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NEWS: In brief BMJ 2001; 323: 650 [Full text]

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If you had suspected CJD, would you be indifferent between placebo or quinacrine ?

David Braunholtz   (4 October 2001)

Re: If you had suspected CJD, would you be indifferent between placebo or quinacrine ?

Ed Cooper   (6 October 2001)

If you had suspected CJD, would you be indifferent between placebo or quinacrine ? 4 October 2001
David Braunholtz, Senior Research Fellow Department of Public Health & Epidemiology, University of Birmingham Send response to journal: Re: If you had suspected CJD, would you be indifferent between placebo or quinacrine ?	Ethics of a clinical trial of quinacrine in patients with suspected CJD Following the apparent recovery of a patient with suspected vCJD when treated with quinacrine, it is reported [1] that even now such a trial is being designed. Should this be a randomised trial? Should an ethics committee approve such a trial? While there is clearly considerable 'uncertainty' [2] regarding the effect of quinacrine in vCJD and other prion diseases, it is almost inconceivable to us that a rational patient with a suspected prion disease would be in 'equipoise' ie indifferent between quinacrine and placebo. On the one hand: quinacrine was long been used as an anti-malarial, and consequently there is a lot of knowledge about the side-affects of quinacrine, and these are comparatively minor over a wide dose range; quinacrine penetrates the blood-brain barrier moderately well, and has a high activity against prions in vitro and in some animal studies [3]. On the other hand, prion diseases (such as vCJD) are invariably fatal untreated. The balance of risks and benefits for a patient with suspected prion disease clearly lies in taking quinacrine (which is cheap and easily available). Any patient who would be prepared to be randomised to a quinacrine/placebo trial is likely not to have understood properly what the implications are. We therefore argue that such a trial should not, at present, be sponsored and nor should an ethics committee allow such a trial. It has already been recognised that a randomised trial, if launched, would find it difficult if not impossible to recruit patients [4]. This is an example of asymmetry where losses (if any) are limited by the prognosis (months), whereas gains (if any) are limited by life-span (decades) [5]. The alternative to a randomised trial is a 'historically controlled trial'. Prion diseases are invariably and fairly rapidly fatal. Diagnosis is tricky, but it is thought that patients referred to the National CJD Surveillance Unit and classified as "possible CJD" have a 50-60% chance of having CJD, while after a visit by researchers from the National CJD Surveillance Unit, many patients will be classified as "probable CJD" - with a 95% or more chance of having CJD [Dr Richard Knight, National CJD Surveillance Unit, Edinburgh, personal communication]. An ethically acceptable approach would be to offer treatment with quinacrine to all patients classified as "possible" or "probable" CJD. It will quickly become apparent, even allowing for all the potential biases which can arise from using historical controls, whether quinacrine is preventing the deaths of a large proportion of patients with CJD. If so - fantastic! Trials comparing doses, newly designed structurally similar drugs, combinations of drugs, etc could proceed. If on the other hand it is clear that quinacrine is not saving a majority of patients - eg the first 50 patients treated follow courses on average only a little better than historical controls (and perhaps further animal experiments are disappointing) - then the balance of risks and benefits for patients becomes much more equal. Only when the time comes that the ethical committee judges that some fully informed, rational patients might now be prepared to enter a quinacrine/placebo trial, would it be reasonable to allow such a trial to proceed (ensuring, of course, that all potential participants are made fully aware of the potential risks and benefits of treatment with quinacrine). Yours Sincerely David Braunholtz Richard Lilford Judith Harris Department of Public Health & Epidemiology, University of Birmingham (We are not aware of any conceivable conflicts of interest) References 1. "in brief". BMJ 2001;323:650 (22 September) 2. Equipoise and uncertainty principle are not mutually exclusive. R.J. Lilford and Benjamin Djulbegovic. BMJ 2001;322:795 (31 March) 3. Acridine and phenothiazine derivatives as pharmacotherapeutics for prion disease. Carsten Korth, Barnaby C.H. May, Fred E. Cohen, and Stanley B. Prusiner. Proc. Natl. Acad. Sci. 2001; Vol 98 Issue 17:9836-9841 (14 August). 4. First vCJD clinical trial to begin. Emma Young. NewScientist.com News Archive. http://www.newscientist.com/news/news.jsp?id=ns99991307 5. Edwards SJL, Lilford RJ, Braunholtz DA, Thornton J, Jackson J, Hewison J. Ethical Issues in the design and conduct of randomised controlled trials. [Review]. Health Technology Assessment 1998;2(15):1-96.
Re: If you had suspected CJD, would you be indifferent between placebo or quinacrine ? 6 October 2001
Ed Cooper, Consultant Pediatrician Newham General Hospital, London Send response to journal: Re: Re: If you had suspected CJD, would you be indifferent between placebo or quinacrine ?	Is there not a fundamental misunderstanding about double-blind trials in the question of the title? And the meaning of equipoise? "It is almost inconceivable to us that a rational patient with a suspected prion disease would be in 'equipoise' ie indifferent between quinacrine and placebo": I think this is quite true, but I cannot imagine many subjects with a life-threatening disease in any placebo-controlled clinical trial hoping that their packet of tablets is the placebo. What one agrees to is not to take a placebo but to take a treatment with a 50% chance of containing an active ingredient that may or may not be of value. In this way one submits oneself to an unknown fate, but not without hope, and in trust of the blinded investigators that they are in equipoise as to the risk of alternative fates for your life they are taking. A proposed trial of quinacrine seems to meet that criterion. Ed Cooper (No conflict - no involvement in this area of medicine)