 12 weeks of pregnancy reduce miscarriage risk in women with previous unexplained recurrent loss.
It is a randomised, double-blind, placebo-controlled trial:
Randomised Women taking part need to agree to be placed at random in either the treatment or non-treatment (placebo) group
Double-blind The women in the study won’t be told whether they are in the treatment or non-treatment group – and nor will their doctors. So both are “blinded” to this information.
Placebo-controlled The best way to compare the treatment and non-treatment groups is for them to have exactly the same conditions except the actual drug. This is done by giving the non-treatment group a placebo (dummy) tablet that looks exactly like the real treatment, but has no active ingredients.
As of August 2013 the lead researchers have recruited almost as many women as they need to be sure that numbers are big enough to make the eventual results reliable. But they will continue taking people into the trial until the end of October, so if you’d like to take part, here’s what you need to know:
Who can take part?
The researchers are recruiting women who:
- are aged 18 to 39
- have had three or more first trimester miscarriages
- first trimester = before 14 weeks of pregnancy
- the miscarriages don’t have to have been in a row, so if you have had a healthy pregnancy before or in between your miscarriages, you may still be eligible.
- have had normal results for all the usual investigations
- are willing to be selected at random to have either the treatment or a placebo, without knowing which they are given
Where is it taking place?
There are 32 hospitals in the UK and another 8 in the Netherlands already taking part or waiting to start. They are:
Ayrshire Ayrshire Maternity Unit
Birmingham Birmingham Women’s Hospital
Birmingham Heartlands Hospital
Coventry University Hospitals, Coventry and Warwickshire
Exeter Royal Devon & Exeter Trust, Wonford Hospital
Liverpool Liverpool Women’s Hospital
London Guys’ and St Thomas’ Hospitals
Kings College Hospital
St Mary’s Hospital, Paddington
West Middlesex Hospital
Luton and Dunstable
Chelsea and Westminster – waiting to start (at January 2012)
Manchester St Mary’s Hospital
N Cumbria Carlisle and Whitehaven – waiting to start (at January 2012)
Nottingham Queens Medical Centre – waiting to start (at January 2012)
Portsmouth Queen Alexandra Hospital, Portsmouth
Sheffield Royal Hallamshire Hospital
Southampton Princess Anne Hospital
- and hospitals in Amsterdam, Groningen, Heerlen, Leiden, Utrecht, Veldhoven and Zwolle.
If you would like to take part but don’t live near one of these centres, you may still be eligible to join the trial. Please contact the PROMISE trial co-ordinator Dr Ewa Truchanovicz on 0121 623 6835.
You will need to travel to one of the centres to discuss and sign the consent forms, but after that all the follow-ups will be done by phone, and the trial medication will be delivered to your home address.
You can also read more at www.medscinet.net/promise.
A personal view
Our thanks to one of the members of our support forum, who has allowed us to reprint her message to another member regarding the PROMISE trial.
I just thought I would drop you a line as I did the Promise trial in June. It was easy – they just ask past history questions etc. and if you fit the criteria, when you get pregnant, you let them know asap and they request the medication. It is random, so the details are put into the computer which selects what you are having, either placebo or progesterone. As Ruth has already mentioned, you won’t know what you are getting.
You take 2 pessaries in the morning and 2 on the night and although it’s not pleasant, it’s not bad and after a day or two it soon becomes the norm.
Unfortunately for me it didn’t work. However, my first 5 miscarriages were all at 5 1/2 weeks and I went to 6.5 weeks this time. I don’t know what I took – I could have had the placebo. I can’t find out until the whole trial ends, so that will be interesting.
Although it didn’t work for me, I don’t regret doing it at all and would do it again (except you can’t take the trial more than once), As I see it, it can’t hurt and as far as my trial went, yes it didn’t help me, but if it has helped any women in the future going through what all we are, then it was well worth it.
The TABLET trial
The TABLET trial is another randomised, double-blind, placebo-controlled trial which is looking at the role of thyroid antibodies in women with unexplained miscarriage.
They are particularly interested in seeing whether a drug called Levothyroxine reduces the risk of miscarriage in women who have thyroid antibodies even through their thyroid hormones are in the normal range.
As with the PROMISE trial, the lead researchers are keen to recruit as many women as possible so they can be sure that numbers are big enough to make the eventual results reliable. So if you might be interested in taking part, here’s what you need to know:
Who can take part?
The researchers are recruiting women who:
- are aged 16 – 40
- hope to conceive in the next year
- have had a previous miscarriage or are due to have fertility treatment
- do not have known thyroid disease – and
- are willing to be selected at random to have either the treatment or a placebo, without knowing which they are given.
Where is it taking place?
The following hospitals are currently recruiting patients:
- Arrowe Park Hospital, Wirral
- Basildon Hospital
- Birmingham Heartlands Hospital
- Birmingham Women’s Hospital
- City and Sandwell Hospitals
- Countess of Chester Hospital
- Crosshouse Hospital, Ayrshire
- Ealing Hospital, London
- Frimley Park Hospital
- Guy’s Hospital, London
- James Cook Hospital, Middlesbrough
- Kings College Hospital, London
- Liverpool Women’s Hospital
- Queen’s Medical Centre, Nottingham
- Royal Bournemouth Hospital
- Royal London Hospital
- St Bartholomew’s Hospital
- St Mary’s Hospital, Manchester
- St Mary’s Hospital, Paddington, London
- St Thomas’s Hospital, London
- The Royal London Hospital
- Walsgrave Hospital, Coventry
- Watford General Hospital
- Whipps Cross Hospital
- Wrightington, Wigan and Leigh Hospitals
The following hospitals will be recruiting soon:
- University College Hospital, London
- Bradford Royal Infirmary
- Newham Hospital
- Derby Hospital
- Southport & Ormskirk Hospital
- Warrington Hospital
- St Peter’s Hospital, Chertsey
There is also information on the trial website at www.bham.ac.uk/tablet.
If you would like more information or you wish to join the trial, please contact the TABLET office at email@example.com.
If you have other questions or concerns about the trial, you can contact Krys Baker, the trial co-ordinator, at firstname.lastname@example.org, or TABLET research fellow Dr Rima Dhillon at email@example.com.
If your questions are less medical/scientific and more about feelings or concerns, do contact us at firstname.lastname@example.org.
Talking about research
Ruth interviews Professor Arri Coomarasamy , Consultant Gynaecologist and Sub-specialist in Reproductive Medicine and Surgery at Birmingham Women’s Hospital
RBA: Arri, most people who’ve been through miscarriage wish that we knew more about why it happens and how we might prevent it. Is that your experience too?
AC: When I see patients who have had a miscarriage, they generally have two questions: why did it happen? How can we stop it happening again? We are developing a reasonable understanding of why miscarriages happen, although it may be difficult to work out the reasons for a specific couple.
RBA: I know you think research can help, especially trials of certain treatments. Can you say something about that?
AC: The question about how we may prevent miscarriage is the tougher one to answer, although it is possibly the most important question for the couple. Some early studies sometimes suggest a benefit with this or that medicine, but when we eventually study that medicine carefully, we may find that it doesn’t work, or even worse, it is actually harmful.
RBA: Can you give me an example?
AC: A good example of this is aspirin. We use it for women with sticky blood conditions such as antiphospholipid syndrome (APS), and it works to reduce miscarriage in those women. However, even when there is no evidence of a ‘sticky blood’ condition, many clinicians have recommended it and women have diligently taken aspirin in the hope that it will reduce the risk of miscarriage. But when this question was properly researched, the shocking finding was that aspirin resulted in more miscarriages compared with taking the dummy tablets.
Only research can uncover such important findings that help guide treatment for women with miscarriage.
RBA: Hang on a minute. Are you saying that aspirin can increase the risk of miscarriage? And if so, in all women? Or just the ones who don’t have APS or other sticky blood conditions? That’s pretty scary!
AC: This is right, Ruth, it is scary… how a treatment given with best of intentions could achieve exactly the opposite of what was expected. However, I must emphasise: for women with sticky blood conditions, the available evidence is that they will benefit from aspirin and heparin, and if their doctors prescribe these, then it would be a good idea to take them.
However, if there is no evidence of a sticky blood condition, women are well advised to keep a mile away from aspirin, unless their doctor prescribes it to them for some other reason.
RBA: That’s really important information, Arri – thank you for highlighting it.
To go back to the question of research. I imagine some of it, like trying to find out the causes of miscarriage, doesn’t directly involve patients – that is, they don’t take an active part in the research except, perhaps, for allowing blood or tissue samples to be analysed.
Arri: This is correct Ruth. We often do what is known as ‘basic science’ or ‘bench’ research in the laboratories to understand the science behind why miscarriages occur and how a treatment may work. This research does not normally involve patients directly, but relies on the blood or tissue samples.
Such research is really important to find out potential new therapies, which can then be tested in clinical trials. As an example of this, we are currently studying the blood of women with thyroid antibodies to see if there is an immunological cause for miscarriage in these patients. If we unearth important findings here, this may help us develop and test potentially important therapies.
RBA: That’s good to know. And you are also involved in some clinical research trials where you are looking at the effects of certain treatments – like aspirin. Some of them, like the PROMISE (progesterone) and TABLET (thyroxine) trial, are randomised controlled trials, or RCTs. Can you explain what these terms mean?
Arri: Sure. It is really important to evaluate treatments in high quality studies, so that patients and their doctors can be confident that the treatment does really work. The highest quality studies for doing this are called randomised controlled studies, or RCTs.
PROMISE and TABLET are randomised controlled studies. In PROMISE, women will receive either progesterone or a placebo – that is, something that looks like the real treatment but doesn’t have any active ingredients. Neither the doctor nor the patient knows if the patient is taking progesterone or placebo tablets. Only after the study has been completed will we know which treatment a patient was taking.
This is important to avoid any ‘biases’, so that if the study shows that progesterone works, then we can be confident that it does really work. Equally, if the PROMISE trial shows progesterone does not work, then we can be confident that it does not work. Patients and doctors need to have confidence in the treatment that they receive and provide, and RCTs gives everyone confidence in the results of a study.
RBA: You’re saying that if patient or doctor knows whether they are having the real treatment or the placebo, then that could cause a bias, make a difference to the outcome. Why? How?
Arri: It is possible that the doctor could consciously influence the outcome of a study, say by promoting one treatment over another or over the placebo. The doctor may offer additional care for patients in one group, and this could influence and prejudice the results.
In fact, there doesn’t even need to be a conscious influence. There is evidence that if we know who is in the treatment group, we may even unconsciously influence the findings and let all sorts of biases creep in. Patients and doctors need trustworthy evidence, and a study which is not properly randomised or blinded may not produce trustworthy evidence.
RBA: Hmm. Thinking about it, though, if I had had repeated miscarriages and nobody knew why – AND if there’s a treatment which is being tried out – I don’t know that I’d want to risk being given the placebo drug and possibly missing out on a good treatment. Why shouldn’t I just go out and find someone who’ll prescribe the treatment?
Arri: This is a very reasonable concern. However, you must then remember that the whole reason for doing a study is because we do not genuinely know if a treatment works! If we thought it did, then we would be prescribing it.
Sometimes we think we know the answer, but then you only have to look at the aspirin story to realise that rushing in and taking a treatment without good evidence can actually cause harm. In fact, if it weren’t for the women who willingly took part in that research, we may have unwittingly continued to cause harm.
RBA: I suppose there might also be people who are anxious about taking the treatment in case of possible harm or side-effects.
Arri: This is true. However, any clinical study goes through rigorous assessment to ensure the study is ethical and does not cause harm to the patients. Moreover, as the study is conducted, there is continual assessment to ensure there is no emerging evidence of serious harm to mothers or babies. This task is carried out by an independent body called the Data Monitoring Committee. This should give reassurance to patients in a study.
RBA: I’ve just got one more question, Arri, going back to the idea of the psychological aspects of being in a trial. I understand that there is some evidence that just taking part in a clinical trial can improve outcomes, whether women are taking the treatment or the placebo. It might be to do with having extra care and monitoring, perhaps. Is this really true?
Arri: This is correct, although there is some controversy over this. What is true is that patients taking part in trials do tend to get additional care and monitoring, and there is of course some evidence that enhanced care can have a positive impact in reducing miscarriage risks. I certainly think that trials such as PROMISE and TABLET have very little scope for harm, while carrying a potential chance for benefit.
RBA: So overall, it looks like taking part in clinical trials on miscarriage can be a really positive thing to do. It helps us to work out which treatments are effective and which should be avoided because they either don’t work or are positively harmful. That’s a great gift to others who go through the sadness of miscarriage.
What’s more, it looks like even if the treatment doesn’t turn out to be effective, just being in the trial can itself be helpful. Now that’s a bonus.
Thank you very much, Arri.