Assessment Study of Steroid Effect in Relapsing Multiple Sclerosis Subjects Treated With Glatiramer Acetate (ASSERT)

A Multi-Centered, Randomized, Double-Blind, Placebo Controlled Study Assessing the Add-on Effect of Oral Steroids in Relapsing Remitting Multiple Sclerosis Subjects Treated With Glatiramer Acetate (GA)

This is a study evaluating the effect on brain volume of daily glatiramer acetate (GA) and add-on pulse steroids.

Study Overview

• Status: Terminated
• Conditions: Relapsing Remitting Multiple Sclerosis
• Intervention / Treatment: Drug: Glatiramer Acetate; Drug: Placebo; Drug: Prednisone

Detailed Description

One interim analysis was planned for possible early termination due to proven efficacy when 75% of the preplanned 500 (approx. 375 patients) recruited patients completed the entire study duration or early discontinued.

In addition to the stopping rule already given for proven efficacy, the sponsor was also interested in examining the data for futility (i.e., absence of the desired treatment effect) with the view to terminating the trial if an "insufficient" effect of the treatment is seen. The reasons why the need for futility arose were:

1. Recruitment difficulties
2. Increasing dropout rate
3. Budgetary constraints

The primary efficacy measure is defined as the percent change from baseline to termination (Month 36 or Early Termination) in normalized brain volume (Brain Atrophy) measured according to the SIENA (Structural Imaging Evaluation using Normalization of Atrophy) method. However, since not many patients had completed the entire study at the time of futility analysis, it was the sponsor's decision that the futility analysis be performed on patients with MRI scans at months 24 or 36 or at early termination visits - the latest available.

Based on the recalculation of study power (probability is unconditioned on the interim result and provide the real power of the study if designed anew), conditional power (based on the interim results) and risk assessment of a false negative, the Data Monitoring Committee agreed that the study should be terminated early.

• Study Type: Interventional
• Enrollment (Actual): 414
• Phase: Phase 4

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 53 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Clinically definite multiple sclerosis (CDMS) according to Poser (Ann. Neurol. 1983) or McDonald (Ann. Neurol. 2001)
2. Subjects eligible for GA treatment based on the investigator's clinical assessment and according to the current indication.
3. Subjects must have a relapsing remitting disease course.
4. Subjects must have had at least 1 documented relapse within the last year prior to study entry.
5. Subjects may be male or female. Women of childbearing potential must practice an acceptable method of birth control. Acceptable methods include oral contraceptive, contraceptive patch, long-acting injectable contraceptive, double-barrier method (condom or intrauterine device [IUD] with spermicide), or partner's vasectomy.
6. Subjects must be between the ages of 18 and 55 years inclusive.
7. Subjects must be ambulatory, with a Kurtzke Expanded Disability Status Scale (EDSS) score between 0 and 5.0 inclusive.
8. Subjects must be willing and able to give written informed consent prior to entering the study.

Exclusion Criteria:

1. Long-term glatiramer acetate users who have been on therapy within 6 months of the baseline magnetic resonance imaging (MRI). New glatiramer acetate users who have initiated therapy for more than 6 weeks prior to the baseline MRI.
2. Previous use of cladribine.
3. Previous use of mitoxantrone.
4. Use of digitalis at study entry.
5. Previous use of immunosuppressive agents (such as azathioprine, cyclophosphamide or mycophenolate mofetil) in the last 6 months prior to screening.
6. Use of experimental or investigational drugs, including intravenous (IV) immunoglobulin within 6 months prior to screening.
7. Use of interferon agents within 1 month prior to the baseline MRI.
8. Use of corticosteroids (IV, intramuscular [IM] and/or by mouth [PO]) within 30 days prior to the baseline MRI.
9. Chronic corticosteroid (IV, IM and/or PO) treatment (more than 30 consecutive days) in the 6 months prior to the screening visit.
10. Subjects with diabetes.
11. Previous total body irradiation or total lymphoid irradiation.
12. Pregnancy or breast feeding.
13. Significant medical or psychiatric condition that affects the subject's ability to give informed consent, or to complete the study, or any condition which the investigator feels may interfere with participation in the study (e.g. alcohol or drug abuse).
14. Other diseases that can cause brain atrophy (ex. neurodegenerative disorder, cerebrovascular disease, history of alcohol abuse).
15. Bone density less than -2.5 standard deviations (SD) (osteoporosis).
16. A known history of sensitivity to mannitol.
17. Contraindication to, or known history of, sensitivity or severe reaction to steroids.
18. A known history of sensitivity to gadolinium.
19. Inability to successfully undergo MRI scanning.
20. Previous use of natalizumab.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: GA + Placebo; Glatiramer acetate (GA) 10mg as a subcutaneous injection daily, plus a placebo to mimic prednisone given daily.	Drug: Glatiramer Acetate; 20mg glatiramer acetate (GA) administered by daily subcutaneous injections; Other Names: Copaxone; Drug: Placebo; Placebo for prednisone given daily
Experimental: GA + Prednisone; Glatiramer acetate (GA) 20mg daily as a subcutaneous injection, plus 1250 mg of prednisone daily.	Drug: Glatiramer Acetate; 20mg glatiramer acetate (GA) administered by daily subcutaneous injections; Other Names: Copaxone; Drug: Prednisone; Prednisone 1250 mg taken daily; Other Names: corticosteroid

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percent Change From Baseline to Termination in Normalized Brain Volume Measured According to the SIENA (Structural Imaging Evaluation Using Normalization of Atrophy) Method	Results represent the database as of January 29, 2009. Brain volume was measured at baseline and at months 24, 36 and at early termination visits by magnetic resonance imaging (MRI). Brain atrophy was measured by comparing the change in brain volume from baseline to the latest scan at the three during study timeframes. SIENA is a fully automated method of analyzing longitudinal brain change. Adjusted (least square) mean values are presented.	Day 0, latest scan at month 24, 36 or early termination visit

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cumulative Number of Enhancing Lesions at Months 12, 24 and 36	Results represent the database as of January 29, 2009. Enhancing lesions are lesions that show inflammation on an MRI and are assumed to be new lesions. The sum of enhancing lesions observed in MRIs taken at months 12, 24 and 36 are offered.	Months 12, 24, and 36
Change From Baseline to Month 36 or Early Termination Visit in Volume of T2-Lesions	Results represent the database as of January 29, 2009. The difference in T2 brain lesion volume as observed in MRIs from baseline to Month 36 or the early termination visit. T2 lesions are hyperintense lesions meaning that they appear as bright spots on the MRI image. These tend to show the total number of lesions and disease burden.	Day 0, Month 36 or the early termination visit
Change From Baseline to Month 36 or Early Termination Visit in Volume of Hypointense Lesions	Results represent the database as of January 29, 2009. The difference in hypointense brain lesion volume as observed in MRIs from baseline to Month 36 or the early termination visit. Hypointense lesions display as dark areas on the MRI image, and represent areas of permanent axonal damage.	Day 0, Month 36 or early termination visit

Collaborators and Investigators

• Sponsor: Teva Branded Pharmaceutical Products R&D, Inc.
• Investigators: Study Chair: Jean-Louis Stril, MD, Teva Neuroscience Canada

Publications and helpful links

General Publications

• Milo R, Panitch H. Combination therapy in multiple sclerosis. J Neuroimmunol. 2011 Feb;231(1-2):23-31. doi: 10.1016/j.jneuroim.2010.10.021. Epub 2010 Dec 15.

Study record dates

Study Major Dates

• Study Start: January 1, 2005
• Primary Completion (Actual): May 1, 2009
• Study Completion (Actual): May 1, 2009

Study Registration Dates

• First Submitted: September 13, 2005
• First Submitted That Met QC Criteria: September 13, 2005
• First Posted (Estimate): September 20, 2005

Study Record Updates

• Last Update Posted (Estimate): January 6, 2014
• Last Update Submitted That Met QC Criteria: November 15, 2013
• Last Verified: November 1, 2013

More Information

Terms related to this study

• Keywords: Multiple Sclerosis; brain atrophy; Prednisone; Steroids; Copaxone; Glatiramer Acetate
• Additional Relevant MeSH Terms: Pathologic Processes; Nervous System Diseases; Immune System Diseases; Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Demyelinating Diseases; Autoimmune Diseases; Multiple Sclerosis; Sclerosis; Multiple Sclerosis, Relapsing-Remitting; Physiological Effects of Drugs; Anti-Inflammatory Agents; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Adjuvants, Immunologic; Prednisone; Glatiramer Acetate; (T,G)-A-L
• Other Study ID Numbers: TNC GA MS 2004_01