Atacicept in Multiple Sclerosis Extension Study, Phase II (ATAMS ext)
This study (28851) is a long-term follow-up study of subjects enrolled in ATAMS study 28063 (NCT00642902). The aim of this study is to monitor the safety and tolerability of atacicept administered for up to 5 years to subjects with relapsing multiple sclerosis (RMS).
This extension study consists of two parts. Part A will be double blind and Part B will be open label. During Part A, subjects initially randomized to atacicept will continue to receive the atacicept dose to which they have been randomized in study 28063 (ATAMS) once a week subcutaneously (under the skin). Subjects randomized to placebo in ATAMS will receive atacicept at 150 mg once a week subcutaneously during Part A. Once the results of ATAMS are available and the atacicept dose with the best benefit / risk ratio has been identified, all subjects will be switched to this dose and will continue the extension study open-label (Part B). Throughout the study, subjects and investigators will remain blinded with respect to initial and part A treatment allocation/dose.
|Study Design:||Allocation: Randomized
Endpoint Classification: Safety Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
|Official Title:||An Open-label, Multicenter Phase II Extension of Study 28063 (ATAMS) to Obtain Long-term Follow-up Data in Subjects With Relapsing Multiple Sclerosis Treated With Atacicept for up to 5 Years (ATAMS-Extension)|
- Number of Subjects With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, Injection Site Reactions, Infections, and Malignancies by Severity [ Time Frame: From the first dose of study drug administration up to Week 24 ] [ Designated as safety issue: Yes ]TEAEs were defined as AEs with a start date after or on the date of the first DB treatment injection in ATAMS Extension and that occurred anytime after treatment discontinuation, or up to the day before first Rebif® rescue medication injection in ATAMS Extension. A serious TEAE was an AE that resulted in any of the following: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect. TEAE severity was graded as per Qualitative Toxicity Scale. Local injection site reactions (injection site: pain, redness, itching and swelling) throughout ATAMS Extension, starting after the first trial medication administration. If the subject experienced 1 or more of the above injection site symptoms, these were reported with the AE verbatim term "injection site reaction". For all randomized subjects, there was an option of rescue treatment with Rebif® for 1 year beginning with the first injection of Rebif®).
- Change From Baseline in Vital Signs: Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) [ Time Frame: Baseline, Week 2, 4, 8, 12, 16, 20, 24 and 36 ] [ Designated as safety issue: Yes ]Blood pressure (systolic and diastolic) was measured after at least 3 minutes resting, with the subject in the seated position.
- Change From Baseline in Vital Signs: Pulse Rate [ Time Frame: Baseline, Week 2, 4, 8, 12, 16, 20, 24 and 36 ] [ Designated as safety issue: Yes ]
- Change From Baseline in Vital Signs: Temperature [ Time Frame: Baseline, Week 2, 4, 8, 12, 16, 20, 24 and 36 ] [ Designated as safety issue: Yes ]
- Change From Baseline in Electrocardiogram (ECGs) [ Time Frame: Baseline, Week 12 and 36 ] [ Designated as safety issue: Yes ]
- Number of Subjects With Worsened Post Baseline Shift in Immunoglobulin A (IgA), IgG and IgM Levels [ Time Frame: Baseline up to Week 36 ] [ Designated as safety issue: No ]Number of subjects with shifts from normal Grade (Grade 0) at Baseline to worse value at post-baseline (Grade 1 to Grade 4) according to the following criteria: IgA Grade 0: greater than or equal to (>=) lower limit normal (LLN) 0.7 gram per liter (g/L); Grade 1: less than (<) LLN - 0.5 g/L, Grade 2: <0.5g/L -0.3 g/L, Grade 3: <0.3 g/L -0.1 g/L, Grade 4: < 0.1 g/L; IgG Grade 0: >= LLN (7 g/L), Grade 1: < LLN - 5 g/L, Grade 2: <5g/L -4 g/L, Grade 3: <4 g/L -3 g/L and Grade 4: < 3 g/L; IgM Grade 0: >= LLN (0.4 g/L), Grade 1: < LLN - 0.3 g/L, Grade 2: <0.3 g/L -0.2 g/L, Grade 3: <0.2 g/L -0.1 g/L, and Grade 4: < 0.1 g/L are presented in this outcome measure.
- Number of Subjects With Positive Neutralizing Antibody (NAb) [ Time Frame: Baseline, Week 12 and 36 ] [ Designated as safety issue: No ]
- Number of Subjects With Clinical Attacks/Relapses [ Time Frame: Baseline up to Week 24 ] [ Designated as safety issue: No ]
A clinical attack/relapse was defined as the fulfillment of all the following criteria:
- Neurological abnormality, either newly appearing or re-appearing, with abnormality specified by both i) neurological abnormality separated by at least 30 days from onset of a preceding clinical event, and ii) neurological abnormality lasting for at least 24 hours.
- Absence of fever or known infection (fever with temperature (axillary, orally, or intra-auriculary) > 37.5°C/99.5 °Fahrenheit).
- Objective neurological impairment, correlating with the subject's reported symptoms, defined as either i) increase in at least 1 of the functional systems of the Expanded Disability Status Scale (EDSS), or ii) increase of the total EDSS score. EDSS overall score ranging from 0 (normal) to 10 (death due to MS) was calculated.
- Change From Baseline in Expanded Disability Status Scale (EDSS) Scores at Week 12 [ Time Frame: Baseline, Week 12 ] [ Designated as safety issue: No ]EDSS is an ordinal scale in half-point increments that qualifies disability in participants with multiple sclerosis (MS). It assesses the 8 functional systems (visual, brainstem, pyramidal, cerebellar, sensory, bowel/bladder, cerebral and other) as well as ambulation. EDSS overall score ranging from 0 (normal) to 10 (death due to MS) was calculated.
- Change in Multiple Sclerosis Functional Composite (MSFC) Score at Week 12 [ Time Frame: Week 12 ] [ Designated as safety issue: No ]The MSFC is a multidimensional clinical outcome measure which consists of three sub-tests; Timed 25-Foot Walk, 9-Hole Peg Test and Paced Auditory Serial Addition Test-3(PASAT-3). The Timed 25-Foot Walk is a quantitative measure of lower extremity function. The 9-Hole Peg Test is a quantitative measure of upper extremity (arm and hand) function. The PASAT is a measure of cognitive function that specifically assesses auditory information processing speed and flexibility, as well as calculation ability. Standardized results (Z-scores) of these sub-tests and the overall MSFC Z-score as an average of these three Z-scores was calculated. Higher Z-scores reflect better neurological function and a positive change from baseline indicates improvement. An increase in score indicates an improvement (range -3 to +3).
- Magnetic Resonance Imaging (MRI) Parameters: Number of T1 Gadolinium (Gd)-Enhancing Lesions Per Subject [ Time Frame: Baseline, Week 12 and 24 ] [ Designated as safety issue: No ]
- Magnetic Resonance Imaging (MRI) Parameters: Volume of T2 Lesions (New or Enlarging T2 Lesions) Per Subject [ Time Frame: Baseline, Week 12 and Week 24 ] [ Designated as safety issue: No ]
- Concentrations of Free and Total Atacicept [ Time Frame: Baseline and Week 12 ] [ Designated as safety issue: No ]
- Free B-Lymphocyte Stimulator (BLyS) and Free A Proliferation-Inducing Ligand (APRIL) Serum Concentrations. [ Time Frame: Baseline, Week 12 and 36 ] [ Designated as safety issue: No ]Levels of free APRIL and free BLyS: Free APRIL serum samples were to be analyzed by using a validated enzyme-linked immunosorbent assay (ELISA) with limits of detection of 0.3125 nanogram per milliliter (ng/mL) for free APRIL and free BlyS serum samples were analysed using a validated ELISA with limits of detection of 1.56 ng/mL.
- Pharmacogenetics/Pharmacogenomics Analysis [ Time Frame: Day 1 and Week 36 ] [ Designated as safety issue: No ]
Gene expression profiling and gene polymorphism identification were to be used to identify putative markers for response to treatment.
- Genome-wide gene polymorphism characterization by genome-wide scan.
- Targeted gene polymorphism identification of B-Lymphocyte Stimulator (BLyS) , APRIL, (receptor for B cell activating factor of the tumor necrosis factor [TNF] family) BAFF-R, (Transmembrane Activator) TACI and (B Cell Maturation Antigen) BCMA and HLA-DRB1 by direct genotyping or sequencing .
|Study Start Date:||March 2009|
|Study Completion Date:||February 2011|
|Primary Completion Date:||September 2009 (Final data collection date for primary outcome measure)|
|Experimental: Part A: Double blind: Atacicept||
Subjects who received atacicept 25 milligram (mg), 75 mg, and 150 mg subcutaneously (SC) as loading dose twice weekly for first 4 weeks, followed by atacicept 25 mg, 75 mg, and 150 mg SC for 32 weeks, in 28063 study will be continued with atacicept 25 mg, 75 mg, 150 mg and 150 mg (without loading) SC, respectively once weekly up to 5 years or up to early termination of treatment or early termination of the study. Subjects who received placebo SC twice weekly for first 4 weeks, followed by placebo SC for 32 weeks, in 28063 study will be continued with atacicept 150 mg (without loading dose) SC once weekly up to 5 years or up to early termination of treatment or early termination of the study.
|Experimental: Part B: Open Label: Atacicept||
Subjects will receive the atacicept dose with best benefit/risk ratio treatment which will be identified in ATAMS study.
Please refer to this study by its ClinicalTrials.gov identifier: NCT00853762
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|Study Director:||Daniel Mikol, MD, PhD||EMD Serono|