Clinical Trial Comparing Treatment of Relapsing-Remitting Multiple Sclerosis (RR-MS) With Two Doses of Glatiramer Acetate (GA).

• Sponsor: Teva Branded Pharmaceutical Products R&D, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00337779
• Collaborator: (none)
• Enrollment: 1,155
• Arms: 2
• Duration (Months): 26

Study Details

Study Description

Brief Summary

Teva is developing a 40 mg/ml GA Injection, administered once daily under the skin, for the treatment of R-R MS. The study drug is a higher dose formulation of Copaxone® (20 mg/ml GA), a marketed medication, approved for the treatment of R-R MS. GA is an immunomodulating drug that has anti inflammatory and neuroprotective properties. The study treatment duration is 12 months.

Condition or Disease	Intervention/Treatment	Phase
Relapsing Remitting Multiple Sclerosis	Drug: Glatiramer Acetate (GA) 40 mg; Drug: glatiramer acetate 20 mg	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 1155 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Multinational, Multicenter, Randomized, Parallel-Group, Double-Blind Study to Compare the Efficacy, Tolerability and Safety of Glatiramer Acetate Injection 40 mg/ml to That of Glatiramer Acetate Injection 20 mg/ml Administered Once Daily by Subcutaneous Injection in Subjects With Relapsing Remitting (R-R) Multiple Sclerosis (MS)
• Study Start Date: Aug 1, 2006
• Actual Primary Completion Date: Oct 1, 2008
• Actual Study Completion Date: Oct 1, 2008

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: glatiramer acetate 40 mg	Drug: Glatiramer Acetate (GA) 40 mg; Glatiramer Acetate Injection 40 mg/ml Daily subcutaneous injection for 12 months; Other Names: Copaxone®
Active Comparator: glatiramer acetate 20 mg	Drug: glatiramer acetate 20 mg; Glatiramer Acetate Injection 20 mg/ml Daily subcutaneous injection for 12 months; Other Names: Copaxone®

Outcome Measures

Primary Outcome Measures

1. The Rate of Confirmed Relapses During the Double-blind Phase (12 Months). [12 months]

   A confirmed relapse is defined as the appearance of one or more new neurological abnormalities or the reappearance of one or more previously observed neurological abnormalities. This change in clinical state must last at least 48 hours and be immediately preceded by an improving neurological state of at least thirty (30) days from onset of previous relapse.

Secondary Outcome Measures

1. The Number of New T2 Lesions at Month 12 as Compared to the Baseline Scan. [12 months]

   The analysis of this endpoint was based on the outcome of a contrast derived from a baseline-adjusted Negative Binomial Regression including the number of T1 Gd-enhancing lesions at baseline, the volume of T2 lesions at baseline and (pooled) center as covariates.

2. The Cumulative Number of T1-Gd Enhancing Lesions at Months 3, 6, 9 and 12 (in the Frequent MRI Cohort-described Below). [12 months]

   The Frequent MRI Cohort was a subset of subjects consisting of 234 subjects, for whom MRI scans were performed at months 0 (baseline), 1, 2, 3, 6, 9 and 12. Analysis of the endpoint was based on the outcome of a contrast derived from a baseline-adjusted Negative Binomial Regression with an "offset" variable employing the log of the porportion of the number of available post-baseline scans to adjust for missing MRI scans (if any) and including the number of T1 Gd-enhancing lesions at baseline and (pooled) center as covariates.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 55 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Diagnosis of confirmed and documented MS defined by the Revised McDonald criteria.

2. Subjects must be of the relapsing-remitting (R-R) type.

3. Subject has experienced prior to screening at least one documented relapse in 12 months or at least 2 documented relapses in the 24 months or one documented relapse between 12 - 24 months with at least 1 documented T1-Gd enhancing lesion in the MRI performed 12 months prior screening.

4. Disease duration for at least 6 months.

5. Ambulatory with converted Kurtzke EDSS score of 0 - 5.

6. Relapse free and stable neurological condition at least for 30 days prior screening.

7. Age - 18-55 (inclusive)

Exclusion Criteria:

1. Previous use of Copaxone (glatiramer acetate)

2. Treatment with corticosteroids within 30 days prior screening or between screening and baseline.

3. Chronic corticosteroids treatment - more than 30 consecutive days.

4. Subject with any clinically significant or unstable medical condition.

5. Subjects participating in any other clinical trial (within 12 weeks prior to screening and thereafter).

6. Known history of sensitivity to Gadolinium and inability to successfully undergo MRI scanning.

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

• Teva Branded Pharmaceutical Products R&D, Inc.

Investigators

• Study Chair: Chen Duksin, MD, Teva Pharmaceutical Industries, Ltd.
• Principal Investigator: Giancarlo Comi, Prof, Istituto Scientifico Fondazione Centro S. Raffaele

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Teva Branded Pharmaceutical Products R&D, Inc.
• ClinicalTrials.gov Identifier: NCT00337779
• Other Study ID Numbers: GA/9016 (FORTE)
• First Posted: Jun 16, 2006
• Last Update Posted: Oct 10, 2011
• Last Verified: Oct 1, 2011

• Additional relevant MeSH terms: Multiple Sclerosis; Multiple Sclerosis, Relapsing-Remitting; Sclerosis; Glatiramer Acetate; (T,G)-A-L

Study Results

Participant Flow

Recruitment Details	Study was conducted according to laws, regulations and administrative provisions related to implementation of Good Clinical Practice as applicable by legislation directives and Standard Operating Procedures. Subjects entered study after being informed and given time to contemplate consent. Enrollment began September 2006 and completed May 2007
Pre-assignment Detail	All subjects underwent evaluations including vital signs (blood pressure, pulse, and temperature,) adverse events, concomitant medications and neurological evaluation prior to study entry.

Arm/Group Title	Glatiramer Acetate 20 mg	Glatiramer Acetate 40 mg
Arm/Group Description
Period Title: Overall Study
STARTED	586	569
COMPLETED	534	490
NOT COMPLETED	52	79

Baseline Characteristics

Arm/Group Title	Glatiramer Acetate 20 mg	Glatiramer Acetate 40 mg	Total
Arm/Group Description	Total of all reporting groups
Overall Participants	586	569	1155
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	586 100%	569 100%	1155 100%
>=65 years	0 0%	0 0%	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	36.3 (9.0)	36.3 (9.0)	36.3 (9.0)
Sex: Female, Male (Count of Participants)
Female	421 71.8%	407 71.5%	828 71.7%
Male	165 28.2%	162 28.5%	327 28.3%
Region of Enrollment (participants) [Number]
Argentina	14 2.4%	14 2.5%	28 2.4%
Belgium	0 0%	1 0.2%	1 0.1%
Canada	15 2.6%	13 2.3%	28 2.4%
Czech Republic	33 5.6%	34 6%	67 5.8%
Estonia	11 1.9%	12 2.1%	23 2%
Finland	9 1.5%	7 1.2%	16 1.4%
France	10 1.7%	11 1.9%	21 1.8%
Germany	50 8.5%	48 8.4%	98 8.5%
Hungary	27 4.6%	27 4.7%	54 4.7%
Israel	14 2.4%	14 2.5%	28 2.4%
Italy	47 8%	43 7.6%	90 7.8%
Latvia	14 2.4%	14 2.5%	28 2.4%
Lithuania	14 2.4%	14 2.5%	28 2.4%
Netherlands	7 1.2%	6 1.1%	13 1.1%
Poland	36 6.1%	35 6.2%	71 6.1%
Romania	29 4.9%	28 4.9%	57 4.9%
Russian Federation	87 14.8%	88 15.5%	175 15.2%
Spain	23 3.9%	22 3.9%	45 3.9%
United Kingdom	11 1.9%	10 1.8%	21 1.8%
United States	135 23%	128 22.5%	263 22.8%

Outcome Measures

1. Primary Outcome

Title	The Rate of Confirmed Relapses During the Double-blind Phase (12 Months).
Description	A confirmed relapse is defined as the appearance of one or more new neurological abnormalities or the reappearance of one or more previously observed neurological abnormalities. This change in clinical state must last at least 48 hours and be immediately preceded by an improving neurological state of at least thirty (30) days from onset of previous relapse.
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

ITT

Arm/Group Title	Glatiramer Acetate 20 mg	Glatiramer Acetate 40 mg
Arm/Group Description
Measure Participants	586	569
Mean (Standard Deviation) [Number of relapses per patient]	0.28 (0.58)	0.27 (0.54)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Glatiramer Acetate 20 mg, Glatiramer Acetate 40 mg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.4859
	Comments
	Method	Regression, Poisson
	Comments
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	1.0732
	Confidence Interval	(2-Sided) 95%; 0.8799 to 1.3090
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.1013
	Estimation Comments	980 subjects randomized into two arms provide approximately 90% power to detect significant difference between groups of 30% or more in rate of confirmed relapses.

2. Secondary Outcome

Title	The Number of New T2 Lesions at Month 12 as Compared to the Baseline Scan.
Description	The analysis of this endpoint was based on the outcome of a contrast derived from a baseline-adjusted Negative Binomial Regression including the number of T1 Gd-enhancing lesions at baseline, the volume of T2 lesions at baseline and (pooled) center as covariates.
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Glatiramer Acetate 20 mg	Glatiramer Acetate 40 mg
Arm/Group Description
Measure Participants	586	569
Mean (Standard Deviation) [T2 Lesions]	2.87 (6.57)	2.72 (8.36)

3. Secondary Outcome

Title	The Cumulative Number of T1-Gd Enhancing Lesions at Months 3, 6, 9 and 12 (in the Frequent MRI Cohort-described Below).
Description	The Frequent MRI Cohort was a subset of subjects consisting of 234 subjects, for whom MRI scans were performed at months 0 (baseline), 1, 2, 3, 6, 9 and 12. Analysis of the endpoint was based on the outcome of a contrast derived from a baseline-adjusted Negative Binomial Regression with an "offset" variable employing the log of the porportion of the number of available post-baseline scans to adjust for missing MRI scans (if any) and including the number of T1 Gd-enhancing lesions at baseline and (pooled) center as covariates.
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

Frequent MRI cohort

Arm/Group Title	Glatiramer Acetate 20 mg	Glatiramer Acetate 40 mg
Arm/Group Description
Measure Participants	121	101
Log Mean (Standard Deviation) [T1 Enhancing Lesions]	2.83 (6.58)	3.49 (8.19)

Adverse Events

Arm/Group Title	Glatiramer Acetate 20 mg		Glatiramer Acetate 40 mg
Arm/Group Description
All Cause Mortality
	Glatiramer Acetate 20 mg		Glatiramer Acetate 40 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Glatiramer Acetate 20 mg		Glatiramer Acetate 40 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	25/586 (4.3%)		24/569 (4.2%)
Cardiac disorders
Coronary Artery Disease	0/586 (0%)	0	1/569 (0.2%)	1
Myocardial Infarction	0/586 (0%)	0	1/569 (0.2%)	1
Palpitations	1/586 (0.2%)	1	0/569 (0%)	0
Supraventricular Tachycardia	0/586 (0%)	0	1/569 (0.2%)	1
Tachycardia	0/586 (0%)	0	1/569 (0.2%)	1
Ear and labyrinth disorders
Vertigo	2/586 (0.3%)	2	0/569 (0%)	0
Gastrointestinal disorders
Abdominal Pain	1/586 (0.2%)	1	1/569 (0.2%)	1
Constipation	0/586 (0%)	0	1/569 (0.2%)	1
Diarrhoea	0/586 (0%)	0	1/569 (0.2%)	1
Intestinal Obstruction	1/586 (0.2%)	1	0/569 (0%)	0
Nausea	0/586 (0%)	0	1/569 (0.2%)	1
Swollen Tongue	1/586 (0.2%)	1	0/569 (0%)	0
Vomiting	0/586 (0%)	0	1/569 (0.2%)	1
General disorders
Chest Discomfort	1/586 (0.2%)	1	0/569 (0%)	0
Chest Pain	0/586 (0%)	0	2/569 (0.4%)	2
Chillls	1/586 (0.2%)	1	1/569 (0.2%)	1
Face Oedema	0/586 (0%)	0	1/569 (0.2%)	1
Palatal Oedema	1/586 (0.2%)	1	0/569 (0%)	0
Swelling Face	0/586 (0%)	0	1/569 (0.2%)	1
Pyrexia	1/586 (0.2%)	1	0/569 (0%)	0
Hepatobiliary disorders
Cholecystitis Acute	1/586 (0.2%)	1	0/569 (0%)	0
Cholelithiasis	1/586 (0.2%)	1	0/569 (0%)	0
Biliary Dyskinesai	0/586 (0%)	0	1/569 (0.2%)	1
Immune system disorders
Anaphylactic Reaction	1/586 (0.2%)	1	0/569 (0%)	0
Anaphylactic Shock	0/586 (0%)	0	1/569 (0.2%)	1
Hypersensititvity	0/586 (0%)	0	2/569 (0.4%)	2
Infections and infestations
Bronchitis	0/586 (0%)	0	2/569 (0.4%)	2
Candidiasis	1/586 (0.2%)	1	0/569 (0%)	0
Herpes Zoster	1/586 (0.2%)	1	0/569 (0%)	0
Device Related Infection	1/586 (0.2%)	1	0/569 (0%)	0
Influenza	0/586 (0%)	0	1/569 (0.2%)	1
Pyelonephritis Chronic	1/586 (0.2%)	1	0/569 (0%)	0
Injury, poisoning and procedural complications
Complicated Fracture	1/586 (0.2%)	1	0/569 (0%)	0
Crush Injury	0/586 (0%)	0	1/569 (0.2%)	1
Multiple Fractures	0/586 (0%)	0	1/569 (0.2%)	1
Fall	0/586 (0%)	0	1/569 (0.2%)	1
Investigations
Arteriogram Coronary	0/586 (0%)	0	1/569 (0.2%)	1
Troponin Increased	0/586 (0%)	0	1/569 (0.2%)	1
Metabolism and nutrition disorders
Diabetes Mellitus	0/586 (0%)	0	1/569 (0.2%)	1
Musculoskeletal and connective tissue disorders
Arthralgia	1/586 (0.2%)	1	0/569 (0%)	0
Chondropathy	1/586 (0.2%)	1	0/569 (0%)	0
Back Pain	0/586 (0%)	0	1/569 (0.2%)	1
Muscular Weakness	1/586 (0.2%)	1	0/569 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Breast Cancer	2/586 (0.3%)	2	1/569 (0.2%)	1
Fibroadenoma of Breast	1/586 (0.2%)	1	0/569 (0%)	0
Metastases to Lymph Nodes	1/586 (0.2%)	1	0/569 (0%)	0
Nervous system disorders
Aphasia	0/586 (0%)	0	1/569 (0.2%)	1
Presyncope	0/586 (0%)	0	1/569 (0.2%)	1
Facial Palsy	0/586 (0%)	0	1/569 (0.2%)	1
Tension Headache	1/586 (0.2%)	1	0/569 (0%)	0
Migraine	1/586 (0.2%)	1	0/569 (0%)	0
Multiple Sclerosis Relapse	0/586 (0%)	0	1/569 (0.2%)	1
Radicular Syndrome	0/586 (0%)	0	1/569 (0.2%)	1
Paraesthesia	1/586 (0.2%)	1	1/569 (0.2%)	1
Loss of Consciousness	0/586 (0%)	0	1/569 (0.2%)	1
Psychiatric disorders
Panic Attack	1/586 (0.2%)	1	0/569 (0%)	0
Anxiety	0/586 (0%)	0	1/569 (0.2%)	2
Psychotic Disorder	0/586 (0%)	0	1/569 (0.2%)	1
Renal and urinary disorders
Neophrolithiasis	1/586 (0.2%)	1	0/569 (0%)	0
Respiratory, thoracic and mediastinal disorders
Dyspnoea	1/586 (0.2%)	1	4/569 (0.7%)	4
Skin and subcutaneous tissue disorders
Angioedema	0/586 (0%)	0	1/569 (0.2%)	1
Surgical and medical procedures
Cholecystectomy	1/586 (0.2%)	1	0/569 (0%)	0
Coronary Arterial Stent Insertion	0/586 (0%)	0	1/569 (0.2%)	1
Laparoscopy	1/586 (0.2%)	1	0/569 (0%)	0
Malignant Breast Lump Removal	1/586 (0.2%)	1	0/569 (0%)	0
Mastectomy	1/586 (0.2%)	1	0/569 (0%)	0
Oophorectomy	1/586 (0.2%)	1	0/569 (0%)	0
Spinal Laminectomy	1/586 (0.2%)	1	0/569 (0%)	0
Tonsillectomy	1/586 (0.2%)	1	0/569 (0%)	0
Varicose Vein Operation	1/586 (0.2%)	1	0/569 (0%)	0
Vascular disorders
Deep Vein Thrombosis	1/586 (0.2%)	1	0/569 (0%)	0
Blood Pressure Increased	0/586 (0%)	0	1/569 (0.2%)	1
Other (Not Including Serious) Adverse Events
	Glatiramer Acetate 20 mg		Glatiramer Acetate 40 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	499/586 (85.2%)		490/569 (86.1%)
Gastrointestinal disorders
Nausea	33/586 (5.6%)	41	33/569 (5.8%)	45
General disorders
Fatigue	39/586 (6.7%)	43	41/569 (7.2%)	44
Chest Discomfort	32/586 (5.5%)	43	28/569 (4.9%)	33
Injection Erythema	183/586 (31.2%)	200	196/569 (34.4%)	231
Injection Site Bruising	31/586 (5.3%)	35	21/569 (3.7%)	22
Injection Site Irritation	57/586 (9.7%)	62	42/569 (7.4%)	47
Injection Site Induration	46/586 (7.8%)	47	54/569 (9.5%)	62
Injection Site Mass	53/586 (9%)	55	63/569 (11.1%)	70
Injection Site Swelling	47/586 (8%)	49	55/569 (9.7%)	58
Injection Site Pain	109/586 (18.6%)	123	99/569 (17.4%)	112
Injection Site Pruritus	90/586 (15.4%)	95	93/569 (16.3%)	99
Pain in Extremity	30/586 (5.1%)	32	19/569 (3.3%)	23
Infections and infestations
Upper Respiratory Tract Infection	49/586 (8.4%)	65	54/569 (9.5%)	68
Nasopharyngitis	78/586 (13.3%)	102	74/569 (13%)	95
Urinary Tract Infection	43/586 (7.3%)	50	30/569 (5.3%)	38
Musculoskeletal and connective tissue disorders
Back Pain	28/586 (4.8%)	34	36/569 (6.3%)	39
Nervous system disorders
Headache	63/586 (10.8%)	115	68/569 (12%)	113
Depression	23/586 (3.9%)	24	36/569 (6.3%)	36
Dizziness	30/586 (5.1%)	45	26/569 (4.6%)	29
Respiratory, thoracic and mediastinal disorders
Dyspnoea	44/586 (7.5%)	67	54/569 (9.5%)	79
Vascular disorders
Flushing	26/586 (4.4%)	42	36/569 (6.3%)	49

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Sponsor has the right 60 days before submission for publication to review/provide comments. If the Sponsor's review shows that potentially patentable subject matter would be disclosed, publication or public disclosure shall be delayed for up to 90 additional days in order for the Sponsor, or Sponsor's designees, to file the necessary patent applications. In multicenter trials, each PI will postpone single center publications until after disclosure or publication of multicenter data.