Multiple sclerosis trials

Miller, D. H., Khan, O. A., Sheremata, W. A. et al, International Natalizumab Multiple Sclerosis Trial Group. A controlled trial of natalizumab for relapsing multiple sclerosis. N. Engl J. Med. 348 15-23, 2003. 

MUler DH, Khan OA, Sheremata WA, Blumhardt LD et al., for the International Natalizumab Multiple Sclerosis Trial Group (2003) A controUed trial of natalizumab for relapsing multiple sclerosis New England Journal of Medicine, 348, 15-23 Moher D, Schulz KF and Altman DG (2001) The CONSORT statement Revised recommendations for improving the quahty of reports of paraUel-group randomized trials Annals of Internal Medicine, 134, 657-694... 

There are two main reasons for blinding the trial clinicians first, so that the use of non-trial treatments and interventions is not influenced by a knowledge of whether or not the patients received the trial treatment second, so that clinicians are not biased in then-assessment of clinical outcomes. The potential for bias depends on the subjectivity of the trial outcome. Biased assessment of neurological impairment and disability was clearly demonstrated in a multiple sclerosis trial in which blind and non-blind outcome assessment produced very different results (Noseworthy et al. 1994). Trials with blind assessment should also report whether or not blinding was effective. It is, of course, sometimes impossible to blind clinical assessment, but non-blind trials should report data on non-trial treatments given to patients during follow-up to ensure that these were not biased. 

Kappos L, Weinshenker B, Pozzilli C, Thompson AJ, Dahike F, Beckmann K, Polman C, McFarland H, and for the European and North American Interferon beta-lb in Secondary Progressive Multiple Sclerosis Trial Steering Committees and Independent Advisory Boards. Interferon beta-1 b in secondary progressive MS A combined analysis of the two trials. Neurology 63 1779-1787, 2004. 

Rudick RA, Cutter G, Reingold S. The multiple sclerosis functional composite A new clinical outcome measure for multiple sclerosis trials. Mult Scler 2002 8 359-365. 

Paty, D.E., Willoughby, E., and Whitakek, J. 1992. Assessing the outcome of experimental therapies in multiple sclerosis. In Treatment of Multiple Sclerosis Trial Design, Results, and Future Perspectives, pp. 47-90. London, Springer-Verlag. 

This experimental drug is a derivative of myriocin. After phosphorylation FTY720 modulates chemotactic responses and lymphocyte trafficking, leading to reversible lymphocyte sequestration in secondary lymphoid tissues. It is in clinical trials for the treatment of multiple sclerosis. 

PRS-211,096 (8.8) is a CB2-selective agonist, thus avoiding the psychotropic side effects related to CBl. It is currently in clinical trial for the treatment of multiple sclerosis. 

There have been a number of studies to evaluate the therapeutic effect of carmabinoids against spastic disorders, including multiple sclerosis and spinal cord injury. For example, a randomised placebo-controlled trial in more than... 

Biologic response modifiers (BRMs) are indicated in patients who have failed an adequate trial of DMARD therapy.1 BRMs may be added to DMARD monotherapy (i.e., methotrexate) or replace ineffective DMARD therapy.22 The decision to select a particular agent generally is based on the prescriber s comfort level with monitoring the safety and efficacy of the medications, the frequency and route of administration, the patient s comfort level or manual dexterity to self-administer subcutaneous injections, the cost, and the availability of insurance coverage.23 In general, BRMs should be avoided in patients with serious infections, demyelinating disorders (e.g., multiple sclerosis or optic neuritis) or heart failure.21... 

Fig. 5. Structures of (A) CP-481,715, (B) BX 471, and (C) T487. CP-481,715 and BX 471 are specific CCR1 antagonists from Pfizer and Berlex/Schering AG, and both failed to exhibit efficacy for rheumatoid arthritis and multiple sclerosis, respectively, in phase II trials. T487 is a specific CXCR3 antagonist from Amgen/Turalik that failed in phase Ha psoriasis clinical trials due to lack of efficacy.

Zajicek J, Fox P, Sanders H, Wright D, Vickery J, Nunn A and Thompson A (2003). Cannabinoids for the treatment of spasticity and other symptoms related to multiple sclerosis (CAMS study) Multicentre randomised placebo-controlled trial. Lancet, 362, 1517-1526. 

Other clinical trials with CCR2 antagonists are underway [1], but no reports have been forthcoming. Both MLN-1202, a humanized anti-CCR2 antibody, and MK-0812, a small molecule antagonist, were examined in rheumatoid arthritis (vide supra) and are also being examined in multiple sclerosis. Two additional small molecules - CCX-915 and INCB-8696 - have entered phase 1 trials with multiple sclerosis as a projected phase 2 trial. An intention to study INCB-8696 in systemic lupus erythematosus has also been declared. Finally, phase 2 clinical... 

Luo, J., J. H. Yin, H. Z. Wu, and Q. Wei. Extract from Fructus cannabis activating calcineurin improved learning and memory in mice with chemical drug-induced dysmnesia. Acta Pharmacol Sin 2003 24(11) 1137-1142. Degenhardt, L., W. Hall, and M. Lynskey. Exploring the association between cannabis use and depression. Addiction 2003 98(11) 1493-1504. Zajicek, J., P. Pox, H. Sanders, et al. Cannabinoids for treatment of spasticity and other symptoms related to multiple sclerosis (CAMS study) multicentre randomised placebo-controlled trial. Lancet 2003 362(9395) 1517-1526. 

Figure 16.1 Patient disposition in the SENTINEL trial. (Rudick RA Stuart WH, Calabresi PA, Confavreux C et at. for the SENTINEL Investigators (2006) Natalizumab plus interferon beta-la for relapsing multiple sclerosis New England Journal of Medicine, 354, 911-923. (2006) Massachusetts Medical Sodety.)...

Cutter, N.C., Scott, D.D., Johnson, J.C., and Whiteneck, G. (2000) Gabapentin effect on spasticity in multiple sclerosis a placebo-controlled, randomized trial. Arch Phys Med Rehabil 81 164-169. 

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