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CompletedNCT00666224PreCISeUpdated Jun 25, 2012Results posted

Evaluate Early Glatiramer Acetate Treatment in Delaying Conversion to Clinically Definite Multiple Sclerosis of Subjects Presenting With Clinically Isolated Syndrome

A Phase 3 interventional study of Glatiramer Acetate (DB) and Placebo in Multiple Sclerosis, sponsored by Teva Branded Pharmaceutical Products R&D, Inc.. Completed. Open to participants aged 18 Years to 45 Years. Per ClinicalTrials.gov, last updated 2012-06-25.

Sponsored by Teva Branded Pharmaceutical Products R&D, Inc. · Phase 3, Interventional, and Treatment

Phase
Phase 3
Study type
Interventional
Enrollment
481
Allocation
Randomized
Ages
18 Years to 45 Years
Sex
All
01

Study summary

The primary objective is to assess the effect of treatment with glatiramer acetate (GA) compared to placebo on the time to conversion to CDMS, as determined by Poser criteria (the occurrence of the second clinical attack) during the double-blind period. The secondary objective is to assess, within the time frame of the up to 3-year double-blind, placebo-controlled study period, the effect of GA on clinical and Magnetic Resonance Imaging (MRI) parameters. The long-term objectives of the study (exploratory in nature) are to assess, within the time frame of 5 years, the neuroprotective effect of early versus delayed treatment with GA as reflected by clinical and MRI parameters measuring the accumulated irreversible brain tissue damage.

A pre-planned interim analysis was performed on all efficacy and safety data accumulated in the database up to October 14, 2007, i.e. when 81% of exposure to treatment in the double-blind, placebo-controlled period had been collected. Upon review of the interim analysis results, the Data Monitoring Committee (DMC) recommended that the double-blind portion of the study be stopped and that subjects be switched to the 2-year Open-label period, during which time they would have the option of receiving GA therapy. The sponsor (Teva) adopted the DMC recommendations and took the necessary action towards its implementation.

02

Conditions studied

  • Multiple Sclerosis

Keywords

  • Clinically Definite Multiple Sclerosis
  • Clinically Isolated Syndrome
  • Multiple Sclerosis
03

In context

Multiple Sclerosis

3,460 studies on the registry are indexed under Multiple Sclerosis; 661 are open to participants now.

This study's enrollment of 481 is above the median of 50 across 2,342 interventional studies indexed under Multiple Sclerosis.

Browse Multiple Sclerosis studies →

Lead sponsor

Teva Branded Pharmaceutical Products R&D, Inc. is the lead sponsor of 205 studies on the registry; none are open to participants now.

Of its 49 completed or terminated interventional studies of FDA-regulated products, 47 (96%) have results posted.

Counted across the registry records on this site, refreshed daily.

04

Who can participate

Ages eligible
18 Years to 45 Years
Sexes eligible
All
Accepts healthy volunteers
No

Inclusion criteria

  1. The subject must have undergone a single clinical attack.
  2. The subject must have a unifocal clinical presentation.
  3. The subject should be enrolled within the period of 90 days after onset of a single unifocal clinical attack (index attack).
  4. There must be 2 or more cerebral lesions highly suspicious of multiple sclerosis (MS) on the screening Magnetic Resonance Imaging (MRI), measuring 6mm or more in diameter.
  5. Subjects must be between the ages of 18 and 45 years inclusive.
  6. Subjects must not have taken corticosteroids within the 30 days prior to the MRI at the baseline visit.
  7. Subjects may be male or female. Women of child-bearing potential must practice a medically acceptable method of birth control. Acceptable methods include oral contraceptive, contraceptive patch, long-acting injectable contraceptive, or double-barrier method (condom or intrauterine device with spermicide).
  8. The subjects must be willing and able to give written informed consent, prior to entering the study.

Exclusion criteria

Exclusion Criteria:

  1. Multifocal clinical presentation.
  2. Diseases other than MS responsible for the clinical/MRI presentation. The following laboratory tests must be part of the subject's medical history for differential diagnosis of clinically isolated syndrome (CIS): erythrocyte sedimentation rate (ESR), antinuclear antibody (ANA), complement (C3, C4) and anticardiolipin IgG - IgM. In the event that the results of these tests are inconclusive, the following additional tests may be requested by the Eligibility Evaluation Committee: syphilis screening, vitamin B12 and folic acid. In the case of spinal cord CIS presentation, a spinal cord MRI is required for confirmation of diagnosis in the medical history of the subject.
  3. Use of experimental or investigational drugs, including IV immunoglobulin, and/or participation in an investigational drug study within 6 months prior to study entry.
  4. Use of interferon agents within 6 months prior to the screening visit.
  5. Chronic corticosteroid treatment (more than 30 consecutive days) in the 6 months prior to study entry.
  6. Pregnancy or breast feeding.
  7. Subjects who experience a relapse between the screening (month -1) and baseline (month 0) visits.
  8. Life-threatening or other clinically significant disease.
  9. A medical or psychiatric condition that affects the subject's ability to give informed consent, or to complete the study, or if the subject is considered by the treating neurologist/physician to be, for any other reason, an unsuitable candidate for this study.
  10. A known history of sensitivity to mannitol.
  11. A known history of sensitivity to gadolinium.
  12. Inability to successfully undergo MRI scanning.
05

Study design

Phase
Phase 3
Primary purpose
Treatment
Allocation
Randomized
Intervention model
Parallel assignment
Masking
Quadruple (Participant, Care provider, Investigator, Outcomes assessor)
Enrollment
481 participants (actual)

Study arms

  • Experimental
    Glatiramer acetate

    Glatiramer acetate 20 mg once daily by subcutaneous injection is administered in both the double-blind and open label periods.

    Drug: Glatiramer Acetate (DB) · Drug: Glatiramer Acetate (OL)

  • Placebo comparator
    Placebo (DB) to GA (OL)

    Placebo matching glatiramer acetate once daily by subcutaneous injection during the double-blind period (DB). Glatiramer acetate (GA) 20 mg once daily by subcutaneous injection during the open-label period (OL).

    Drug: Placebo · Drug: Glatiramer Acetate (OL)

Interventions

  • DrugGlatiramer Acetate (DB)

    Double blind period (DB): glatiramer acetate (GA) by subcutaneous injection, 20mg, once daily, for up to 36 months or until conversion to clinically definite multiple sclerosis (CDMS).

    Also known as: Copaxone®

  • DrugPlacebo

    Double blind period (DB): subcutaneous injection of placebo, once daily, for up to 36 months or until conversion to CDMS

  • DrugGlatiramer Acetate (OL)

    Open label period (OL): glatiramer acetate (GA), 20 mg, subcutaneous injection, once daily, given for up to an additional 24 months.

    Also known as: Copaxone®

06

What researchers measure

Primary outcomes

  1. Time to Clinically Definite Multiple Sclerosis (CDMS) Conversion

    Data from interim analysis with database lock on October 14, 2007. The time from randomization to conversion to CDMS as determined by the occurrence of a second clinical attack during the double-blind period. Poser criteria are: Two relapses and clinical evidence of two separate lesions; clinical evidence of one lesion and paraclinical evidence of another separate lesion. The two relapses must involve different parts of Central Nervous System and must be separated by a period of at least one month. Lesions are determined by Magnetic Resonance Imaging (MRI).

    Time frame: up to 3 years

  2. Twenty-fifth Percentile (25%) Kaplan-Meier Estimates for Time From Randomization to Conversion to Clinically Definite Multiple Sclerosis (CDMS) During the Double-blind Period

    Data from interim analysis with database lock on October 14, 2007. Due to the number of participants in the glatiramer acetate group that converted to CDMS (see outcome #6), the 25th percentile was considered when running the Kaplan-Meier estimate for time to conversion to CDMS. Conversion to CDMS is determined by the occurrence of the second clinical attack.

    Time frame: up to 3 years

Secondary outcomes

  1. Number of New T2 Brain Lesions Observed at the Last Observed Value (LOV) in the Double-blind Period

    Data from interim analysis with database lock on October 14, 2007. T2 lesions are brain lesions that show on magnetic resonance imaging (MRI) and are associated with multiple sclerosis. This outcome measures the number of new lesions at the last observed value. Last Observed Value (LOV) is defined as the last post baseline measurement taken on study drug but no more than 30 days after study drug cessation.

    Time frame: up to 3 years

  2. Change From Baseline to Last Observed Value (LOV) in T2 Brain Lesion Volume in the Double-blind Period

    Data from interim analysis with database lock on October 14, 2007. The difference in T2 brain lesion volume as observed in MRIs from baseline to the last observed value. Last Observed Value (LOV) is defined as the last post baseline measurement taken on study drug but no more than 30 days after study drug cessation.

    Time frame: Day 0 (baseline), up to 3 years

  3. Percentage Change in Brain Volume From Baseline to the Last Observed Value (LOV) During the Double-blind Period Using the Structural Image Evaluation of Normalized Atrophy (SIENA) Technique

    Data from interim analysis with database lock on October 14, 2007. Brain volume was measured annually by magnetic resonance imaging (MRI) during the Double-blind period. Brain atrophy was measured by comparing the change in brain volume from baseline to the Last Observed Value (LOV). LOV is defined as the last post baseline measurement taken on study drug but no more than 30 days after study drug cessation. SIENA is a fully automated method of analyzing longitudinal brain change.

    Time frame: Day 0 (baseline), up to 3 years

  4. Percentage of Participants Who Converted to Clinically Definite Multiple Sclerosis (CDMS) During the Double-blind Period

    Data from interim analysis with database lock on October 14, 2007. Conversion to CDMS as determined by the occurrence of a second clinical attack during the double-blind period. Poser criteria are: Two relapses and clinical evidence of two separate lesions; clinical evidence of one lesion and paraclinical evidence of another separate lesion. The two relapses must involve different parts of Central Nervous System and must be separated by a period of at least one month. Lesions are determined by Magnetic Resonance Imaging (MRI).

    Time frame: up to 3 years

07

Results

Posted Jun 13, 2012

Participant flow

A clinically isolated syndrome (CIS) is a first neurological episode, lasting at least 24 hours, caused by inflammation/demyelination in one or more sites in the central nervous system (CNS.) Subjects were enrolled within 90 days of the event and randomized up to 32 days following screening.

Double-Blind
Participant flow — Double-Blind
MilestoneGlatiramer AcetatePlacebo (DB) to GA (OL)
Started243238
Completed198211
Not completed4527
Withdrew: Adverse event155
Withdrew: Lost to follow-up22
Withdrew: Withdrawal by subject1814
Withdrew: Physician decision03
Withdrew: Sponsor decision10
Withdrew: Pregnancy32
Withdrew: Noncompliance10
Withdrew: Death10
Withdrew: Undefined/unknown41
Open-Label
Participant flow — Open-Label
MilestoneGlatiramer AcetatePlacebo (DB) to GA (OL)
Started198211
Completed163126
Not completed3585
Withdrew: Adverse event843
Withdrew: Lost to follow-up45
Withdrew: Withdrawal by subject1225
Withdrew: Physician decision75
Withdrew: Pregnancy15
Withdrew: Noncompliance21
Withdrew: Undefined/unknown11

Outcome measures

PrimaryTime to Clinically Definite Multiple Sclerosis (CDMS) Conversion

Data from interim analysis with database lock on October 14, 2007. The time from randomization to conversion to CDMS as determined by the occurrence of a second clinical attack during the double-blind period. Poser criteria are: Two relapses and clinical evidence of two separate lesions; clinical evidence of one lesion and paraclinical evidence of another separate lesion. The two relapses must involve different parts of Central Nervous System and must be separated by a period of at least one month. Lesions are determined by Magnetic Resonance Imaging (MRI).

Time frame:
up to 3 years
Reported as:
Mean · days
Time to Clinically Definite Multiple Sclerosis (CDMS) Conversion
daysGlatiramer Acetate (Double-blind Period)Placebo (Double-blind Period)
Time to Clinically Definite Multiple Sclerosis (CDMS) Conversion657.85 ± 349.3590.54 ± 340.2
Statistical analysis
  • Glatiramer Acetate (Double-blind Period) vs Placebo (Double-blind Period) · Regression, Cox · p = 0.0005 (Type of unifocal presentation at baseline, past corticosteroid treatment (Yes/No) for the initial attack prior to randomization, and center effects as covariates.) · Cox proportional hazard: 0.55 · 95% CI 0.40 to 0.77
SecondaryNumber of New T2 Brain Lesions Observed at the Last Observed Value (LOV) in the Double-blind Period

Data from interim analysis with database lock on October 14, 2007. T2 lesions are brain lesions that show on magnetic resonance imaging (MRI) and are associated with multiple sclerosis. This outcome measures the number of new lesions at the last observed value. Last Observed Value (LOV) is defined as the last post baseline measurement taken on study drug but no more than 30 days after study drug cessation.

Time frame:
up to 3 years
Reported as:
Mean · new T2 lesions
Number of New T2 Brain Lesions Observed at the Last Observed Value (LOV) in the Double-blind Period
new T2 lesionsGlatiramer Acetate (Double-blind Period)Placebo (Double-blind Period)
Number of New T2 Brain Lesions Observed at the Last Observed Value (LOV) in the Double-blind Period0.7 ± 1.71.8 ± 3.6
Statistical analysis
  • Glatiramer Acetate (Double-blind Period) vs Placebo (Double-blind Period) · Quasi-Likelihood NB* Regression · p = <0.0001 · Rate ratio: 0.42 · 95% CI 0.29 to 0.61\*NB = Negative Binomial Center and baseline number of enhancing lesions as covariates.
SecondaryChange From Baseline to Last Observed Value (LOV) in T2 Brain Lesion Volume in the Double-blind Period

Data from interim analysis with database lock on October 14, 2007. The difference in T2 brain lesion volume as observed in MRIs from baseline to the last observed value. Last Observed Value (LOV) is defined as the last post baseline measurement taken on study drug but no more than 30 days after study drug cessation.

Time frame:
Day 0 (baseline), up to 3 years
Reported as:
Mean · ml
Change From Baseline to Last Observed Value (LOV) in T2 Brain Lesion Volume in the Double-blind Period
mlGlatiramer Acetate (Double-blind Period)Placebo (Double-blind Period)
Change From Baseline to Last Observed Value (LOV) in T2 Brain Lesion Volume in the Double-blind Period1.2 ± 2.62.6 ± 3.9
Statistical analysis
  • Glatiramer Acetate (Double-blind Period) vs Placebo (Double-blind Period) · ANCOVA · p = 0.0013 · Geometric means ratio: 0.87 · 95% CI 0.79 to 0.95Used log-transformed measurements comparing the adjusted geometric means of T2 volume. Center and baseline T2 volume used as covariates.
SecondaryPercentage Change in Brain Volume From Baseline to the Last Observed Value (LOV) During the Double-blind Period Using the Structural Image Evaluation of Normalized Atrophy (SIENA) Technique

Data from interim analysis with database lock on October 14, 2007. Brain volume was measured annually by magnetic resonance imaging (MRI) during the Double-blind period. Brain atrophy was measured by comparing the change in brain volume from baseline to the Last Observed Value (LOV). LOV is defined as the last post baseline measurement taken on study drug but no more than 30 days after study drug cessation. SIENA is a fully automated method of analyzing longitudinal brain change.

Time frame:
Day 0 (baseline), up to 3 years
Reported as:
Mean · percent change
Percentage Change in Brain Volume From Baseline to the Last Observed Value (LOV) During the Double-blind Period Using the Structural Image Evaluation of Normalized Atrophy (SIENA) Technique
percent changeGlatiramer Acetate (Double-blind Period)Placebo (Double-blind Period)
Percentage Change in Brain Volume From Baseline to the Last Observed Value (LOV) During the Double-blind Period Using the Structural Image Evaluation of Normalized Atrophy (SIENA) Technique-0.3 ± 0.6-0.4 ± 0.7
PrimaryTwenty-fifth Percentile (25%) Kaplan-Meier Estimates for Time From Randomization to Conversion to Clinically Definite Multiple Sclerosis (CDMS) During the Double-blind Period

Data from interim analysis with database lock on October 14, 2007. Due to the number of participants in the glatiramer acetate group that converted to CDMS (see outcome #6), the 25th percentile was considered when running the Kaplan-Meier estimate for time to conversion to CDMS. Conversion to CDMS is determined by the occurrence of the second clinical attack.

Time frame:
up to 3 years
Reported as:
Number · days
Twenty-fifth Percentile (25%) Kaplan-Meier Estimates for Time From Randomization to Conversion to Clinically Definite Multiple Sclerosis (CDMS) During the Double-blind Period
daysGlatiramer Acetate (Double-blind Period)Placebo (Double-blind Period)
Twenty-fifth Percentile (25%) Kaplan-Meier Estimates for Time From Randomization to Conversion to Clinically Definite Multiple Sclerosis (CDMS) During the Double-blind Period722 (505 to NA)336 (260 to 456)
SecondaryPercentage of Participants Who Converted to Clinically Definite Multiple Sclerosis (CDMS) During the Double-blind Period

Data from interim analysis with database lock on October 14, 2007. Conversion to CDMS as determined by the occurrence of a second clinical attack during the double-blind period. Poser criteria are: Two relapses and clinical evidence of two separate lesions; clinical evidence of one lesion and paraclinical evidence of another separate lesion. The two relapses must involve different parts of Central Nervous System and must be separated by a period of at least one month. Lesions are determined by Magnetic Resonance Imaging (MRI).

Time frame:
up to 3 years
Reported as:
Number · percentage of total participants
Percentage of Participants Who Converted to Clinically Definite Multiple Sclerosis (CDMS) During the Double-blind Period
percentage of total participantsGlatiramer Acetate (Double-blind Period)Placebo (Double-blind Period)
Percentage of Participants Who Converted to Clinically Definite Multiple Sclerosis (CDMS) During the Double-blind Period24.742.9
Statistical analysis
  • Glatiramer Acetate (Double-blind Period) vs Placebo (Double-blind Period) · Regression, Logistic · p = <0.0001 (Type of unifocal presentation, past corticosteroid treatment (Yes/No) for the initial attack prior to randomization and center effects as covariates.) · Odds ratio (or): 0.41 · 95% CI 0.27 to 0.61

Adverse events

Collected over The double-blind period was up to three years. The entire study included the double-blind period (up to three years) and the open-label period (up to an additional two years).. Non-serious events are listed at a 5.0% frequency threshold.

Adverse event summary by group
GroupDeathsSeriousOther
Placebo (Double-blind Period)—19/238 (8%)165/238 (69.3%)
Glatiramer Acetate (Double-blind Period)—11/243 (4.5%)191/243 (78.6%)
Glatiramer Acetate (Entire Study)—44/454 (9.7%)352/454 (77.5%)
Most frequent serious events
Showing 10 of 74
Most frequent serious events
EventPlacebo (Double-blind Period)Glatiramer Acetate (Double-blind Period)Glatiramer Acetate (Entire Study)
Anaphylactic ReactionImmune system disorders0/2380/2434/454
Chest painGeneral disorders0/2380/2432/454
HypersensitivityImmune system disorders0/2381/2432/454
Hepatic enzyme increasedInvestigations0/2380/2432/454
DyspnoeaRespiratory, thoracic and mediastinal disorders0/2380/2432/454
UrticariaSkin and subcutaneous tissue disorders0/2381/2432/454
CholecystectomySurgical and medical procedures0/2381/2432/454
HydroceleCongenital, familial and genetic disorders1/2380/2430/454
DeafnessEar and labyrinth disorders1/2380/2430/454
SinusitisInfections and infestations1/2380/2430/454
Most frequent other events
Showing 10 of 35
Most frequent other events
EventPlacebo (Double-blind Period)Glatiramer Acetate (Double-blind Period)Glatiramer Acetate (Entire Study)
Injection site erythemaGeneral disorders15/23872/243140/454
Injection site painGeneral disorders18/23854/243105/454
HeadacheNervous system disorders43/23854/24380/454
NasopharyngitisInfections and infestations49/23848/24394/454
InfluenzaInfections and infestations34/23827/24355/454
Injection site pruritusGeneral disorders4/23831/24358/454
Injection site swellingGeneral disorders6/23824/24353/454
FatigueGeneral disorders22/23826/24340/454
DyspnoeaRespiratory, thoracic and mediastinal disorders3/23818/24348/454
Back painMusculoskeletal and connective tissue disorders19/23825/24347/454

Baseline characteristics

Age, Categorical
Age, Categorical(Participants)Glatiramer Acetate (Double-blind Period)Placebo (Double-blind Period)Total
<=18 years000
Between 18 and 65 years243238481
>=65 years000
Age Continuous
Age Continuous(years)Glatiramer Acetate (Double-blind Period)Placebo (Double-blind Period)Total
Mean31.5 ± 6.930.8 ± 7.031.2 ± 6.9
Sex: Female, Male
Sex: Female, Male(Participants)Glatiramer Acetate (Double-blind Period)Placebo (Double-blind Period)Total
Female159163322
Male8475159
Race/Ethnicity, Customized
Race/Ethnicity, Customized(participants)Glatiramer Acetate (Double-blind Period)Placebo (Double-blind Period)Total
Asian / Oriental213
Black or African American112
Caucasian233229462
Hispanic325
Other (not specified)459
Region of Enrollment
Region of Enrollment(participants)Glatiramer Acetate (Double-blind Period)Placebo (Double-blind Period)Total
Argentina7613
Australia7613
Austria5611
Denmark5611
Finland101020
France111122
Germany323163
Hungary161531
Italy5657113
New Zealand437
Norway224
Romania283058
Spain232245
Sweden202
United Kingdom151227
United States202141
Participants Who Used Corticosteroids for Initial Attack
Participants Who Used Corticosteroids for Initial Attack(participants)Glatiramer Acetate (Double-blind Period)Placebo (Double-blind Period)Total
Used corticosteroids149159308
Did not use corticosteroids9479173
08

Study locations

No study locations are listed for this record.

09

References and documents

Publications

  • Comi G, Martinelli V, Rodegher M, Moiola L, Bajenaru O, Carra A, Elovaara I, Fazekas F, Hartung HP, Hillert J, King J, Komoly S, Lubetzki C, Montalban X, Myhr KM, Ravnborg M, Rieckmann P, Wynn D, Young C, Filippi M; PreCISe study group. 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. Lancet. 2009 Oct 31;374(9700):1503-11. doi: 10.1016/S0140-6736(09)61259-9. Epub 2009 Oct 6. Erratum In: Lancet. 2010 Apr 24;375(9724):1436. PubMed 19815268 ↗
10

Updates

Tracking since Sep 25, 2026
No changes since tracking began. The registry record was last updated on Jun 25, 2012, before this site started recording changes on Sep 25, 2026. Its history is on ClinicalTrials.gov ↗
11

Registry details

Key details

Study ID
NCT00666224
Lead sponsor
Teva Branded Pharmaceutical Products R&D, Inc.
Responsible party
Sponsor
First posted
Apr 24, 2008
Start date
Jan 2004
Primary completion
Oct 2007
Completion
Jun 2010
Results posted
Jun 13, 2012
Last update
Jun 25, 2012

Oversight

Data monitoring committee
Yes
View the source record on ClinicalTrials.gov ↗

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