Randomized controlled trial of interferon- beta-1a in secondary

progressive MS: Clinical results

Secondary Progressive Efficacy Clinical Trial of Recombinant Interferon-beta-1a in MS
(SPECTRIMS) Study Group*
Neurology 2001;56;1496-1504
DOI 10.1212/WNL.56.11.1496

This information is current as of June 12, 2001

The online version of this article, along with updated information and services, is
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0028-3878. Online ISSN: 1526-632X.
Randomized controlled trial of interferon-
beta-1a in secondary progressive MS
Clinical results
Secondary Progressive Efficacy Clinical Trial of Recombinant Interferon-beta-1a in MS
(SPECTRIMS) Study Group*

Article abstract—Background: The beneficial effect of interferon beta on exacerbations in relapsing-remitting MS has
been demonstrated repeatedly, but results concerning disability vary. Objective: This multicenter, randomized, parallel-
group, placebo-controlled study tested two doses of interferon beta-1a in patients with secondary progressive MS, which
may include relapses but is dominated by accumulating disability. Methods: A total of 618 patients received subcutaneous
placebo or interferon beta-1a, 22 or 44 ␮g three times weekly for 3 years. Patients were assessed every 3 months. Results:
The primary outcome, time to confirmed progression in disability, was not significantly affected by treatment (hazard
ratio, 0.83; 95% CI, 0.65 to 1.07; p ⫽ 0.146 for 44 ␮g versus placebo). Relapse rate was reduced from 0.71 per year with
placebo to 0.50 per year with treatment (p ⬍ 0.001 for both doses). Significant treatment effects were seen on other
exacerbation-related outcomes and on a composite measure incorporating five separate clinical and MRI outcomes. The
hazard ratio for time to progression for the combined interferon beta-1a groups compared with placebo was 0.74 among
patients reporting relapses in the 2 years before study (p ⫽ 0.055), and 1.01 for those without prestudy relapses (p ⫽
0.934). An unexpected treatment-by-sex interaction favored women. The drug was well tolerated. Conclusions: Treatment
with interferon beta-1a did not significantly affect disability progression in this cohort, although significant treatment
benefit was observed on exacerbation-related outcomes. Exploratory post hoc analyses suggested greater benefit in women
and in patients who had reported at least one relapse in the 2 years before the study.
NEUROLOGY 2001;56:1496 –1504

MS is a chronic disabling disease of the CNS that
presents in either relapsing or progressive forms.
The most common form at onset, relapsing-remitting
MS (RRMS), affects 70% to 80% of patients. The
remainder of patients present with primary progres-
sive or progressive relapsing disease.1 Most patients
with RRMS eventually develop the secondary pro-
gressive (SP) form, in which disability accumulates
steadily with or without superimposed relapses.
Interferon beta (IFN␤) has demonstrated consis-
tent reductions in exacerbation frequency in both
RRMS2-4 and SPMS,5 ranging from 18% to 32% based
on intent-to-treat analysis. Dose and frequency of
administration appear to have an important effect,
particularly in the first year. Weekly doses between
66 and 132 ␮g are associated with reductions in re-
lapse rate of 33% to 37% compared with placebo dur-
ing the first year,2,4 whereas reductions of 0% to 19%
are seen with weekly doses of 22 to 44 ␮g over the
same period.2,3,6 Reduction in exacerbations in these
trials were accompanied by highly significant effects
on MRI variables, including proton density–T2-
weighted, T1-weighted– gadolinium-enhanced, and
combined unique (proton density–T2 plus T1– gado-
linium) lesion activity, proportions of scans showing
activity, and changes in lesion burden.4,7,8
Effect on disability has been less consistent: two
IFN␤-1a trials in patients with RRMS that examined
slightly different populations showed significant in-
creases in time to sustained progression over 2
years,3,4 whereas a trial of IFN␤-1b in RRMS did not
show this benefit.2
Recent data from MRS9,10 and pathologic studies11
have indicated that axonal dysfunction and damage
are more common in MS than previously believed,
and occur early in the disease course.12 These find-
ings support prompt initiation of therapy to delay or
limit the development of a more disabling phase of
MS.
A recently published trial of a single dose level of
IFN␤-1b in SPMS showed significant reduction (by 1
point) in time to sustained progression on the Ex-
panded Disability Status Scale (EDSS), with benefi-
cial effects on exacerbation rate and MRI variables.5

See also page 1505

*A complete list of the participants in the Secondary Progressive Efficacy Clinical Trial of Recombinant Interferon-beta-1a in MS (SPECTRIMS) Study Group
in provided in the Appendix on page 1503.
Funded by Serono International SA, Geneva, Switzerland.
Received June 21, 2000. Accepted in final form February 15, 2001.
Address correspondence and reprint requests to Dr. Gordon Francis, MS CDU, 15 Ch. des Mines, Geneva 1202, Switzerland; e-mail:
gordon.francis@serono.com

1496 Copyright © 2001 by AAN Enterprises, Inc.

The IFN␤-1b study was terminated after a 2-year
interim analysis demonstrated efficacy. However,
preliminary results of a second study of the same
product in SPMS showed no disability benefit.13 This
report of 3 years of therapy provides the first infor-
mation on the effects of two different doses of
IFN␤-1a in SPMS.
Patients and methods. Design. This randomized,
double-blind, placebo-controlled study enrolled 618 pa-
tients in 22 centers in Europe, Canada, and Australia.
An independent monitoring panel consisting of a statis-
tician, an interferon biologist, and two MS specialists who
were otherwise uninvolved in the study reviewed safety
data and supervised analyses. MRI analysis was per-
formed centrally by the University of British Columbia
MS/MRI Analysis Group, Vancouver.
Patient population. Eligible patients had clinically def-
inite SPMS, defined as progressive deterioration of disabil-
ity for at least 6 months with an increase of at least 1
EDSS point over the last 2 years (or 0.5 point between
EDSS score of 6.0 and 6.5), with or without superimposed
exacerbations, following an initial RR course. At study en-
try, patients were between 18 and 55 years old, with EDSS
scores from 3.0 to 6.5 and pyramidal functional score of at
least 2. Exclusion criteria included immunosuppressive or
immunomodulatory treatments during the previous 3 to 12
months depending on the drug, prior treatment with inter-
feron or total lymphoid irradiation, corticosteroid use or a
disease exacerbation in the previous 8 weeks, severe con-
current illness, and pregnancy or lactation. Potentially fer-
tile women were required to use effective contraception.
Treatments and randomization. After screening, pa-
tients were randomized to receive 22 or 44 ␮g IFN␤-1a
(Rebif; Serono International, Geneva, Switzerland) or
matching placebo subcutaneously three times a week for 3
years. Treatment was assigned using a computer-
generated randomization list provided by Serono, stratified
by center; treatments were equally allocated with a block
size of six. The block size was not revealed to the investi-
gators. Study medications were supplied as solutions. To
allow patients to adjust to the medication, the volume ad-
ministered was increased gradually over the first 4 to 8
weeks. In case of toxicity, the dose could be reduced or
treatment interrupted according to guidelines in the
protocol.
Treatment was discontinued in case of severe toxicity or
pregnancy, and could be discontinued for protocol viola-
tions, adverse events, or noncompliance. Patients who dis-
continued treatment and who consented were observed
until the end of the planned 3-year period. Patients who
withdrew were not replaced.
Acetaminophen was recommended for prevention or re-
lief of IFN side effects such as fever and influenza-like
symptoms. Steroids were to be given only for acute exacer-
bations, using a standard regimen of 1.0 g/d IV methyl-
prednisolone for 3 consecutive days.
Blinding. Solutions of IFN␤-1a and placebo were
physically indistinguishable, and packaging and labeling
were prepared to preserve blinding. The manufacturer la-
beled containers of study medication with patient identifi-
cation numbers based on the randomization list, and
patients received the medication labeled with their num-
bers. Treatment assignments were provided to investiga-
tors in sealed envelopes for emergency use: two envelopes
were opened at the request of patients who withdrew due
to adverse events.
Because IFN side effects are well recognized, a treating
physician supervised drug administration, monitored
safety, and managed adverse events, and a separate eval-
uating physician conducted neurologic assessments and
followed-up exacerbations. Patients were instructed to
cover injection sites and to discuss only neurologic matters
during neurologic evaluations. Clinical and neurologic data
were recorded in separate binders. At the end of the study
a questionnaire was administered to patients and evaluat-
ing physicians to determine the success of blinding.
Study assessments. Patients underwent clinical evalu-
ations at 3-month intervals, or more frequently in case of
exacerbations or high-frequency MRI scanning. Cranial
MRI scans were performed at baseline and every 6
months; subsets of patients underwent monthly scans.
MRI methods and results are included in this issue of
Neurology.14
Treatment effect on disability was assessed in terms of
time to confirmed progression, defined as increase from
baseline by at least 1 EDSS point (or 0.5 point if baseline
EDSS was ⱖ5.5), confirmed 3 months later with no inter-
vening score lower than the minimum required level. The
EDSS has known interrater variability: accordingly, each
patient was to be examined by the same evaluating physi-
cian throughout the study, and guidelines for evaluation of
the EDSS and other neurologic rating scales were provided
in the protocol. Confirmation of EDSS change at a second
visit was required to reduce the chance of intrarater and
intrapatient variability producing nonsustained EDSS
changes. Scoring of the EDSS was based on Kurtzke func-
tional scores up to and including an EDSS score 5.0. Above
this level, ambulation took precedence.
During the trial, an exacerbation was defined as the
appearance of a new symptom or worsening of an old
symptom attributable to MS, accompanied by an appropri-
ate new neurologic abnormality or focal neurologic dys-
function lasting at least 24 hours in the absence of fever
and preceded by stability or improvement for at least 30
days.15 Evaluating physicians described each exacerbation
and its worst observed severity in terms of change in
Scripps Neurologic Rating Scale (SNRS) score. A mild re-
lapse was defined by SNRS change of 0 to 7 points, a
moderate relapse by change of 8 to 15 points, and a severe
relapse by change of more than 15 points. Where SNRS
evaluation was not possible, severity was described in
terms of effects on the activities of daily living (ADL): mild
attacks did not interfere with ADL, moderate attacks im-
paired but did not prevent ADL, and severe attacks re-
quired hospitalization. Adverse events and changes in
concomitant medications were followed throughout the
study, and clinical laboratory evaluation was performed at
the 3-month evaluation visits or as needed.
Patients were tested for neutralizing antibodies to IFN␤
at 6-month intervals using a viral cytopathic bioassay
(data on file); positivity was defined as a titer of at least 20
neutralizing units per milliliter.
Because of concerns about a possible association of
IFN␤ with depression, psychological instruments were ad-
ministered to the 337 patients in English-speaking centers
June (1 of 2) 2001 NEUROLOGY 56 1497
(the General Health Questionnaire,16 the Center for Epide-
miologic Studies Depression Mood Scale,17 and the Beck
Hopelessness Scale18).
Analyses and outcomes. The primary efficacy outcome
was time to confirmed progression in disability, as defined
above. This outcome included all study time including
month 36; for patients progressing for the first time at 36
months, confirmation used the EDSS score from the month
39 visit (during the study’s extension phase). Time to con-
firmed progression was analyzed using the Cox propor-
tional hazards (PH) model. Hazard ratios (HR, with 95%
CI and p values) smaller than 1.0 indicate a reduced risk
of the event (progression) compared with a reference group
(placebo). The assumption of proportional hazards was as-
sessed by the inclusion of a time-dependent covariate.
Time-to-progression curves were constructed using the
Kaplan–Meier method. Because the primary comparison
was between the 44-␮g dose of IFN␤-1a and placebo, no
adjustment was made for multiple comparisons. Differ-
ences between the low-dose and placebo groups were ex-
amined for information and assessment of dose effect.
A significant treatment-by-sex interaction in the pri-
mary outcome prompted further analyses. A list of poten-
tially important covariates was defined by an investigator
liaison committee after study unblinding but before analy-
ses were undertaken. The association of these factors with
time to progression was analyzed using the Cox PH model
in conjunction with the likelihood ratio test.
Secondary clinical outcomes (with corresponding regres-
sion methods) included proportion of patients progressing
(logistic), exacerbation count (Poisson), time to first exacerba-
tion (Cox PH), time between first and second exacerbations
(Cox PH), number of moderate and severe exacerbations
(Poisson), number of steroid courses for MS (Poisson), num-
ber of hospitalizations for MS (Poisson), and Integrated Dis-
ability Status Score (IDSS, defined by area under an EDSS
time-curve adjusted for baseline19; analysis of variance on
ranks). All models included center as a covariate, and all
Poisson and logistic regression models included time on study
as an offset. The likelihood ratio test was used to evaluate
the significance of interaction terms incorporated in models.
Proportions of patients experiencing adverse events were
compared across treatments using either ␹2 or Fisher’s exact
tests, as appropriate.
Composite measures permit summarization of results
from multiple outcomes in complex diseases like MS, al-
lowing assessment of overall treatment efficacy. In this
study, a prospectively defined composite score was deter-
mined using rank values for five major outcomes: time to
progression, exacerbation rate, MRI lesion burden, MRI T2
activity, and IDSS.20 Log rank scores were used for time to
progression in calculating the composite score.
Serono Biometrics (Geneva) performed statistical analy-
sis, using SAS (SAS Institute, Cary, NC) and S-Plus soft-
ware (Math Soft, Cambridge, MA). All p values were
derived from two-sided significance tests. Analyses were
performed on an intent-to-treat basis, including all ran-
domly assigned patients. Patients who dropped out were
considered as censored at the time of dropout for time-to-
event outcomes, and their time on study was used for
event count analyses. No imputation was used for any
outcome.
Two subgroup analyses were undertaken at the request
1498 NEUROLOGY 56 June (1 of 2) 2001
of regulatory authorities: patients were grouped by sex and
by presence or absence of relapses in the 2 years preceding
the study. In the subgroup analysis by presence or absence
of before-study relapses, active treatment groups were
combined to maintain statistical power. It should be noted
that p values obtained from subgroup and exploratory
analyses do not have their nominal type I error value and
should be interpreted with caution.
Sample size and interim analysis. Natural history
studies suggested that 60% of placebo-treated patients
would progress by 1 EDSS point over 3 years. On the
assumption that 40% of patients treated with high-dose
IFN would progress, it was determined that for 80% power
and a significance level of 0.05 (allowing for one interim
analysis), 98 evaluable patients per group were needed to
detect significant difference between placebo and high-dose
IFN in the proportion of patients progressing (log-rank
test). Based on an estimated 20% dropout rate, 118 pa-
tients per group would be enrolled. Centers recruited much
faster than expected, leading to over-enrollment. The deci-
sion to continue accrual was not based on interim results;
the interim analysis was not performed until accrual had
been completed. The increased number of patients allowed
for 80% power to determine a smaller reduction (from 60%
for placebo to 46% for high-dose IFN) in the proportion of
patients who would progress by 1 EDSS point over 3 years.
An interim analysis was performed when 300 patients
had completed 18 months of treatment to allow for early
stopping of the study or termination of the placebo arm.
Only the primary outcome was analyzed. The study was to
be stopped for significance in favor of placebo (p ⫽ 0.005,
two-sided). If the treatment were significantly better
(p ⫽ 0.005) than placebo, patients receiving placebo would
be randomly reassigned to one of the two IFN doses. Re-
sults were presented to the independent monitoring panel,
which decided that the study should continue to its
planned termination. The final analysis of the primary
outcome was performed with a nominal significance level
of 0.048.
Ethics. The study was conducted in accordance with
the Declaration of Helsinki. Consent was obtained from
the ethics committees of all participating institutions be-
fore study initiation. Written informed consent was ob-
tained from all patients before beginning prestudy
assessments.
Results. Study population and patient disposition. Of
618 patients enrolled, 506 (82%) completed 3 years of
treatment, and an additional 65 who stopped therapy were
followed for the remainder of the 3 years, providing full
data for 92.4% of patients (figure 1). One hundred twelve
patients discontinued therapy prematurely (18%). Reasons
for discontinuation included adverse events (38 patients: 5
placebo, 15 low-dose and 18 high-dose IFN), disease pro-
gression (20 patients: nine placebo, seven low-dose and
four high-dose IFN), death (four patients: one placebo, one
low-dose and two high-dose IFN; a second placebo-treated
patient died during follow-up), protocol deviation (four pa-
tients: one low-dose and three high-dose IFN) and patient
decision (44 patients: 17 placebo, 12 low-dose and 15 high-
dose IFN). Forty-seven (47) patients were lost to follow-up,
14 each in the high-dose and low-dose IFN groups and 19
in the placebo group. Baseline characteristics were similar
among treatment groups (table 1).

Figure 1. Patient enrollment and disposition.
Disability progression (primary endpoint). The differ-
ence in time to sustained progression in disability between
patients receiving 44 ␮g IFN␤-1a and placebo was not
significant (p ⫽ 0.146; figure 2 and table 2). A transient
effect of the high dose was observed, lasting approximately
1 year. No significant difference was noted between pa-
tients receiving low-dose IFN and placebo (HR ⫽ 0.88; p ⫽
0.305). The assumption of PH in this model was examined
by incorporation of a time-varying component in the Cox
PH model, and was not found to be violated. Subgroup
analyses required by regulatory authorities highlighted a
difference in treatment effect between male and female
patients (figure 3). Detection of a treatment-by-sex interac-
tion (p ⫽ 0.035) confirmed this difference, which had not
been anticipated. Women, comprising 62% of the study
population, showed delay in progression compared with
placebo at both doses (p ⫽ 0.006 for 44 ␮g and p ⫽ 0.038
for 22 ␮g), whereas men did not. Unexpectedly, a differ-
ence was seen in placebo group behavior as well: male
patients had consistently better outcomes than female pa-
tients receiving placebo, although only time to progression
Figure 2. Kaplan–Meier curves for time to confirmed Ex-
panded Disability Status Scale (EDSS) progression for all
patients.
differed significantly (HR ⫽ 0.64; 95% CI, 0.43 to 0.95; p ⫽
0.016). In an attempt to explain these differences, baseline
characteristics (age, EDSS, before-study EDSS change, du-
ration of MS or SPMS, SNRS, Ambulation Index, before-
study relapse rate, and baseline MRI lesion burden) were
examined with respect to sex. No significant imbalances
were found.
In a further attempt to explain the treatment-by-sex
interaction for the primary outcome, the investigator liai-
son committee was asked to identify other factors that
might directly influence time to progression. Age, before-
study relapse rate and change in EDSS, disease duration,
duration of the SP phase, body mass index, baseline EDSS,
SNRS, Ambulation Index, and pyramidal scores were pro-
spectively identified. Their association with time to pro-
gression was analyzed using the Cox PH model, and three
factors were found to be joint significant predictors: base-
line SNRS (low score unfavorable), duration of SP disease
(long duration unfavorable), and rate of EDSS change pre-
ceding the study (rapid change favorable). Duration of SP
disease, prestudy exacerbation rates, and prestudy
changes in EDSS were determined from medical records or

Table 1 Baseline characteristics by treatment group

All, Placebo, IFN␤-1a 22 ␮g, IFN␤-1a 44 ␮g,

Characteristics n ⫽ 618 n ⫽ 205 n ⫽ 209 n ⫽ 204

Age, y 42.8 (7.1) 42.7 (6.8) 43.1 (7.2) 42.6 (7.3)

Percent female 63 60 62 67
Percent exacerbation-free over 2 years before 53 52 54 52
entry (n ⫽ 616)
Exacerbations in 2 years before study (n ⫽ 616) 0.9 (1.3) 0.9 (1.2) 0.9 (1.4) 0.9 (1.3)
EDSS score at entry 5.4 (1.1) 5.4 (1.1) 5.5 (1.1) 5.3 (1.1)
Change in EDSS score over 2 years before study 1.6 (0.9) 1.7 (1.0) 1.6 (0.9) 1.5 (0.8)
(n ⫽ 616)
Duration of MS, y 13.3 (7.1) 13.7 (7.2) 13.3 (7.4) 12.9 (6.9)
Duration of SPMS, y 4.0 (3.0) 4.1 (3.2) 4.2 (3.1) 3.7 (2.7)
SNRS score (n ⫽ 617) 63.5 (11.8) 63.4 (12.2) 63.1 (12.0) 63.9 (11.3)
Ambulation index 3.6 (1.4) 3.6 (1.4) 3.7 (1.4) 3.5 (1.4)

Data are mean (SD) except where specified.

SNRS ⫽ Scripps Neurologic Rating Scale; EDSS ⫽ Expanded Disability Status Scale; IFN ⫽ interferon; SPMS ⫽ secondary progressive MS.
June (1 of 2) 2001 NEUROLOGY 56 1499
Table 2 Hazard ratios for time to progression based on protocol- ence or absence of before-study relapses was not
defined planned analysis (adjusted for center), covariate-adjusted significant (p ⫽ 0.289, Cox PH). OR for the proportion of
analysis (center, SNRS, duration of SPMS disease, rate of patients progressing in the combined IFN␤-1a groups com-
progression before study), and subgroup analyses based on
pared with placebo was 0.52 for patients with (95% CI,
presence or absence of prestudy relapses and sex
0.29 to 0.93; p ⫽ 0.027) and 1.07 for patients without
Hazard prestudy relapses (95% CI: 0.64 –1.78, p ⫽ 0.802). HR for
Variable ratio 95% CI p Value time to first progression for IFN-treated relapsing patients
was 0.74 compared with placebo (p ⫽ 0.055), whereas HR
Planned analysis 0.83 0.65–1.07 0.146
for IFN-treated patients without relapse was 1.01 com-
Adjusted analysis 0.78 0.60–1.00 0.046 pared with placebo (p ⫽ 0.934). The HR for time to pro-
Patients with prestudy 0.76 0.53–1.10 0.142 gression for patients treated with 44 ␮g IFN␤-1a compared
relapse with placebo was 0.76 for relapsing (p ⫽ 0.14) and 0.93 for
Patients without prestudy 0.93 0.65–1.33 0.688 nonrelapsing patients (p ⫽ 0.69).
relapse Exacerbations. A highly significant benefit was seen
on exacerbation rate for both doses. Treatment benefit was
Female patients 0.63 0.45–0.87 0.006
also observed with respect to time to first exacerbation,
Male patients 1.30 0.85–2.01 0.226 time between first and second exacerbations, numbers of
All comparisons 44-␮g versus placebo groups; treatment effects moderate and severe exacerbations, steroid use, and hospi-
in the 22-␮g group followed the same patterns but were smaller talization (table 3). Relapse rates in men were 0.49 per
in magnitude. year for 44 ␮g IFN, 0.43 for 22 ␮g IFN, and 0.66 for
SNRS ⫽ Scripps Neurologic Rating Scale; SPMS ⫽ secondary placebo (p ⫽ 0.007 for 44 ␮g versus placebo and p ⫽ 0.025
progressive MS. for 22 ␮g versus placebo). In women, corresponding rates
were 0.51 for 44 ␮g IFN, 0.53 for 22 ␮g IFN, and 0.75 for
from retrospective review. Although these numbers may be placebo (p ⫽ 0.009 for 44 ␮g versus placebo and p ⫽ 0.012
somewhat inaccurate, there is no reason to believe that for 22 ␮g versus placebo). There was no treatment-by-sex
this inaccuracy would affect treatment comparisons. When interaction for this measure (p ⫽ 0.888). As with EDSS
these three factors were added to the Cox PH model, a progression, treatment effect was greater in the subgroup
stronger treatment effect on time to progression was de- with than the subgroup without prestudy relapse (treat-
tected (for 44 ␮g IFN␤-1a compared with placebo, HR ⫽ ment by relapse history interaction: p ⫽ 0.004). With treat-
0.78; 95% CI, 0.60 to 1.00; p ⫽ 0.046). However, adjust- ment, relapse rates among patients with prestudy relapse
ment for these covariates failed to lessen the treatment-by- were 0.57 per year for the 22 ␮g group and 0.67 for 44 ␮g
sex interaction. IFN groups versus 1.08 per year for placebo (p ⬍ 0.001 for
Patients with SPMS may or may not continue to experi- both doses compared with placebo). Corresponding rates
ence relapses. Therefore, the main study outcome mea- among nonrelapsing patients were 0.43 and 0.36 per year
sures were analyzed separately for patients who did (n ⫽ (p value for both nonsignificant compared with the placebo
293) and did not report (n ⫽ 325) relapses during the 2 rate of 0.39 per year).
years preceding the study. The subgroup with relapses Composite score. The composite score showed a
before the study was significantly younger, had a shorter marked treatment benefit for each dose (p ⬍ 0.001). A
duration of disease, and had deteriorated slightly faster treatment-by-sex interaction (p ⫽ 0.014) was observed for
than the nonrelapsing group at baseline (data not shown). this outcome.
Patients with before-study relapses were more likely to Safety. Adverse event data are presented in table 4.
benefit from therapy with respect to time to confirmed IFN␤-1a was well tolerated. The most frequent adverse
progression (figure 4 and table 2). It should be noted, how- events clearly associated with treatment were application
ever, that the interaction between treatment and the pres- site disorders, flulike symptoms, and lymphopenia. Treat-
ment was interrupted or the dose reduced because of ad-
verse events in 22 patients receiving placebo, 40 receiving
22 ␮g IFN, and 66 receiving 44 ␮g IFN, of whom only three
patients receiving placebo, eight receiving 22 ␮g, and
seven receiving 44 ␮g permanently discontinued treat-
ment. Liver function abnormalities were more common
with active treatment; however, these were generally mild
or moderate and either resolved with treatment interrup-
tion or were not severe enough to warrant intervention.
Injection site necrosis was reported nine times in seven
patients receiving 22 ␮g IFN and 22 times in 18 patients
receiving 44 ␮g IFN, yielding rates of one episode of necro-
sis per 9,600 injections for 22 ␮g and one per 3,800 injec-
tions for 44 ␮g. One episode of necrosis required surgical
intervention, and three patients stopped treatment be-
cause of this event. Five patients died: one patient receiv-
Figure 3. Kaplan–Meier curves for time to confirmed Ex- ing placebo had a presumed subarachnoid hemorrhage,
panded Disability Status Scale (EDSS) progression for one patient in each treatment group (including placebo)
male and female patients. committed suicide, and one patient receiving 44 ␮g had an
1500 NEUROLOGY 56 June (1 of 2) 2001

Figure 4. Kaplan–Meier curves for time to confirmed Ex-
panded Disability Status Scale (EDSS) progression for
patients with and without relapses during the 2 years be-
fore the study.
intracerebral hemorrhage. Three patients receiving pla-
cebo, three receiving low-dose IFN, and two receiving high-
dose IFN attempted suicide. Depression was reported in
29% of patients receiving placebo, 32% receiving low-dose
IFN, and 35% receiving high-dose IFN. One patient receiv-
ing placebo, five receiving 22 ␮g, and six receiving 44 ␮g
discontinued therapy due to depression (overall treatment
difference: p ⫽ 0.038, Fisher’s exact test). There were,
however, no significant differences between groups in re-
sults of the General Health Questionnaire, Center for Epi-
demiologic Studies Depression scale or Beck Hopelessness
Scale, either at baseline or during the study.
Results of neutralizing antibody (NAb) testing are
shown in table 5. The rate of NAb development was higher
in the group receiving 22 ␮g IFN than those receiving 44
␮g. The majority of NAb developed during the first 18
months of treatment. Development of NAb did not affect
the primary outcome, but there was a suggestion of re-
duced effect on relapses for NAb-positive patients in the 44
␮g group, in which the difference between NAb-positive
patients and those receiving placebo was no longer signifi-
cant (patients with at least one positive titer ⬎ 20 NU/L
were considered NAb-positive). However, the numbers of
patients involved were small.
Blinding. Evaluating physicians guessed treatment
assignments correctly for 29% of patients on active treat-
ment and 26% of patients on placebo. They were incorrect
for 16% of patients on active treatment and 18% of pa-
tients on placebo, and gave no opinion for the rest. Fifty-
nine percent of patients on active treatment and 52% on
placebo guessed their treatment correctly. In the high-dose
group 64% guessed correctly, whereas in the low-dose
group 54% guessed correctly. Patients were incorrect in
21% of active and 27% of placebo cases, and gave no opin-
ion in 20% of cases in the active group and 21% in the
placebo group.
Discussion. This study provides important new
information about IFN use in MS, and in particular
helps to clarify the role of IFN in SPMS. The analy-
sis of the primary outcome, time to sustained pro-
gression, showed minimal evidence of treatment
effect (HR ⫽ 0.83) which did not reach statistical
significance. Despite the lack of significant benefit on
the primary outcome, all secondary outcomes showed
a response to treatment, and the composite score
provided evidence of treatment benefit in this pa-
tient group when multiple endpoints were consid-
ered. The lack of benefit on disability progression was
disappointing given the clinical importance of this out-
come, and initially appeared to contradict the findings
of the European study of IFN␤-1b in SPMS. However,
the results are consistent with those of a more recent
study using the same medication (see below).
Clearly IFN does not provide the same spectrum
of benefits in SPMS as in RRMS. However, absence
of efficacy in this population would be an erroneous
conclusion.
Results of this study were affected by an unex-
pected treatment-by-sex interaction. Additional anal-
yses prompted by this finding and by requests from
health authorities suggested that different sub-
groups of SPMS patients may experience different
responses to treatment.
Analysis by sex showed a significant benefit on
disability progression with both doses in women, but
no benefit in men for this outcome. IFN therapy
showed efficacy on all secondary measures in both
sexes. There are several possible explanations for
this finding. First, women may indeed respond better
to IFN than men, but this finding would be new and
there is no supporting evidence in the literature.
However, additional findings from the European
study of IFN␤-1b in patients with SPMS allude to a
slightly worse treatment outcome in men.21 Second,
baseline characteristics could have been unbalanced,
but close examination showed that there were no
significant differences between groups. Third, vari-
ability in the assessment of disability may have af-
fected the results. However, the finding of similar
treatment-by-sex interactions for MRI measures14 ar-
gues against this explanation. Finally, sex may be a
proxy factor for one or more unmeasured clinical fea-
tures. As a definitive explanation for this interaction
is not evident after extensive review of the data, the
effect of chance must be considered. The combination
of an unexpected difference in time to progression
between male and female patients receiving placebo
and a difference in male and female response to IFN
in SPMS could produce the interaction found. It will
June (1 of 2) 2001 NEUROLOGY 56 1501
Table 3 Exacerbation-related outcomes (all patients)

Placebo IFN␤-1a Contrast: IFN␤-1a Contrast:

Outcomes n ⫽ 205 22 ␮g, n ⫽ 209 22 ␮g vs placebo 44 ␮g, n ⫽ 204 44 ␮g vs placebo

Mean exacerbations per 0.71 0.50 RR ⫽ 0.69 0.50 RR ⫽ 0.69

person-year (0.65–0.78) (0.44–0.56) (0.56–0.84) (0.45–0.56) (0.56–0.85)
p ⬍0.001 p ⬍0.001
Median time to first 281 476 HR ⫽ 0.87 494 HR ⫽ 0.77
exacerbation, d* (167–395) (307–645) (0.69–1.10) (303–685) (0.61–0.98)
p ⫽ 0.237 p ⫽ 0.034
Median time between 279 572 HR ⫽ 0.50 511 HR ⫽ 0.60
first and second (181–377) (241–903) (0.37–0.69) (314–708) (0.44–0.81)
exacerbation, d* p ⬍0.001 p ⫽ 0.001
Mean moderate and 0.39 0.26 RR ⫽ 0.66 0.27 RR ⫽ 0.68
severe exacerbations (0.34–0.44) (0.22–0.31) (0.51–0.86) (0.23–0.31) (0.52–0.87)
per person-year, n p ⫽ 0.002 p ⫽ 0.003
Mean steroid courses per 0.52 0.31 RR ⫽ 0.59 0.34 RR ⫽ 0.66
person-year (0.46–0.58) (0.27–0.36) (0.44–0.81) (0.30–0.39) (0.49–0.89)
p ⫽ 0.001 p ⫽ 0.006
Mean hospitalizations 0.22 0.14 RR ⫽ 0.64 0.15 RR ⫽ 0.63
per person-year (0.18–0.26) (0.11–0.17) (0.46–0.88) (0.12–0.18) (0.46–0.88)
p ⫽ 0.006 p ⫽ 0.005

Numbers in parentheses for individual treatment groups are 95% CI.

* Median survival time, estimated by Kaplan–Meier method.

RR ⫽ rate ratio (Poisson regression model, with center as covariate), with 95% CI; HR: hazard ratio (Cox proportional hazards model,
with center as covariate), with 95% CI.

be important to evaluate this finding prospectively in benefit was shown on all other outcomes. These dis-
subsequent studies. crepant results require consideration.
An additional post hoc analysis requested by To put the findings of these three studies into
health authorities examined the impact of relapses perspective, it is important to consider possible ex-
in the 2 years before study entry on subsequent re- planations for the apparent difference in the main
lapses, disease progression, and response to therapy. outcome. These differences include a shorter obser-
Patients who had reported at least one relapse dur- vation period in the European IFN␤-1b study due to
ing this period had a generally less-advanced disease early termination (2 years compared with 3), shorter
course. In the combined treatment groups, those duration of the prerandomization SP phase in the
with at least one prestudy relapse showed better European IFN␤-1b study (2.2 years compared with
treatment response compared with placebo than
those without prestudy relapses, with respect to both Table 4 Reported adverse events of interest with interferon
progression and relapse rate. These data suggest therapy (all values are percentages)
that IFN therapy has clinical benefit in SPMS, pre-
dominantly affecting relapses, but has only a modest IFN␤-1a IFN␤-1a
effect on disability in those patients still experienc- Placebo, 22 ␮g, 44 ␮g,
Adverse event n ⫽ 205 n ⫽ 209 n ⫽ 204
ing relapses during the few years before treatment
initiation. This finding suggests that treatment early Flulike symptoms 52 51 50
in the disease course, when relapses are usually more Application site disorders 41 81* 87*
frequent, may be more effective than later therapy.
Leukopenia 5 11* 21*
The results on disability in this study differ from
those of the European trial of IFN␤-1b in SPMS, in Lymphopenia 15 22 26*
which there was a significant increase in time to Increased alanine 7 21* 23*
sustained progression in disability with IFN␤-1b aminotransferase (SGPT)
compared with placebo.5 Neither the level of disabil- Increased aspartate 3 12* 13*
ity nor the presence of relapses was reported to affect aminotransferase (SGOT)
outcome. However, the recently reported North Depression 29 32 35
American study of IFN␤-1b in SPMS13 found no ef-
fect on time to confirmed progression (p ⫽ 0.71), The table lists interferon-related adverse events that were re-
although as in the present study (Secondary Progres- ported at least once, regardless of the investigator’s judgment of
severity or causality.
sive Efficacy Clinical Trial of Recombinant
Interferon-beta-1a in MS [SPECTRIMS]) significant * Indicates significant difference from placebo (p ⬍ 0.05).
1502 NEUROLOGY 56 June (1 of 2) 2001
Table 5 Neutralizing antibody formation
IFN␤-1a IFN␤-1a
Placebo, 22 ␮g, 44 ␮g,
Antibodies n ⫽ 205 n ⫽ 209 n ⫽ 204
No. (%) with antibodies 1 (0.5) 43 (20.6) 30 (14.7)
(titer ⱖ20 NU/mL)
No. (%) who lost antibodies 1 (0.5) 13 (6.2) 20 (9.8)
Median time to
progression, d
NAb⫺ 638 729 576
NAb⫹ — 818 730
Exacerbations per year
NAb⫺ 0.71 0.52* 0.47†
NAb⫹ — 0.45* 0.60
All within-group comparisons of neutralizing antibody (NAb)⫹
and NAb⫺ patients were nonsignificant.
Positivity was defined as having any sample with a titer ⱖ20
neutralizing units (NU)/mL. Loss of positivity was defined as a
negative result at the final assessment after a previous titer ⱖ20
NU/mL.
* p ⬍ 0.01 compared to placebo.
† p ⬍ 0.001 compared to placebo.
4.0 in the other trials, although definitions may
vary), a higher rate of treatment discontinuation in
the European IFN␤-1b study despite the shorter ob-
servation period, and most importantly, a higher
proportion of patients with prestudy relapses in the
European IFN␤-1b study (70% versus 48% in SPEC-
TRIMS and 45% in the North American study). As
discussed previously, patients in SPECTRIMS who
experienced prestudy relapses responded best to IFN
according to all outcome measures, including the pri-
mary outcome; this would partially explain the differ-
ence in results between the European IFN␤-1b study
and the SPECTRIMS and North American studies.
The CI of the OR for the proportion of treated
patients who progressed on treatment compared
with placebo (adjusted for center and baseline EDSS)
from SPECTRIMS and the original report of the Eu-
ropean IFN␤-1b study overlap: 0.74 (95% CI, 0.46 to
1.20) for SPECTRIMS and 0.65 (95% CI, 0.52 to
0.83) for the European study. The differences in pa-
tient characteristics and study duration, coupled
with review of the OR for progression, suggest that
any difference in results between these two SPMS
studies is due to patient variability and differences
in the populations studied and the duration of obser-
vation, or to chance. The data further support the
hypothesis that IFN␤ has beneficial effects predomi-
nantly on the presumed inflammatory components of
MS (such as relapses and MRI activity), with at best a
modest effect on continuous progression in disability.
The OR for disability progression in the Prevention of
Relapses and Disability by Interferon-beta-1a Subcuta-
neously in Multiple Sclerosis (PRISMS) study of RRMS
was 0.58 (95% CI, 0.35 to 0.96), which is lower than
that in either of the SPMS trials. As one moves from
pure RRMS into more progressive SPMS, less effect is
seen on disability progression: this finding argues fur-
ther in favor of treatment for MS patients still experi-
encing relapses.
As reported in the companion paper to this arti-
cle,14 both doses significantly reduced MRI T2 activ-
ity, lesion burden accumulation, and combined
unique lesion activity.
The lack of significant impact on disability despite
dramatic effects on relapses supports a recent re-
vival of interest in the contribution of axonal damage
to clinical disability. Relapses and MRI measures are
thought to reflect mostly inflammatory changes,
whereas persistent disability probably also reflects
axonal loss. The observed difference in efficacy be-
tween relapse and disability outcomes suggests that
the axonal damage believed to underlie progressive
accumulation of disability may result from other
pathogenetic mechanisms besides the inflammation
associated with relapsing disease,11 or that there
may be a time lag between inflammation and conse-
quent axonal destruction. The putative additional
mechanisms contributing to axonal dysfunction and
destruction remain unknown, but may involve direct
injury, bystander effects, or a loss of trophic factors.
The adverse event profile of IFN␤-1a in the
present trial was similar to that in PRISMS.4 Over-
all, treatment was well tolerated: 82% of patients
receiving low-dose and 84% of patients receiving
high-dose IFN remained on treatment at 36 months,
compared with 79% of patients receiving placebo.
In conclusion, this study failed to show significant
impact on time to sustained progression of disability.
However, the trial confirmed that IFN␤-1a is as well
tolerated and efficacious with respect to exacerbation-
related and MRI outcomes in SPMS as it is in RRMS.
Subgroup analyses suggest that the maximal benefit of
treatment in SPMS is seen in women and in patients
still experiencing relapses when treatment is started,
and it would appear reasonable to consider treatment
with IFN␤-1a for such patients. Further detailed data
regarding the use of IFN␤ in SPMS are eagerly
awaited to clarify the efficacy of this therapy in more
advanced MS.
Acknowledgment
In addition to the many site personnel instrumental in the suc-
cessful conduct of the study, the authors thank A. Abdul-Ahad, J.
Alsop, K. Diab, M. Dubourgeat, F. Dupont, R. Furcha, S. Gerin, A.
Jaccottet, T. Mattioni, M. Olson, M.-O. Pernin, M. Stam Moraga,
and B. Vayssier-Lemaire of Serono for their contributions to the
study, A. Dubois (Serono medical writer) for manuscript assis-
tance, and the patients who participated in this clinical trial.
Study monitoring was performed by Serono Clinical Research
Associates.
Appendix
The SPECTRIMS study group consists of the following individu-
als. Australia: J. King, Royal Melbourne Hospital, Melbourne; J.
McLeod, University of Sydney, New South Wales. Belgium: R.E.
Gonsette, National Center for MS, Melsbroek. Canada: P. Du-
quette, Hôpital Notre-Dame, Montréal, Quebec; G. Ebers and G.
Rice, University Hospital, University of Western Ontario, London,
Ontario; G. Francis and Y. Lapierre, Montréal Neurologic Insti-
June (1 of 2) 2001 NEUROLOGY 56 1503
tute and Hospital, Montréal, Quebec; M.S. Freedman, Ottawa
General Hospital, University of Ottawa, Ontario; J. Oger and D.
Paty, Vancouver Hospital, University of British Columbia, Van-
couver. Denmark: P. Soelberg Sørensen, The National University
Hospital, Copenhagen. France: J. Pelletier, CHU La Timone, Mar-
seille. The Netherlands: O.R. Hommes and P.J.H. Jongen, Stich-
ting MS Centrum, Nijmegen; E.A.C.M. Sanders, Ignatius
Hospital, Breda. Sweden: O. Andersen, Sahlgrenska University
Hospital, Göteborg; M. Sandberg-Wollheim, University Hospital,
Lund University, Lund. Switzerland: M. Chofflon, Cantonal Hos-
pital, University of Geneva. United Kingdom: D. Bates, Royal
Victoria Hospital, Newcastle; D. Barnes, Atkinson Morley Hospi-
tal, London; L.D. Blumhardt, University Hospital, University of
Nottingham; C. Hawkins, Royal Infirmary, North Staffordshire
Hospital, Stoke-on-Trent; R.A.C. Hughes, Guy’s Hospital, Guy’s,
King’s and St Thomas’ School of Medicine, London; J. Palace and
J.M. Newsom-Davis, Radcliffe Infirmary, University of Oxford;
C.A. Young, Walton Center for Neurology and Neurosurgery, Liv-
erpool. Switzerland: N. Ammoury, M. Bacchi, G. Francis, A. Ga-
lazka, R. Hyde, S. Shah, Serono International SA, Geneva.
The SPECTRIMS investigator liaison committee consists of
R.A.C. Hughes (chair), O. Hommes, D. Paty, and M. Sandberg-
Wollheim. The writing committee consists of R.A.C. Hughes
(chair), O. Hommes, D. Li, D. Paty, M. Sandberg-Wollheim, P.
Soelberg Sørensen, and G. Francis. Members of these committees
have received honoraria for lecturing, travel expenses for attend-
ing meetings, and financial support for their departments from
Serono.
The independent monitoring panel consisted of J. Noseworthy
(chair) and P. O’Brien, Mayo Clinic, Rochester, MN; E. Borden,
Cleveland Clinic, Cleveland, OH; and J. Wolinsky, University of
Texas, Houston, TX.
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 Randomized controlled trial of interferon- beta-1a in secondary progressive MS:
Clinical results
Secondary Progressive Efficacy Clinical Trial of Recombinant Interferon-beta-1a in MS
(SPECTRIMS) Study Group*
Neurology 2001;56;1496-1504
DOI 10.1212/WNL.56.11.1496

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