PRION1 trial reports quinacrine does not increase survival in patients with prion disease
10 March 2009
The drug quinacrine does not increase survival in patients with prion diseases including variant Creutzfeldt-Jakob Disease (vCJD). The finding comes from evidence collected during the PRION-1 trial, the first clinical trial of a potential treatment for human prion diseases in the UK. The results are published in Lancet Neurology.
Human prion diseases, such as Creutzfeldt-Jakob disease (CJD), can arise spontaneously, be inherited through a genetic mutation, or develop through infectious transmission. The most common form is sporadic CJD, which affects about one to two people in a million worldwide every year. The neurodegenerative disorders caused by prion disease are fatal and progress rapidly. Currently, there are no therapeutic interventions that prevent or reverse progression in human prion diseases.
The Chief Medical Officer for England asked the Medical Research Council to prepare a protocol for a clinical trial in human prion disease to investigate quinacrine’s therapeutic potential, activity and safety. There are no other drugs currently available which are considered suitable for human evaluation. PRION-1 was led by Professor John Collinge, Director of the MRC Prion Unit, and was funded by the MRC and Department of Health.
Quinacrine (Mepacrine), a drug used to treat malaria and some arthritic illnesses, has been shown to be effective in treating prion-infected cells in the laboratory, by blocking the conversion of normal prion proteins into the abnormal disease-causing form. Oral quinacrine is also known to be safe and well-tolerated in humans and can cross the difficult blood-brain barrier. Interest in this potential treatment grew, and some patients requested immediate access to quinacrine.
A formal consultation process with patients, families, carers and representatives of patients was undertaken to develop an acceptable study design to assess the efficacy and safety of oral quinacrine in all forms of prion disease in the UK.
Patients in the PRION-1 trial were offered the choice of quinacrine, no quinacrine, or to be randomly assigned to receive quinacrine either immediately or after a delay. In total 107 patients with prion disease were recruited to the trial from across the UK using a national referral system. Of these people, 45 had sporadic prion disease, two had iatrogenic (acquired from a hospital procedure), 18 had variant CJD and 42 had inherited prion disease. Patients were eligible if they had any form of prion disease and were more than 12 years old. Neurological assessments and clinical investigations were carried out at the start of the study, again after one, two, four and six months, and then at regular intervals of three months.
Only two of 84 patients, or their carers where the individuals did not have the capacity to make the decision themselves, agreed to randomisation. This means that PRION-1 was primarily an observational study of patients who did or did not choose quinacrine. The authors identified disease severity as a strong determinant of this choice, with those least and most severely affected least likely to choose the drug.
In total, 78 patients died—one randomly assigned to deferred treatment, 26 of 38 who took the drug immediately, and 51 of 69 who initially chose no quinacrine. Mortality was lower in patients who chose to take quinacrine than in those who did not, but after adjusting for confounding factors such as disease severity and type of disease there was no difference in survival significant enough to suggest quinacrine is a successful treatment option.
Importantly, the authors believe that although the study demonstrated that national recruitment and retention to trials of treatment of prion disease is both feasible and acceptable to patients and carers, it highlighted the difficulty of conducting randomised controlled trials. Patients who have a fatal disease that progresses rapidly often want whatever potential treatment is available. This means they are reluctant to be randomised to a deferred treatment option. Similarly when a patient has advanced disease, families are not prepared to accept an intervention that is expected to merely slow or halt disease progression.
The authors conclude that earlier diagnosis must be: ‘‘A high priority if patients are to be included in treatment trials, as those with mild to moderate disease are probably most likely to accept randomisation, and likely to benefit most from any effective treatment.”
Original research paper: Safety and efficacy of quinacrine in human prion disease (PRION-1 study): a patient-preference trial is published in Lancet Neurology 2009; 8: 334–44.
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