Evidence Table 15Characteristics of trials in patients with clinically isolated syndrome

Author
Year
Country
Trial name
Study design
Setting
Inclusion/exclusion criteriaInterventionsAge
Gender
Ethnicity
Other population characteristicsNumber screened/eligible/enrolledNumber withdrawn/lost to follow- up/analyzedResultsMethod of adverse events assessmentAdverse events reportedTotal withdrawals; withdrawals due to adverse eventsFundingComments
Comi
2009
16 countries; 80 sites from USA, Europe, Argentina, Australia and New Zealand

PreCISe Study
DB
RCT (3 year)
Placebo-controlled
Parallel
Multicenter
Inclusion: Age 18–45 years; one unifocal neurological event, and positive brain MRI at screening scan (at least 2 cerebral lesions on the T2- weighted images at least 6 mm in diameter - lesions on 2 consecutive slices each of which was 3 mm thick); enrolled within 90 days after onset of first clinical attack

Exclusion: multifocal clinical presentation; diseases other than MS responsible for the clinical or MRI presentation; use of experimental or investigational drugs; any use of IFN β or chronic corticosteroids treatment within 6 months of screening; a relapse between screening and BL visits; pregnancy or breastfeeding; known sensitivity to mannitol or gadolinium
GA 2 mg daily SQ injection (n=243)

Placebo daily SQ injection (n=238)
Mean age (SD): 31.2 (6.9)
Median (range): 30.5 (18.1–45.8)

33% male
67% female

96% white
4% other
Mean number of T2 lesions (SD): 31.5 (30.7)

Mean volume of T2 lesions (SD): 6.0 (6.9) mL

Mean brain volume (SD): 1540 (105) mL

Mean number of gadolinium enhancing lesions (SD): 1.5 (2.9)

Mean volume of gadolinium enhancing lesions (SD): 0.3 (0.6) mL
Screened: 619
Eligible: 481
Enrolled: 481
GA (n=243) vs Placebo (n=238)

WDs: 37 (15.2%) vs 21 (8.8%)

Loss to FU: NR

Analyzed: 243 vs 238
GA (n=243) vs Placebo (n=238)

Risk of conversion to clinically definite MS: HR, 0.55; 95% CI, 0.40 to 0.77; P=0.0005

Time of conversion to clinically definite MS (based on 25% of patients who converted): 336 days vs 722 days; P=0.0041

Number of new T2 lesions: 0.7 vs 1.8; RR, 0.42; 95% CI, 0.29 to 0.61

T2 lesions volume: reduction in GA compared to P; geometric means ratio 0.75; 95% CI, 0.64 to 0.87; P=0.0002

Percent change from BL in brain volume: −0.33% vs −0.38%; P=NS

Proportion of patients converted: 42.9% vs 24.7%; OR, 0.41; 95% CI, 0.28 to 0.62; P<0.0001
Assessments included AEs, standard clinical laboratory tests, vital signs, weight, physical examinations, and electrocardiograph measurementsGA vs Placebo
ISRs: 135 (56%) vs 56 (24%)
Immediate post-injection reactions: 47 (19%) vs 12 (5%)
Lymphadenopathy: 13 (5.3%) vs 1 (0.4%)
Urticaria: 6 (2.5%) vs 1 (0.4%)
Influenza-like illness: 10 (4.1%) vs 2 (0.8%)
Constipation: 6 (2.5%) vs 2 (0.8%)
Pruritus: 9 (3.7%) vs 3 (1.3%)
Erythema: 9 (3.7%) vs 3 (1.3%)
Vomiting: 14 (5.8%) vs 5 (2.1%)
Rash: 8 (3.3%) vs 3 (1.3%)
Vision blurred: 5 (2.1%) vs 0 (0%)
Injection-site necrosis: 2 (0.8%) vs 0 (0%)
Injection-site atrophy or lipoatrophy: 10 (3%) vs 0 (0%)
Suicide: 1 (0.4%) vs 0 (0%) - occurred during day 50 of GA treatment
Serious AEs occurred in 19 (8%) of patients in GA group and in 11 (5%) in the placebo group.
GA vs Placebo
WDs: 37 (15.2%) vs 21 (8.8%)
AE WDs: 14 (5.8%) vs 4 (1.7%); P=0.0184
Funded by Teva Pharmaceutical Industries

The sponsor was involved in the study design, conduct, monitoring, data analysis, and writing of the report.
Efficacy Analysis: Results are findings from the interim analysis that occurred when patients had a mean overall exposure to GA of 2.32 years (SD 0.65).

Note: Placebo group was stopped after reviewing data at interim analysis and the Drug Monitoring Committee recommended that patients in the placebo group receive GA in the open label extension.

193 (40%) patients were still in the DB phase at the cut-off date of the interim analysis; 230 (48%) patients completed the DB phase either because of conversion to clinically definite MS or after 3 years of treatment.

No major differences between the two groups in laboratory, vital signs, and electrocardiograph findings (data NR)
Comi; Fillipi
2001; 2004
ETOMS
Multiple European Countries
DB
Parallel
Multicenter
Setting: Specialty Clinic
Inclusion: Clinical syndromes indicating unifocal or multifocal involvement of the CNS; age 18–40 years; first neurological episode suggestive of MS in 3 months prior to study entry; one or more abnormalities in neurological exam; positive MRI brain scan

Exclusion: Previous immunosuppressive or immunomodulatory treatment; participation in an experimental procedure during year before study; other serious intercurrent systemic illness or psychiatric disorders; pregnancy; unwillingness to use reliable contraception
IFN β-1a (Rebif)

Placebo SQ injection once a week, for 2 years
Mean age (SD): 28 (6.1)

112 (36.2%) male
197 (63.8%) female

Ethnicity: NR
Percentage treated with steroids: 70%

Percentage treated with gadolinium enhancing lesions on T1: 58%

Median volume of lesions on T2 weighted MRI: 4964–5542 mm2
Screened: 375
Eligible: NR
Enrolled: 309
Rebif vs Placebo

WDs: 13 (8%) vs 18 (11.6%)

Lost to FU: NR

Analyzed: 308
Rebif vs Placebo

Number of patients converting to MS at 2 years: 52 (34%), P=0.047 vs 69 (45%), P=0.045

Time to conversion for CIS to MS: 5698 days, P=0.034 vs 252 days, P=NR

Annualized relapse rate at 2 years: 0.33, P=0.045 vs 0.43, P=NR
Rebif vs Placebo
Chills: 17/154 (11%) vs 17/154 (11%)
Fever: 43/154 (27.9%) vs 18/154 (11.7%)
ISRs (e.g. bleeding): 92/154 (59.7%) vs 18/154 (11.7%)
Myalgia: 26/154 (16.9%) vs 14/154 (9.1%)
Total WDs: 31
AE WDs: NR
Serono International SA (Geneva, Switzerland)Subgroup analysis based on brain- volume change on MRI scan: 41/131(31%) IFN-1a vs 62/132 (47%) placebo patients converted to MS at 24 months
Jacobs et al (CHAMPS Study; 3 publications)
2000, 2001
US and Canada CHAMPS
DB

Parallel

Multicenter
Setting: Specialty Clinic
Inclusion: Age 18–50; first isolated well-defined neurologic event consistent with demyelination and involving the optic nerve, spinal cord or brain stem/cerebellum; confirmed on ophthalmologic or neurologic exam; ≥2 lesions at least 3 mm in diameter on MRI; onset of visual or neurologic symptoms no more than 14 days before corticosteroid therapy was begun

Exclusion: Prior neurologic or visual event consistent with demyelination lasting longer than 48 hours
IFN β-1a (Avonex) IM 30 μg once per week, up to 3 years

Placebo IM once per week
Mean age (SD): 33 (7)

24.54% male
75.46% female

86% white
8% black
1% Asian
3% Hispanic
3% other
Percentage treated with steroids: 100%

Percentage treated with gadolinium enhancing lesions: 28%

Median volume of lesions on T2 weighted MRI: 2051 mm2
Screened: NR
Eligible: NR
Enrolled: 383
Withdrawn: 57

Lost to FU: 16

Analyzed: 383
IFN β-1a
Cumulative probability of conversion to MS: ARR 0.49 at 3 years, P<0.001; 95% CI, 0.33 to 0.73
IFN β-1a vs placebo
Depression: 20.2% vs 13%
Flu-like illness: 53.9% vs 25.8%
WDs: 73
AE WDs: 8
Supported by BiogenOn outcome: Subgroup analysis of only patients presenting with optic neuritis (n=192):
Conversion to clinically definite MS IFN- 1a vs placebo: ARR 0.58 (0.34–1.00; P=0.05)

On intervention: Run-in: 1 g methylprednisolone every day via IV for 3 days followed by 1 mg/kg prednisone orally every day for 11 days and a 4-day tapering period according to the following schedule: 20mg day 1; 10 mg day 2; 0 mg day 3; 10 mg day 4.
Kappos
2006
Kappos 2007 3 year extension
Kappos 2009 5 year extension
Multiple European; Canada; Israel BENEFIT

Efficacy Quality: Good
AE Quality: Fair/Good
DB
Parallel
Multicenter
Setting: NR
Inclusion: Patients with a CIS, defined as a first neurologic event suggestive of MS lasting for at least 24 hours and with symptoms and signs indicating either a single lesion (monofocal) or more than one lesion (multifocal) within the CNS; age 18–45 years; have presented with a first neurologic event suggestive of MS that lasted for at least 24 hours, and had to have at least two clinically silent lesions on their T2-weighted brain MRI scan with a size of at least 3 mm, at least one of which being ovoid, periventricular, or infratentorial; BL EDSS between 0 and 5

Exclusion: Patients in whom any disease other than MS could explain their signs and symptoms; any previous episode that could possibly be attributed to an acute demyelinating event; patients with complete transverse myelitis or bilateral optic neuritis; patients who had received prior immunosuppressive therapy
IFN β-1b (Betaseron) 250 μg, SQ, qod up to 2 years

Placebo SQ qod, up to 2 years
Mean age: 30

29.27% male
70.73% female

white: 98%
other: 2%
Percentage treated with steroids: 71%

Monofocal: 47%

Percentage with gadolinium enhancing lesions on T1: 42%

Median volume of T2 lesions: 1951.5–1858.5 mm2 (range 592–5029)
Screened: 603
Eligible: 511
Enrolled: 487
Withdrawn: 62

Lost to FU: 31

Analyzed: 468
Betaseron vs Placebo

Patients progressing to Clinically
Definite Multiple Sclerosis: 75 (26%) vs 77 (44%)
HR: 0.50 (95% CI, 0.36 to 0.70), NNT 6

Patients progressing to McDonald criteria MA: 191 vs 142

HRQOL: No significant change from BL in either group
Betaseron vs Placebo
ISR: 141/292 (48.3%) vs 15/176 (9%)
Flu-like illness: 129/292 (44.2%) vs 32/176 (18.2%)
Depression: 30/292 (10.3%) vs 20/176 (11.4%)
Abnormal LFT (ALT): 52/292 (18%) vs 8/176 (5%)
Abnormal LFT (AST): 18/292 (6.2%) vs 1/176 (0.56%)
Total WDs: 93
AE WDs: 33
Funded by Schering AGOn design: 13 IFN β-1b and 6 placebo patients were randomized but never received treatment.

On Population: Only white race reported. Other 2% of patients not described by race

On WDs: Includes patients lost to FU and WDs
Pakdaman
2007
Iran
DB
RCT (3 year)
Placebo-controlled
Parallel
Multicenter (4 centers)
Inclusion: Age 19–50 years; presented with a first neurological event consistent with demyelination of the CNS (optic neuritis, spinal cord syndrome, brain-stem or cerebellar syndrome) in the previous 3 months confirmed by neurologic examination and had an abnormal brain MRI consisting of ≥2 clinically silent lesions that were at least 3 mm in diameter and at least one had to be periventricular or ovoid

Exclusion: Pregnant or desired to be pregnant during the study; if they had any serious systemic illness or psychiatric disorder or were on immunomodulatory or immunosuppressive treatment during the year before the study
IFN β-1a IM injections once weekly (n=98)

Placebo IM injections once weekly (n=104)
IFNβ-1a (n=98) vs P (n=102)

Age: 26.4 vs 29.5

Male: 31 (31.6%) vs 32 (31.4%)
Female: 67 (68.4%) vs 70 (68.6%)

Iranian patients Ethnicity: NR

BL
characteristics was based on 200 of the 217 randomized patients
IFNβ-1a vs Placebo

Mean number of T2- weighted MRI lesions on screening: 4.9 vs 5.5

Number of T1 gadolinium- enhancing lesions on screening: 0.73 vs 0.63
Screened: NR
Eligible: NR
Enrolled: 217
WDs: 15

Lost to FU: NR

Analyzed: not clear
IFN β-1a vs Placebo

Proportion of patients who developed clinically definite MS at 3 years: 38/98 (36.6%) vs 57/104 (58.2%) - cumulative probability of conversion to clinically definite MS lower in IFN β-1a group (P<0.003)

Annual relapse rate: 13% vs 22%

Mean number of new and enlarging lesions on T2-weighted MRI scans at 6 months: 5.2 vs 5.9; P<0.001

Mean number of new and enlarging lesions on T2-weighted MRI scans at 12 months: 5.6 vs 6.6; P<0.003

Mean number of new and enlarging lesions on T2-weighted MRI scans at 24 months: 5.8 vs 7.7; P<0.002

Mean number of new and enlarging lesions on T2-weighted MRI scans at 36 months: 6.1 vs 8.9; P<0.001
Safety assessments, including vital signs, hematologic, and serum biochemical tests performed at the end of months 1, 6, 12, 18, 24, 30, and 36“Over the first 6 months, an influenza-like syndrome was reported more frequently in IFN β-1a group than in the placebo group (64% vs 76%, P=0.002)”

No description of other AEs were reported by the authors

Serious AEs, none of which was reported to be treatment-related, were reported in 9 patients in the IFN β-1a group and 7 patients in the placebo group.
Total WDs: 15
AE WDs: NR
NREfficacy Analysis: The diagnosis of clinical definite MS was the consequence of a second demyelinating attack in all but 3 of the patients.

Reporting: See Table 1: BL data on 17 patients were missing. Also, the number of patients in the placebo group (n=104) stated in the table (3rd column) does not equal the number of patients listed below it (i.e. 32 males + 70 females = 102 patients)

From: Evidence Tables

Cover of Drug Class Review: Disease-modifying Drugs for Multiple Sclerosis
Drug Class Review: Disease-modifying Drugs for Multiple Sclerosis: Final Update 1 Report [Internet].
Smith B, Carson S, Fu R, et al.
Portland (OR): Oregon Health & Science University; 2010 Aug.
Copyright © 2010 by Oregon Health & Science University, Portland, Oregon 97239. All rights reserved.

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