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PreCISe

Effect of glatiramer acetate on conversion to clinically definite multiple sclerosis in patients with clinically isolated syndrome (PreCISe study): a randomised, double-blind, placebo-controlled trial

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Year of Publication: 2009

Authors: G Comi, V Martinelli, M Rodegher, ..., for the PreCISe study group

Journal: The Lancet

Citation: Lancet 2009; 374: 1503-11

Link: https://doi.org/10.1016/S0140-6736(09)61259-9

Clinical Question

Does early treatment with glatiramer acetate delay conversion to clinically definite multiple sclerosis in patients presenting with clinically isolated syndrome and brain lesions on MRI?

Bottom Line

Early treatment with glatiramer acetate significantly reduced the risk of conversion to clinically definite MS by 45% (HR 0.55, p=0.0005) and prolonged time to conversion by 115%. The drug also significantly reduced MRI disease activity. The trial was stopped early at interim analysis due to demonstrated efficacy.

        Major Points
        Glatiramer acetate reduced risk of conversion to CDMS by 45% (HR 0.55, 95% CI 0.40-0.77, p=0.0005)
Time to 25% conversion prolonged from 336 days (placebo) to 722 days (glatiramer acetate) - 115% improvement
24.7% of glatiramer acetate patients vs 42.9% of placebo patients converted to CDMS (OR 0.41, p<0.0001)
Number needed to treat (NNT) to prevent one conversion = 5.49
Cumulative new T2 lesions reduced by 58% (RR 0.42, p<0.0001) at last observed value
Cumulative GdE lesions reduced by 60% (RR 0.40, p<0.0001)
T1 hypointense lesions reduced by 58% (RR 0.42, p<0.0001)
No significant effect on brain atrophy (pseudoatrophy effect may have confounded results)
Trial stopped early at preplanned interim analysis (81% of 3-year exposure) due to demonstrated efficacy
Safety profile consistent with known glatiramer acetate profile; injection-site reactions most common AE

      

Design

Study Type: Phase 3, multicenter, randomized, double-blind, placebo-controlled, parallel-group trial

Randomization: 1

Blinding: Double-blind; patients and all personnel masked to treatment assignment; treating and examining neurologists masked to MRI results; study drugs identical in appearance, shape, color, and smell

Enrollment Period: January 2004 to January 2006

Follow-up Duration: Up to 36 months or until conversion to CDMS; mean exposure at interim analysis 2.32 years (SD 0.65)

Centers: 80

Countries: USA, Argentina, Australia, New Zealand, Austria, Denmark, Finland, France, Germany, Hungary, Italy, Norway, Romania, Spain, Sweden, UK

Sample Size: 481

Analysis: Intention-to-treat; preplanned interim analysis at 81% of 3-year exposure; Cox proportional hazards model for primary endpoint; Kaplan-Meier curves; hierarchical approach for type-1 error control (α=0.05); interim analysis significance threshold p≤0.0244; confirmatory analyses in completers and per-protocol cohorts

Inclusion Criteria

Age 18-45 years inclusive
One unifocal neurological event (clinically isolated syndrome)
Positive brain MRI at screening: ≥2 cerebral T2 lesions ≥6mm in diameter (present on two consecutive 3mm slices)
Enrolled within 90 days after onset of first clinical attack
Unifocal presentation: signs/symptoms attributable to single lesion in cerebrum, infratentorial/supratentorial, spinal cord, or optic nerve

Exclusion Criteria

Multifocal clinical presentation
Diseases other than MS responsible for clinical or MRI presentation
Use of experimental or investigational drugs
Any use of beta interferon or chronic corticosteroids within 6 months of screening
Relapse between screening and baseline visits
Pregnancy or breastfeeding
Known sensitivity to mannitol or gadolinium

Arms

Field	Glatiramer acetate	Control
Intervention	Glatiramer acetate (Copaxone) 20mg in 1mL solution with 40mg mannitol, administered as daily subcutaneous injection via single-use prefilled syringe	Matching placebo, administered as daily subcutaneous injection; identical appearance, shape, color, and smell to active drug
Duration	Up to 36 months or until conversion to CDMS; patients converting to CDMS transferred to open-label glatiramer acetate	Up to 36 months or until conversion to CDMS; patients converting to CDMS transferred to open-label glatiramer acetate

Outcomes

Outcome	Type	Control	Intervention	HR / OR / RR	P-value
Time to conversion to clinically definite multiple sclerosis (CDMS) during the placebo-controlled phase. CDMS defined by second relapse: appearance of new or reappearance of previous neurological abnormalities lasting ≥48 hours, preceded by stable/improving state for ≥30 days, with objective neurological changes (EDSS increase ≥0.5 or FS increase ≥1 grade in ≥2 systems or ≥2 grades in 1 system)	Primary	102/238 (42.9%) converted; time to 25% conversion = 336 days	60/243 (24.7%) converted; time to 25% conversion = 722 days	0.55	0.0005
Number of new T2 lesions at last observed value (LOV)	Secondary	1.8 (adjusted mean)	0.7 (adjusted mean)	RR 0.42 (95% CI 0.29-0.61)	<0.0001
T2 lesion volume at LOV (baseline-adjusted)	Secondary	Higher	Lower (geometric means ratio 0.75, 95% CI 0.64-0.87)		0.0002
Brain atrophy (% change from baseline to LOV in brain volume)	Secondary	-0.38%	-0.33%		Not significant
Proportion converting to CDMS	Secondary	42.9%	24.7%	OR 0.41 (95% CI 0.28-0.62)	<0.0001
Cumulative new T2 lesions up to LOV (exposure-adjusted)	Secondary	Higher	Lower	RR 0.47 (95% CI 0.37-0.61)	<0.0001
Cumulative GdE lesions up to LOV	Secondary	Higher	Lower	RR 0.40 (95% CI 0.30-0.55)	<0.0001
Cumulative T1 hypointense lesions up to LOV	Secondary	3.6	1.7	RR 0.42 (95% CI 0.31-0.56)	<0.0001
Relapse-free at 48 weeks	Secondary	~66% (from figure)	~89% (from figure)
Cumulative new T2 lesions at 12 months (non-converters only)	Secondary	4.2	3.0	RR 0.57 (95% CI 0.45-0.72)	<0.0001
Cumulative new T2 lesions at 24 months (non-converters only)	Secondary	9.8	6.1	RR 0.48 (95% CI 0.38-0.61)	<0.0001
Any adverse event	Adverse	Not specified as %	Not specified as %
Injection-site reactions	Adverse	56/238 (24%)	135/243 (56%)
Immediate post-injection reactions	Adverse	12/238 (5%)	47/243 (19%)
Serious adverse events	Adverse	19/238 (8%)	11/243 (5%)
Discontinuation due to AE	Adverse	4/238 (1.7%)	14/243 (5.8%)		0.0184
Death	Adverse	0	1 (suicide on day 50, unrelated history)
Injection-site necrosis	Adverse	0	2 (0.8%)
Injection-site atrophy/lipoatrophy	Adverse	Not reported	10 (4%)
Lymphadenopathy	Adverse	1 (0.4%)	13 (5.3%)
Vomiting	Adverse	5 (2.1%)	14 (5.8%)
Influenza-like illness	Adverse	2 (0.8%)	10 (4.1%)
Pruritus	Adverse	3 (1.3%)	9 (3.7%)
Erythema	Adverse	3 (1.3%)	9 (3.7%)

Subgroup Analysis

Post-hoc subgroup analyses showed significant benefit of glatiramer acetate in most subgroups. Women showed 48% risk reduction (HR 0.52, p=0.0037) vs 43% in men (HR 0.57, p=0.0593). Younger patients (<30 years) showed 53% risk reduction (HR 0.47, p=0.0060) vs 37% in ≥30 years (HR 0.63, p=0.0531). Patients with ≥1 GdE lesions at baseline showed 71% risk reduction (HR 0.29, p<0.0001) vs 44% with no GdE lesions (HR 0.56, p=0.0423). Patients with ≥9 T2 lesions showed 58% risk reduction (HR 0.42, p<0.0001).

Criticisms

Trial stopped early at interim analysis - may overestimate treatment effect
Only unifocal CIS patients included; results may not generalize to multifocal presentations
Eligibility Evaluation Committee review process may have selected more homogeneous population than clinical practice
No effect on brain atrophy detected - may be due to pseudoatrophy from inflammation suppression, exposure bias, or underpowering
MRI endpoints biased by differential exposure time (glatiramer acetate patients had longer exposure due to delayed conversion)
Relapse definition (48h duration) more stringent than standard clinical definition (24h)
Patient/investigator masking not formally assessed
138/619 (22%) screened patients excluded by Eligibility Evaluation Committee - potential selection bias
Higher discontinuation rate in glatiramer acetate group due to adverse events (5.8% vs 1.7%, p=0.0184)
Post-hoc subgroup analyses not corrected for multiplicity - results should be interpreted cautiously
No active comparator arm - cannot directly compare to interferon beta treatments
Open-label extension after conversion limits long-term blinded assessment

Funding

Teva Pharmaceutical Industries, Israel

Based on: PreCISe (The Lancet, 2009)

Authors: G Comi, V Martinelli, M Rodegher, ..., for the PreCISe study group

Citation: Lancet 2009; 374: 1503-11

Content summarized and formatted by NeuroTrials.ai.

PreCISe

(2009)

Objective

To assess the efficacy of early treatment with glatiramer acetate in delaying conversion to clinically definite multiple sclerosis (CDMS) in patients presenting with clinically isolated syndrome (CIS)

Study Summary

• Glatiramer acetate reduced risk of CDMS by 45% vs placebo (HR 0.55, p=0.0005)
• Time to 25% conversion prolonged by 115% (722 vs 336 days)
• 58% reduction in cumulative new T2 lesions at last observation

Intervention

Glatiramer acetate 20mg SC daily vs matching placebo for up to 36 months or until conversion to CDMS

Inclusion Criteria

Age 18-45 years, unifocal CIS within 90 days, ≥2 T2 brain lesions ≥6mm on MRI, EDSS 0-6.5

Study Design

Arms: Glatiramer acetate 20mg SC daily vs Placebo

Patients per Arm: 243 vs 238

Outcome

• Primary: 24.7% vs 42.9% converted to CDMS (HR 0.55, 95% CI 0.40-0.77, p=0.0005)
• NNT = 5.49 to prevent one conversion
• New T2 lesions reduced by 58% (RR 0.42, p<0.0001)

Bottom Line

Major Points

Glatiramer acetate reduced risk of conversion to CDMS by 45% (HR 0.55, 95% CI 0.40-0.77, p=0.0005)
Time to 25% conversion prolonged from 336 days (placebo) to 722 days (glatiramer acetate) - 115% improvement
24.7% of glatiramer acetate patients vs 42.9% of placebo patients converted to CDMS (OR 0.41, p<0.0001)
Number needed to treat (NNT) to prevent one conversion = 5.49
Cumulative new T2 lesions reduced by 58% (RR 0.42, p<0.0001) at last observed value
Cumulative GdE lesions reduced by 60% (RR 0.40, p<0.0001)
T1 hypointense lesions reduced by 58% (RR 0.42, p<0.0001)
No significant effect on brain atrophy (pseudoatrophy effect may have confounded results)
Trial stopped early at preplanned interim analysis (81% of 3-year exposure) due to demonstrated efficacy
Safety profile consistent with known glatiramer acetate profile; injection-site reactions most common AE

Study Design

Study Type: Phase 3, multicenter, randomized, double-blind, placebo-controlled, parallel-group trial
Randomization: Yes
Blinding: Double-blind; patients and all personnel masked to treatment assignment; treating and examining neurologists masked to MRI results; study drugs identical in appearance, shape, color, and smell
Sample Size: 481
Follow-up: Up to 36 months or until conversion to CDMS; mean exposure at interim analysis 2.32 years (SD 0.65)
Centers: 80
Countries: USA, Argentina, Australia, New Zealand, Austria, Denmark, Finland, France, Germany, Hungary, Italy, Norway, Romania, Spain, Sweden, UK

Primary Outcome

Definition: Time to conversion to clinically definite multiple sclerosis (CDMS) during the placebo-controlled phase. CDMS defined by second relapse: appearance of new or reappearance of previous neurological abnormalities lasting ≥48 hours, preceded by stable/improving state for ≥30 days, with objective neurological changes (EDSS increase ≥0.5 or FS increase ≥1 grade in ≥2 systems or ≥2 grades in 1 system)

Control	Intervention	HR/OR	P-value
102/238 (42.9%) converted; time to 25% conversion = 336 days	60/243 (24.7%) converted; time to 25% conversion = 722 days	0.55 (0.40-0.77)	0.0005

Limitations & Criticisms

Trial stopped early at interim analysis - may overestimate treatment effect
Only unifocal CIS patients included; results may not generalize to multifocal presentations
Eligibility Evaluation Committee review process may have selected more homogeneous population than clinical practice
No effect on brain atrophy detected - may be due to pseudoatrophy from inflammation suppression, exposure bias, or underpowering
MRI endpoints biased by differential exposure time (glatiramer acetate patients had longer exposure due to delayed conversion)
Relapse definition (48h duration) more stringent than standard clinical definition (24h)
Patient/investigator masking not formally assessed
138/619 (22%) screened patients excluded by Eligibility Evaluation Committee - potential selection bias
Higher discontinuation rate in glatiramer acetate group due to adverse events (5.8% vs 1.7%, p=0.0184)
Post-hoc subgroup analyses not corrected for multiplicity - results should be interpreted cautiously
No active comparator arm - cannot directly compare to interferon beta treatments
Open-label extension after conversion limits long-term blinded assessment

Citation

Lancet 2009; 374: 1503-11

View Original Publication →

PreCISe

Effect of glatiramer acetate on conversion to clinically definite multiple sclerosis in patients with clinically isolated syndrome (PreCISe study): a randomised, double-blind, placebo-controlled trial

Clinical Question

Bottom Line

Major Points

Design

Inclusion Criteria

Exclusion Criteria

Arms

Outcomes

Subgroup Analysis

Criticisms

Funding

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