Multiple Sclerosis Express Report
European Consortium of Treatment and Research in Multiple Sclerosis (ECTRIMS)
Toulouse, France

Assessing Options for Multiple Sclerosis Treatment

This report was reviewed for medical and scientific accuracy by William H. Stuart, MD , Director,Multiple Sclerosis Center of the Shepherd Center, Founding Partner Peachtree Neurological Clinic, Medical Director for Rehabilitation Services, Piedmont Hospital, Atlanta,GA; Chairman, HealthMed Advisory Board, .

EARLY TREATMENT IN MULTIPLE SCLEROSIS In the US, there are three disease-modifying drugs available for the treatment of MS: interferon beta-1a (Avonex®), interferon beta-1b (Betaseron®), and glatiramer acetate (Copaxone®) (also called the ABC drugs). All three of these drugs are given by injection on different schedules. In relapsing-remitting MS patients, these treatments have been proven to slow the rate of relapse, control worsening on MRI, and slow the severity of disability. These same effects have been seen to a lesser extent in progressive-relapsing MS patients as well.

When to begin treatment of MS with one of these drugs has been the subject of much debate in the medical community. People with beginning stages of MS, or "mild" MS, with few or no symptoms may not want to use an injectable drug because they perceive themselves as not being sick enough to warrant drug therapy.

Studies now show that treatment should be initiated early in the course of disease, after just one attack of MS, if the MRI of a person's brain shows at least two lesions characteristic of MS. At the recent ECTRIMS meeting in Toulouse, France, two studies were discussed that support the validity of treating MS early in the course of disease: CHAMPS and ETOMS.

The CHAMPS (Controlled High-Risk Avonex® MS Prevention Study), which compared active treatment with interferon beta-1a (Avonex®) with placebo in patients with a first attack (or clinically isolated syndrome, CIS) and MRI evidence of at least two MS lesions, showed that early treatment with interferon beta-1a reduced the rate of conversion from CIS to clinically definite MS (CDMS) by 44 percent. MRI brain studies of patients included in CHAMPS also showed a robust treatment effect; the number of new MS lesions was reduced by 57 percent and the volume of MS lesions was reduced by 91 percent compared to placebo. The percent change in new MS lesion volume in any single patient was reduced by 94 percent.

The MRI scans of patients included in CHAMPS showed the process of demyelination has already begun at the time of the first attack and further, that demyelination progresses rapidly over a period of two years if not treated with one of the ABC drugs.

A second study of patients with early MS conducted in Europe, called ETOMS (Early Treatment of MS), also showed that low-dose interferon beta-1a (Rebif®, registered and available in Europe) reduced the rate of conversion to CDMS by 24 percent compared to placebo and also significantly delayed the time to conversion. As in CHAMPS, the MRI portion of the study also demonstrated that treatment significantly reduced the number and volume of MS lesions compared to placebo.

Although both CHAMPS and ETOMS support the principle of starting treatment early in the course of disease, the effect of early treatment was more robust in CHAMPS than in ETOMS. This difference was attributed to the types of patients included in the two studies: CHAMPS included patients with just one type of symptom (i.e., unifocal disease), whereas ETOMS enrolled patients with onset of several types of symptoms at once (multifocal disease). Therefore, the patients in ETOMS may have had more widespread disease at enrollment, which could explain why the treatment effect was not as strong.

"The type[s] of patients enrolled in ETOMS more closely represent the general population, and therefore the results can be transferred to everyday clinical practice. We believe that patients who have a first demyelinating attack and MRI findings typical of MS should be started on early treatment with a disease-modifying agent," stated Professor Giancarlo Comi, Director, MS Center, Hopital San Raffaele, Milan, Italy.

Dr. Comi emphasized that these studies only provide guidance for patients with a first attack and MRI evidence of MS. "These trials do not provide advice about patients with a first attack and a normal brain MRI or an atypical brain MRI that does not suggest MS is present," he told the audience.

"Further, the CHAMPS data illustrates how much better the results can be if treatment is started earlier for specific relapse events," said William Stuart, Medical Director of the MS Center at the Shepherd Center in Atlanta, Georgia.


Although scientists think it is likely that genetics contribute to MS, exactly which genes are involved in determining the course of disease, or whether genes determine the course of disease at all, is not well understood, explained Jan Hillert, MD, Karolinska Institute, Huddinge, Sweden. Dr. Hillert is one of a handful of researchers who studies genes in MS.

Studies show that MS has an inherited component, but no specific genes that influence the course of disease-whether a patient develops primary-progressive MS (PPMS) versus relapsing-remitting MS (RRMS)-have been identified.

Conclusions from studies thus far are that primary progressive MS and relapsing remitting MS are not genetically distinct diseases. Both types of MS share certain genetic associations. Other genes, not yet identified, may contribute to the course of disease.

"There is only weak evidence that the course of MS is genetically inherited. As in other diseases with a genetic component, the course of MS is probably determined by an interaction between genes, the environment, and chance," Dr. Hillert told attendees.

At this point in time, Dr. Hillert said that he would not put much effort into studying PPMS as a separate phenotype. "Our studies have probably added to confusion in the area of PPMS. We don't know whether this is a promising path or a dead-end."


Mitoxantrone (Novantrone®), a drug used to treat cancer patients, may be helpful in selected patients with very active MS. Studies discussed at the ECTRIMS meeting suggest that mitoxantrone could be used as "rescue" therapy for patients whose disease is rapidly progressing and also that mitoxantrone used as induction therapy prior to starting treatment with a beta interferon may further improve the course of disease in selected, more severe cases.

Two small studies of mitoxantrone have been conducted in Europe with encouraging results. The first, a preliminary study, included 44 patients with early stage MS and highly active disease, as determined by an increase of at least two points of the EDSS and in MRI studies. Patients were randomized to receive either intravenous (IV) methylprednisolone (Medrol®) alone or the combination of that drug plus mitoxantrone. Only 16 patients completed the study.

After six months of treatment, the combination therapy (mitoxantrone plus IV methylprednisolone) was superior. As evidenced by MRI scans, treatment with the combination reduced the number of new MS lesions by 86 percent. Also, patients treated with the combination had a reduction in disability and in the number of relapses compared to those treated with IV methylprednisolone alone, as measured by the EDSS. At six months, there were almost no relapses in the combination group, said Gilles Edan, MD, Centre Hospitalier Universitaire Pontchaillou, Rennes, France.

"The strong and rapid reduction in the number of MS lesions, along with the clear clinical benefit seen in the group treated monthly with mitoxantrone 20 mg plus methylprednisolone 1 g for six months, suggests a potential role for this regimen as rescue therapy for very active cases of MS," said Dr. Edan.

A second study, which included 52 patients with very active relapsing-remitting MS treated with mitoxantrone every three months suggested that monthly mitoxantrone would be a useful induction regimen given before disease-modifying therapy (i.e., either Avonex®, Betaseron®, or Copaxone® in the US). A new trial will begin in Europe this year to determine whether using mitoxantrone as induction, followed by a beta interferon, will be more effective than beta interferon alone in slowing progression of disease.

The MIMS (Mitoxantrone in MS) study, conducted in four European countries, included more than 190 patients with secondary-progressive MS (SPMS) with or without relapses. Patients received either mitoxantrone or placebo for two years. In the 110 patients who completed the trial, mitoxantrone slowed the progression of disability, reduced the rate of relapse, and reduced the number and volume of MS lesions shown on MRI. Further, the effect of mitoxantrone was sustained 12 months after therapy was stopped.

Based on results of the MIMS trial, European investigators are considering use of mitoxantrone in patients with SPMS and no relapses as first-line therapy. Mitoxantrone should also be considered for people with SPMS who experience relapses while on beta interferon therapy or who cannot tolerate beta interferon therapy, suggested Hans Peter Hartung, MD, University of Graz, Austria. Dr. Hartung said that in the European trials of Betaseron®, 40 percent of patients failed to respond to beta interferon. Finally, mitoxantrone should be considered as rescue therapy in rapidly progressing MS, he concluded.

Because mitoxantrone is a powerful drug that can be toxic to the heart, certain precautions are necessary when using the drug. First, it should only be given for a finite period of time-not indefinitely. Second, mitoxantrone should not be given to patients who have cardiac problems, including a left ventricular ejection fraction of 50 percent or less, ECG abnormalities, or an abnormal echocardiogram.

If patients develop heart problems on mitoxantrone, such as a worsening left ventricular ejection fraction, then the drug should be stopped and a cardiologist should be consulted. Other common side effects that are associated with mitoxantrone, such as nausea, urinary tract infection, and amenorrhea, can be treated, explained Dr. Hartung.

The MIMS trial studied two doses of mitoxantrone-12 mg/m2 given ten times or 5 mg/m2 given over 24 months, for a total cumulative dose of 120 mg/m2. Both of these doses were superior to placebo, and both doses are lower than the doses used to treat cancer. Dr. Hartung suggested that the dose could be tailored to each patient and that the lower dose was definitely an option. Also, he stressed that mitoxantrone should only be used to treat patients with active disease.


Now that there are partially effective treatments for slowing the progression of MS, appropriate guidelines relating to the ethics of conducting placebo-controlled clinical trials are needed. In other words, if an available treatment can help patients with MS, it may not be ethical to enter them into a trial that compares a new treatment with no treatment (placebo). An international task force convened to consider the ethics of placebo-controlled clinical trials and came up with the following recommendations.

The group concluded that placebo-controlled trials are ethical under the following circumstances:

1. If there is no effective agent available, as in the case of primary progressive MS. 2. If an agent is available for a certain form of disease, a placebo-controlled trial is still viable if the patient is educated about the options and has been urged to use the available agent but still declines to use it. Informed consent should be emphasized under these circumstances. 3. For patients with newly diagnosed RRMS, the panel agreed that a placebo-controlled trial is not an ethical first option. First, the available therapy should be offered and the patient encouraged to take it. If the patient refuses, then a placebo-controlled trial can be considered. 4. Patients who fail to improve with available therapies should be offered other available alternatives before being considered for a placebo-controlled trial. For example, if a patient does not respond to Betaseron®, he or she should be offered Avonex® or Copaxone®. "These recommendations were made in the context of currently available, partially effective drugs. If fully effective drugs are developed, the recommendations will change," explained Stephen Reingold, MD, National MS Society, New York, New York.