T. Jock Murray

A Multicenter, Open-Label, Phase II Study of the Immunogenicity and Safety of a New Prefilled Syringe (Liquid) Formulation of Avonex in Patients with Multiple Sclerosis

BACKGROUND A new liquid formulation of Avonex (interferon beta-1a [IFNbeta-1a]) in a prefilled syringe has been developed to make administration of the drug easier for patients with multiple sclerosis (MS). This formulation does not contain human serum albumin (HSA), often added to interferon (IFN) products for stabilization. However, formulation changes may alter the secondary, tertiary, and quaternary structures of IFNbeta products. These kinds of structural changes could lead to the formation of antibodies directed against IFNbeta. Some of these anti-IFN antibodies may neutralize the biologic activity of IFNbeta. OBJECTIVE This study was designed to determine the immunogenicity and safety of the new prefilled syringe (liquid) HSA-free formulation of Avonex in patients with relapsing MS. METHODS This was a multicenter, single-arm, open-label study. Patients with relapsing MS received liquid, HSA-free Avonex 30 microg by IM injection from a prefilled syringe once weekly for up to 24 months. Immunogenicity and safety were assessed every 3 months. Serum levels of neutralizing antibodies (NAbs) were measured at baseline and every 3 months using a 2-step enzyme-linked immunosorbent assay and antiviral cytopathic effect assay. RESULTS A total of 153 patients (121 women, 32 men; mean [SD] age, 39.6 [9.9] years; age range, 19.0-59.0 years) were enrolled in the study. Sera were available for analysis from 125 and 119 patients after 18 and 24 months of treatment, respectively. By 18 months, 1 patient (1%) had > or =2 consecutive titers of > or =20, a level at which the persistent presence of NAbs has been shown in some studies to have clinical consequences. By 24 months, 1 additional patient (total 2%) had > or =2 consecutive titers of > or =20. At 18 months, 5 patients (4%) had > or =1 NAb titer of > or =5; at 24 months, 6 patients (5%) had > or =1 NAb titer of > or =5. The safety profile of liquid Avonex was comparable to the lyophilized form containing HSA. CONCLUSIONS The prefilled syringe (liquid) HSA-free formulation of Avonex was well tolerated and showed a low level of immunogenicity. Over 24 months, 2% of patients developed persistent NAbs (> or =2 consecutive titers of > or =20).

The cardiac effects of mitoxantrone: do the benefits in multiple sclerosis outweigh the risks?

Mitoxantrone, an immunosuppressant agent with potent anti-inflammatory activity, has been used to treat patients with multiple sclerosis (MS) who have worsening relapsing-remitting (RRMS) or secondary progressive multiple sclerosis (SPMS) despite prior therapy with interferons or glatiramer acetate. From previous experience of treating cancer with mitoxantrone, it was expected that cardiotoxic effects and occasional malignancy would develop in some patients treated with this agent. From the earliest trials, reduction of left ventricular ejection fraction (LVEF) was seen in 2 – 3% of cases, and in some this effect may persist and less commonly there can be congestive heart failure and even death. There are also occasional reports of leukaemia developing in MS patients treated with this agent. Mitoxantrone has been shown to reduce relapses, the number of new lesions visualised on magnetic resonance imaging and stop or reduce the progression of the disease in many patients treated. The drug has found a place in MS therapy because in this progressing group of MS patients who are failing on the disease-modifying therapies with interferons or glatiramer acetate, trials have shown that mitoxantrone may arrest or even improve many patients. Recognising the risks, mitoxantrone therapy is a reasonable option for MS patients with RRMS and SPMS who are progressing despite current disease-modifying therapy.

Hand dexterity and direct disease related cost in multiple sclerosis

METHODS The nine hole peg test (9HPT) is an emerging outcome measure in clinical trials in multiple sclerosis (MS). In this study we investigated how performance on the 9HPT at baseline is related to annualized direct MS related cost. METHODS We enrolled patients with a definite diagnosis of MS from two Canadian MS centers. 9HPT and demographic information were recorded at baseline, and patients prospectively recorded all MS related costs for 6months. Costs were compared among five groups according to the baseline 9HPT, and we built a multiple linear regression model including cost (dependent variable) and 9HPT at baseline, age, disease duration, sex and disease course (independent predictor variables). RESULTS We analyzed data from 298 patients. Cost significantly increased with increasing 9HPT scores (p<0.0001), with the costs for health care providers, changes to the home or car and long-term care dominating in the most disabled patient groups. The 9HPT score was a significant predictor of cost in the regression model (p=0.006). CONCLUSION Performance on the 9HPT is closely related to cost. Our data add another aspect of patient relevance to using the 9HPT as an outcome measure in clinical trials.

Rationale and design of the prospective and retrospective observational study of Avonex and Rebif (PROOF) for the treatment of relapsing-remitting multiple sclerosis.

SUMMARY Previous studies comparing the two available interferon beta (IFNβ)-1a products, Avonex and Rebif, for the treatment of relapsing-remitting multiple sclerosis (RRMS) have been limited and of short duration. Therefore, the Prospective and Retrospective Observational Study of Avonex and Rebif (PROOF) was designed to provide long-term (up to 5 years) comparative data on the efficacy, safety, and tolerability of these two agents. Patients with RRMS receiving treatment with either Avonex* 30 μg intramuscularly once weekly or Rebift 44 μg subcutaneously three times weekly from 12 to 24 months are being enrolled and will continue their respective treatments for the 36-month duration of the study. The primary efficacy endpoint will be change in brain parenchymal fraction, which will be evaluated through magnetic resonance imaging scans by blinded radiologists. Secondary endpoints will include the following: relapse rates; intravenous steroid use; the proportion of patients with an increase of >1 point on the Expanded Disability Status Scale (EDSS) and with an increase in EDSS score sustained for 6 months; mean change in EDSS score; cumulative number of new or enlarging T2 lesions; T2 and T1 lesion volumes; gadolinium-enhanced lesion number and volume; and safety and tolerability. The study design of PROOF will permit more meaningful conclusions regarding the optimal IFNβ-1 a product for the long-term treatment of patients with multiple sclerosis. * Avonex is a registered trade name of Biogen, Inc., Cambridge, MA, USA

Dilemmas in medical ethics in the age of big data

The new genome mapping techniques and the Watson artificial intelligence technology are excellent examples, facilitating the scanning of thousands of scientific data, articles, and other reports and producing in mere hours or days computer-generated answers to questions that otherwise would take months or years. This holds true for advances in science in general and for our purposes, medical practice, and research in particular. There are also profound implications for government policy and funding, and insurance costs. However, these advances inevitably raise concerns over the potential for harm. Societies have frequently dealt post facto with practical, legal, and ethical questions posed by undesirable side effects or outcomes, both anticipated and unanticipated. Many legal and ethical advances have followed rather than preceded these technological changes, and as we struggle to address these issues, the rapid discoveries are already bringing further unforeseen challenges. The original Baltimore/Asilomar rules on genetic manipulation were prompted by molecular genetic discoveries and have been more recently reinforced to meet the challenges posed by the new CRISPR technology. At an earlier time, it was the ethical lapses of the Tuskegee study, which prompted the promulgation of the Common Rule for ethical oversight in the United States.1,2

Serving two masters: the medical and political careers of Sir Charles Tupper

Sir William Osler acknowledged the challenge of serving two masters, in his obituary for Sir Charles Tupper but said that Tupper had applied himself fully as a physician and a politician. Tupper was a physician who championed public health, better hospital care and improved medical education. He

The 1917 Halifax Explosion: the first coordinated local civilian medical response to disaster in Canada

SUMMARY The 1917 Halifax Explosion was an unfortunate but predictable tragedy, given the sea traffic and munitions cargo, resulting in sudden large-scale damage and catastrophic injuries, with 1950 dead and 8000 injured. Although generous support was received from the United States, the bulk of the medical work was undertaken using local resources through an immediate, massive, centrally coordinated medical response. The incredible care provided 100 years ago by these Canadian physicians, nurses and students is often forgotten, but deserves attention. The local medical response to the 1917 disaster is an early example of coordinated mass casualty relief, the first in Canada, and remains relevant to modern disaster preparedness planning. This commentary has an appendix, available at canjsurg.ca/016317-a1.

The Halifax Explosion of 1917: The oculist experience

BACKGROUND Despite its prominence in Canadian history, there are few publications about the Halifax Explosion of 1917 that deal with the care of victims with eye injuries. METHODS Archived documents relating to the nature and treatment of eye injuries sustained during the Halifax Explosion were reviewed at the Public Archives of Nova Scotia and the Maritime Museum of the Atlantic. A review of current literature was performed. RESULTS Detailed accounts regarding the personal and surgical experience of 2 ophthalmologists, G.H. Cox and F.T. Tooke, were found. Several unpublished government and personal documents on eye injuries sustained during the Halifax Explosion are filed at the Public Archives of Nova Scotia. Twelve ophthalmologists treated 592 people with eye injuries and performed 249 enucleations. Sixteen people had double enucleations. Most of the eye injuries were caused by shards of shattered glass. Sympathetic ophthalmia was the feared complication for penetrating eye injuries and a common indication for enucleation in 1917. A Blind Relief Fund was established to help treat, rehabilitate, and compensate the visually impaired. INTERPRETATION Many of the eye injuries sustained during the Halifax Explosion were due to flying shards of glass. Details of their treatment provide insight into a unique and devastating event in Canadian medical history and demonstrate how eye injuries were managed in 1917.