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Interferon-Ax and Transfer Factorin the Treatment of Multiple Sclerosis: A

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Interferon-Ax and Transfer Factorin the Treatment of Multiple Sclerosis: A J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.52.5.566 on 1 May 1989. Downloaded from Journal ofNeurology, Neurosurgery, and Psychiatry 1989;52:566-574 Interferon-ax and transfer factor in the treatment of multiple sclerosis: a double-blind, placebo-controlled trial AUSTIMS RESEARCH GROUP* SUMMARY The role of interferon-a (IFN-a) and transfer factor (TF) in the treatment of multiple sclerosis was investigated in a prospective, multi-centric, three year, double-blind, placebo-controlled trial. One hundred and eighty two patients with clinically definite multiple sclerosis were randomised into three treatment groups whose compositions were found to be similar for demographic and prognostic variables including HLA status. Subcutaneous injections ofIFN-a (3 x 106 units), TF (0 5 units) manufactured from leucocytes of cohabiting donors, or placebo were given twice weekly for two months, once weekly for 10 months then fortnightly for 24 months. One hundred and fifty three patients completed the injection regimen. There was no significant difference in the progression of disability for multiple sclerosis patients in either the IFN-a or TF-treated groups compared with the placebo group. Similarly, change in visual evoked responses (VER), and in number of oligoclonal bands (OCB) and the level of myelin basic protein (MBP) in the cerebrospinal fluid (CSF) over the Protected by copyright. trial period did not differ significantly between the three groups. However, the IFN-ae-treated group had significantly more reported adverse drug reactions and patient withdrawals than either of the other two groups. Although the pathogenesis of multiple sclerosis is treatment of the disease have therefore involved trials uncertain, current evidence suggests that the disease is of immunotherapeutic and antiviral agents.23 immunologically mediated in genetically susceptible Use ofinterferons (IFNs), which have both antiviral individuals in response to an environmental factor, and immunomodulatory properties4" has been probably a viral infection.'2 Studies of longer term advocated in multiple sclerosis. However, reported clinical experience of effects of IFN-ax in multiple *AUSTIMS (Australian trial of transfer factor and Interferon as sclerosis has been conflicting.'9 Transfer factor (TF), a treatment for multiple sclerosis): Frith JA, McLeod JG, Hallpike JF, Chambers BR, Danta G, Grainger KMR, Hammond SR, Harris G, dialysable leucocyte extract,'0 which has been claimed Reid AC, Symington G, Walsh JC, Williams DB, Yeo PT, Mackay both to restore cell-mediated immune reactivity and to IR, Basten A, Bradley J, Dawkins RL, English D, Lowenthal RM, have antiviral has also been properties under http://jnnp.bmj.com/ Van der Brink CM, Department of Medicine, University of Sydney, consideration as a therapeutic agent in multiple Department of Neurology and Clinical Immunology, Royal Prince Alfred Hospital, Sydney; Repatriation General Hospital, Heidelberg, sclerosis although results of clinical trials have Clinical Research Unit of the Walter and Eliza Hall Institute of differed." 2 Medical Research and Royal Melbourne Hospital, Melbourne; Royal In order further to define the roles of IFN-a and TF Adelaide Hospital, Department of Clinical Immunology, Flinders in the treatment of multiple sclerosis, the AUSTIMS Medical Centre, Adelaide; Department of Clinical Neurophysiology, Royal Hobart Hospital, Department of Medicine, University of trial (Australian trial of TF and IFN-a in multiple Tasmania, Hobart; Royal Brisbane Hospital, Brisbane; Royal sclerosis) was devised as a collaborative (multi-centre), Canberra Hospital, Canberra; Sir Charles Gairdner Hospital, Perth; prospective, randomised, double-blind, placebo- on October 2, 2021 by guest. NH & MRC Research Unit in Epidemiology and Preventive Medicine controlled, non-crossover study of TF and IFN-a and Department ofClinical Immunology, Queen Elizabeth II Medical Centre, Perth, Australia. involving initial enrolment of 182 multiple sclerosis patients and treatment for a 3-year period. Address for reprint requests: J G McLeod, Department of Medicine, University of Sydney, NSW 2006, Australia. Patients and methods Received 2 September 1988 and in revised form 9 January 1989. Patients Accepted 16 January 1989 One hundred and eighty two patients (I 12 female, 70 male) 566 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.52.5.566 on 1 May 1989. Downloaded from Interferon-a and transferfactor in the treatment ofmultiple sclerosis 567 with symptoms and signs of clinically definite multiple relatives living in the same house as patients suffering with sclerosis'3 and without serious intercurrent illnesses were multiple sclerosis. The mononuclear cells were separated on accepted into the trial. Eighty five per cent of patients had "Ficoll-Hypaque" gradients and a crude cell-free extract was multiple sclerosis for less than 10 years and all patients had prepared by repeated freeze-thawing (10 times). After clinical evidence of disease activity, either one or more ultrafiltration through a PM 30 Amicon filter, the dialysate relapses or progression of more than 1 on the Kurtzke was placed in a freeze drying apparatus and the contents disability status scale (DSS)," within the three pre-trial years. lyophilised for storage as a powder at - 20°C. When needed, At the initial assessment, 82% of patients had DSS scores of the powder from several donors was pooled and recon- less than 4 which represented mild to moderate disability. stituted in sterile pyrogen free water. The reconstituted After fulfilling these selection criteria, patients were product was filtered through a Pall 0 2 pm membrane and randomised into three groups; 60 patients received IFN-oa, 61 samples taken to test for sterility, pyrogens, protein, HBsAg TF and 61 placebo. Patients, attending staffand neurologists and human immunodeficiency virus antibodies. The were blinded to the treatment given. The protocol for the trial chromatographic profile of TF obtained in this way was very was approved by Medical Ethics Review Committees in all similar to that observed with the more classical dialysis participating centres and written informed consent was procedure, the advantage of the present method being that obtained from all patients. sufficient amounts ofTF could be produced for a trial of this The trial protocol allowed for short courses of cortico- size and duration. steroid or ACTH therapy to be given for relapses when The concentration of TF was adjusted so that each 1 ml indicated; it was recommended that the trial injection contained 2 0 x 108 cell-equivalents and one unit of TF was regimen be suspended for the duration of the steroid therapy arbitrarily defined as 4 x 0I cell-equivalents. and for two weeks thereafter. Immunosuppressive agents Placebo consisted of a sterile buffered salt solution con- such as azathioprine and cyclophosphamide were not taining 0 5% human albumin which was also present in the prescribed for any patient for 12 months prior to or during IFN preparation. IFN-a, TF and placebo were stored in 1 ml the trial. Throughout the course of the trial clinical progress vials at - 20°C until used. Each patient received 3 x 106 of patients in each treatment arm and reports of adverse units of IFN-a, 0 5 units of TF or 1 ml of placebo drug reactions were monitored by an Independent Review subcutaneously twice weekly for two months, then once Committee. weekly for 10 months, then fortnightly for 24 months. Thus Protected by copyright. Each trial patient underwent a full neurological assessment each patient who completed the therapeutic regimen had performed by a neurologist before entry, after two months received approximately 100 injections over the three year and six months, and every three months of treatment period ofthe trial. This dosage schedule was based in part on thereafter for the duration of the trial. All neurological those previously used for trials of IFN-a and TF.8" Two assessment forms were later reviewed by one neurologist hours before and two hours after each injection, it was (JGMcL). At each examination the patients' disability was recommended that the patients take paracetamol Ig orally, assessed on the Kurtzke DSS. The DSS ranges from 0 to reduce febrile reactions thereby assisting with blinding of (normal) to 10 (dead); grades 0-3 represent only mild or the study. Despite therapy with paracetamol'6 febrile moderate disability; grade 6 indicates assistance required reactions to injections necessitated a reduction in the dose of with walking and grade 7 restriction to a wheelchair. injections in four patients and indomethacin'7 cover in five Abnormalities in each of the functional systems (FSS) patients. (pyramidal, cerebellar, brainstem, sensory, bowel-bladder, visual, mental, and other)'4 were also graded to indicate Laboratory investigations neurological impairment. Patient disability was further asses- Routine studies Before randomisation, haematological sed on an Ambulatory Status Scoring System (ASSS) which, parameters including erythrocyte sedimentation rate, as an adaptation of the DSS, emphasised the impact of the haemoglobin quantitation, differential leucocyte count and patient's neurological dysfunction on performing the tasks of platelet count, a blood biochemistry profile including urea, daily living (Appendix 1). The number of relapses since the creatinine, electrolytes and liver function tests, and a chest http://jnnp.bmj.com/ previous examination and adverse drug
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