MGA News Spring 2006

A randomized clinical trial to evaluate the benefits of Thymectomy

Background

I explained in a previous issue of the MGA Newsletter that many neurologists and many chest surgeons are uncertain about whether thymectomy is the right treatment for MG patients who do not have a thymoma. (A thymoma is a usually benign tumour of the thymus and thymectomy is normally recommended because the tumour can interfere with local structures and is thus better removed). Some of you with ‘non-thymomatous MG’ who have had a thymectomy will remember that it seemed to help you to get better, but others may have concluded that thymectomy really seemed to make no difference in their case. Those of you who have not had a thymectomy may recall that you were greatly helped by prednisone (‘steroids’) – and indeed many of you may still be taking it, but you are likely also to remember that the side effects of the medications were a real drawback.

The Challenge

The challenge that faced us was how to design a clinical study that would establish the possible benefits of thymectomy. The way this is often done in other medical situations, for example in evaluating a particular treatment, is by means of a ‘randomized double-blind’ study in which a new drug is tested against a ‘placebo’, the word used for a ‘dummy’ drug that looks and tastes like the real thing but actually contains an inert substance. As explained in the previous article, ‘randomized’ means assigning the patient to one or other of the medicines as if by the spin of a coin. ‘Doubleblind’ means that neither the patient nor the doctor evaluating the response know whether the patient is taking the new drug or the placebo – in other words, both the patient and the doctor are ‘blind’ to what the patient is taking. The response (or ‘outcome measure’ as it’s often called) might, for example, be a comparison of muscle strength at the end of the study. Unfortunately, in the case of thymectomy and MG, designing the study in this way is not so simple (we wish it were!). There are two main reasons for this

First, the patient cannot be blind to whether or not they have had a thymectomy! So in order to have an apparently identical ‘placebo’ treatment, we would need to randomize patients either to a ‘real’ thymectomy or to a ‘sham’ thymectomy (in which the chest would be opened as for a real thymectomy, but nothing would be removed and the chest would then be closed). Quite apart from the fact that no patients are likely to be willing to take part in a study where there is a 50% chance of their chest being opened and closed again without anything else being done (an entirely sensible decision on their part!), no Ethics Committee would ever be likely to approve such a study. But though the patients won’t be blind to whether they have had a thymectomy or not, the doctor evaluating their response will be ‘blind. This is not easy to achieve, but patients will be sworn to secrecy about whether they were in the operated group or not, they will be supplied with a handsome polo-necked shirt with the trial logo on it which will ensure that not even the top of a thymectomy scar would be visible and the doctor won’t start doing the ‘blind’ evaluations until at least 3 months after the operation, when any post-surgical clues will no longer be present.

Second, using strength as an ‘outcome measure’ is difficult in MG because of the hour by hour and day by day variations, as many of you know. So we had to think of an additional way to measure ‘outcome’. We also wanted to try to make sure that, independent of thymectomy, both groups had a good chance of getting stronger.

The Design of the Study

We therefore decided to design the study in the following way. We plan to follow up each patient for a three year period. Both groups would receive prednisone according to a set protocol that would be highly likely to result in substantial improvementand one of the two groups would be ‘randomized’ to thymectomy. We are going to use the standard operation employed at centres across the world in which a central (midline) incision is made through the ‘sternum’ (the breast bone). This has to be done within 30 days of entering the study and the prednisone protocol also has to be started within this period. The dose of prednisone is quickly built up to a maximum based on the patient’s weight and kept at that level until no symptoms or restrictions caused by MG are present and the strength score is essentially within the normal range. We call this the ‘minimal manifestation status’ which is a longwinded way of saying ‘in remission’. The dose will then be quite rapidly reduced to the least required to keep the patient in remission. If symptoms come back, the dose would be increased according to the protocol until the patient is in remission again. After an interval, the dose would again be reduced to find the least required to maintain remission.

We will have two outcome measures. First, we shall be asking the patient to take part in simple strength measures (no electrical tests!) at regular intervals - for example, how long an arm can be held horizontal – and we shall then obtain the cumulative result for each patient over the 3 year period. At the end of the study we shall find the average for all patients in each group to see whether one group has become significantly stronger than the other. Our expectation here is that there will be very little difference between the two groups because of the powerful immunosuppressive actions of prednisone that, from past experience, are highly likely to result in greatly improved strength in both groups by the end of the 3 year study.

The second outcome measure is the one which we think will show a real difference if thymectomy is truly beneficial as many believe. This measure is the dose of prednisone necessary to keep patients ‘in remission’. If thymectomy substantially reduces the severity of MG, then a much smaller dose of prednisone (possibly none at all) would be needed to keep patients ‘in remission’.

So at each clinic visit the patients will be issued with a specially prepared package of pills and detailed instructions regarding doses to be taken. Also at each visit, the number of pills taken will be counted. Then, at the end of the study when all patients have completed their 3 year follow-up, we shall calculate the average prednisone dose for the two groups over the 3 year period. A reduction of 30% (or more) in the prednisone dose in the thymectomy group over the 3 year study period would, in our view, establish the benefits of the operation.

Important secondary outcome measures will be the adverse symptoms of the treatments experienced by the patient, both from the prednisone and from the thymectomy. We shall also document any complications (‘side effects’) of the treatments and ask patients to complete a simple Activities of Daily Living questionnaire designed for MG patients (MG-ADL). These will help us to evaluate the two treatments. Incidentally, all patients will be able to continue to take a small dose of pyridostigmine if they find that helpful.

Who is suitable for entry to the trial?

Patients need to have had symptoms of MG for less than 3 years, to have no chest (CT) scan evidence of thymoma, to be aged between 18 and 60 years at the time they enter the study, to be positive for acetylcholine receptor antibodies and to have generalised MG (ocular MG patients are excluded). Patients can already be taking prednisone – we are interested to see whether there is a difference in the effectiveness of thymectomy between those already taking prednisone when they have their thymectomy and those who are not. Patients not suitable include those who are planning pregnancy, those already receiving other immunosuppressive drugs (such as azathioprine), those who have another serious illness and those who would be unable to attend the follow-up visits (monthly for the first 4 months, then a visit at 6 months and every 3 months thereafter to month 36). However, because of these quite frequent visits, we shall be able to reimburse patients for their reasonable travel costs to their nearest centre, on a per visit basis, once they have been entered to the study

Centres where the study will be done.

We need to recruit 200 patients and, as mentioned in the previous article, we have about 70 centres worldwide.

We are very pleased that eight specialist neurological centres in the UK have expressed a strong interest in the study (as have their cardio-thoracic surgeons) and wish to take part. These are in Manchester (Hope Hospital), Liverpool (Walton Centre), Sheffield (Hallamshire), London (Guys/Kings/StThomas’s), Newcastle (Newcastle General), Glasgow (Southern General), Edinburgh (Western General) and Oxford (Radcliffe Infirmary)

Recruitment to the study.

I am glad to report that the UK Multi-Centre Research Ethics Committee (MREC) has given overall approval for the study. Interested patients already attending one of the centres above will be given a detailed information sheet about the study on request. Anyone interested in taking part who does not attend one of the centres above is welcome to contact me through MGA.

We hope to start recruiting patients in April. As always in MG, research is aimed at finding the best treatment, we need your help!

MGA NEWS Spring 2006

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