Rinfocan- Prescription Drug Information for Canadians

Early Initiation of Treatment Delays Development of Multiple Sclerosis

The results of a clinical trial examining the efficacy
of interferon-beta-1a (Avonex ) in patients at high
risk of developing clinically definite multiple
sclerosis (CDMS) were reported during the Late
Breaking News: MS Platform Session held May 1,
2000. at the 52nd Annual Meeting of the American
Academy of Neurology, San Diego. California.
Trial design
Avonex has demonstrated efficacy in patients with
relapsing forms of established multiple sclerosis
(MS).^1,2 However, the efficacy of Avonex in patients
who have experienced a single demyelinating
event was previously unknown, according to
Lawrence D. Jacobs, MD, Professor of Neurology,
State University of New York at Buffalo, Head.
Department of Neurology, Buffalo General
Hospital, Buffalo, New York.
Dr. Jacobs presented the results of the
Controlled High Risk Subjects Avonex Multiple
Sclerosis Prevention Study (CHAMPS), a
randomized, double-blind, placebo-controlled,
multicentre trial designed to evaluate the effect of
Avonex on the rate of conversion to CDMS and
the rate of development of subclinical magnetic
resonance imaging (MRI) abnormalities in high-
risk patients.³
Between April 1996 and April 1998,42 U.S.
centres and 8 Canadian sites enrolled 383 subjects
18-50 years of age who had experienced a first
isolated event of optic neuritis, spinal cord
syndrome or brainstem/cerebellar syndrome and
had an abnormal brain MRI scan into CHAMPS.
The 8 Canadian sites recruited approximately 30%
of the patient population. The Canadian
investigators involved in CHAMPS were:
   Stanley Hashimoto, MD, MS Clinic, University
of British Columbia, Vancouver, BC
  Luanne Metz, MD, MS Program, Foothills
Hospital, Calgary. AB
  George Rice, MD. London MS Clinic.
London, ON
   Paul O'Connor. MD, MS Clinic. St. Michael's
Hospital, Toronto, ON
  Mark Freedman, MD. MS Research Clinic,
Ottawa General Hospital, Ottawa, ON

  Douglas Arnold, MD, Montreal Neurological
Institute, Montreal, QC
   Pierre Duquette. MD, MS Clinic, Hospital
Notre-Dame, Montreal, QC
   T.J. (Jock) Murray. Dalhousie MS Research
Unit. Halifax, NS
Within 2 weeks of enrollment, all patients
received 1 g of intravenous methylprednisolone daily
for 3 days, followed by 15 days of 1 mg/kg of daily
oral prednisone. Patients were then randomized to
receive either 30 ug of Avonex or placebo once a
week via intramuscular (IM) injection.

Primary endpoint: progression to CDMS
The primary trial endpoint was progression to
CDMS, defined as a new neurological event in a
different central nervous system (CNS) location
lasting >48 hours, progression of primary disease
at month 1 or 2, or increase in the Kurtzke
Expanded Disability Status Scale (EDSS) score of
ł1.5 points without relapse,
In February 2000. the trial was terminated
early after review of the interim data by an
independent data monitoring committee because
of the beneficial effects observed with Avonex
according to predetermined efficacy criteria. At
this time, the majority of patients had been in the
trial for ł 24 months.
Evaluation of the CHAMPS data at each 6-month
follow-up period showed that Avonex had an early
effect that persisted throughout the trial.
Kaplan-Meier analysis of the percentage of
patients who developed CDMS over time
demonstrated that progression to CDMS occurred
faster with placebo than with Avonex. Treatment
with Avonex reduced the conversion to CDMS in
high-risk patients by 43% compared with placebo
(p=0.002). Dr. Jacobs said, "This is the first time
such an effect has been shown in this particular
group of high-risk patients."
The safety and tolerability profiles of Avonex
and placebo in CHAMPS were similar. Flu-like
syndrome was the only adverse event that was
significantly higher with Avonex compared with
placebo.

The presence of neutralizing antibodies
(NAbs) against Avonex was evaluated every
6 months. Only 1 patient had a titre of ł 20 NAbs,
indicating low Avonex immunogenicity.
Dr. Jacobs concluded, "These findings
emphasize the value of obtaining an MRI at
the time of the first clinical syndrome to
identify patients who are at high risk and who
might benefit from such early treatment"
Secondary endpoints: brain lesions
In CHAMPS, not only was the conversion to
CDMS delayed by Avonex treatment compared
with placebo, but all MRI measurements in
patients treated with Avonex at all time points
were positive and significantly superior to those
obtained with placebo, stated Jack H. Simon. MD,
University of Colorado, Denver, Colorado.⁴
The secondary endpoints in CHAMPS were
the number of new or enlarging T2 hyperintense
lesions as a measure of cumulative pathological
events, the change in T2 hyperintense lesion
volume as a measure of increase in burden of
disease, and the number and volume of
gadolinium-enhancing lesions as a measure that
reflects inflammatory activity at the time of the
MRI scan.
Baseline MRI scans were conducted in all
patients during the 15-day treatment with
prednisone. Patients had MRI scans 1 and 2
months after randomization and every 6 months
until the end of the trial or development of CDMS.
Treatment arms were well balanced with respect
to baseline MRI measurements. At baseline, a
higher percentage of patients in the Avonex arm
than in the placebo arm had one or more
gadolinium-enhancing lesions: however, this
difference was not statistically significant.
After 18 months of treatment, patients treated
with Avonex had 57% fewer new or enlarging
T2 hyperintense lesions (p<O.OOO1), 91% lower
T2 hyperintense lesion volume (p=0.0001. see
Figure), and 67% fewer gadolinium-enhancing
lesions (p<0.0001) than did patients treated with
placebo. Furthermore, 82% of placebo-treated
patients had one or more T2 hyperintense lesions
after 18 months of treatment compared with 53%
of Avonex-treated patients.

		     Months
Figure. Change in T2 hyperintense lesion volume.

In Canada, Avonex is currently indicated in
the treatment of relapsing forms of MS. The
positive results of CHAMPS suggest that earlier
treatment with Avonex may offer patients more
time without development of CDMS.
In an interview after the session. Dr. Paul
O'Connor. a Canadian CHAMPS investigator,
stated, "These interesting and exciting results
suggest that interferons work best in MS when
given earlier rather than later in the disease,"

References
1.   Jacobs LD, Cookfair DL, Rudick RA. et al.
intramuscular interferon beta-la for disease
progression in relapsing multiple sclerosis. Ann
Neurol 1996:39:285-294.
2.   Rudick RA, Goodkin DE. Jacobs LD, et al.
Impact of interferon beta-la on neurologic
disability in relapsing multiple sclerosis.
Neurology 1997,49:358-363.
3.   Jacobs LD. Beck R. Simon JH, et al. Results of
a phase III trial of interferon beta-la treatment in
patients at high-risk of developing multiple
sclerosis (Abstract LBN.002]. 52nd Annual
Meeting of the American Academy of Neurology;
San Diego, April 29-May 6, 2000.
4.  Simon JH, Beck R, Jacobs LD, et at. MRI results
of a phase III trial of interferon beta-la treatment
in patients at high-risk of developing multiple
sclerosis [Abstract LBN.003]. 52nd Annual
Meeting of the American Academy of Neurology;
San Diego. April 29-May 6. 2000.

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