Atacicept in Multiple Sclerosis Extension Study, Phase II | NCT00853762

Name	Class
Merck KGaA, Darmstadt, Germany	INDUSTRY

Label	Type	Intervention Names
Atacicept 25 mg (With Loading)	Experimental	Drug: Atacicept 25 mg
Atacicept 75 mg (With Loading)	Experimental	Drug: Atacicept 75 mg
Atacicept 150 mg (With Loading)	Experimental	Drug: Atacicept 150 mg
Atacicept 150 mg (Without Loading)	Experimental	Drug: Atacicept 150 mg

Name	Type	Description	Arm Group Labels	Other Names
Atacicept 25 mg	Drug	Subjects who received atacicept 25 milligram (mg) subcutaneously (SC) as loading dose twice weekly for first 4 weeks, followed by atacicept 25 mg SC for 32 weeks, in 28063 study will continue with atacicept 25 mg SC once weekly up to 5 years or up to early termination of treatment or early termination of the study.

Measure	Description	Time Frame
Number of Subjects With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, Injection Site Reactions, Infections, and Malignancies by Severity	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®).	From the first dose of study drug administration up to Week 24
Change From Baseline in Vital Signs: Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP)	Blood pressure (systolic and diastolic) was measured after at least 3 minutes resting, with the subject in the seated position.	Baseline, Week 2, 4, 8, 12, 16, 20, 24 and 36
Change From Baseline in Vital Signs: Pulse Rate		Baseline, Week 2, 4, 8, 12, 16, 20, 24 and 36
Change From Baseline in Vital Signs: Temperature		Baseline, Week 2, 4, 8, 12, 16, 20, 24 and 36
Change From Baseline in Electrocardiogram (ECGs)		Baseline, Week 12 and 36
Number of Subjects With Worsened Post Baseline Shift in Immunoglobulin A (IgA), IgG and IgM Levels

Measure	Description	Time Frame
Number of Subjects With Clinical Attacks/Relapses	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.

Eligibility Module

Eligibility Criteria

Inclusion Criteria:

Participation in study 28063.
Completion of Week 36 visit of the core study 28063.
Willingness and ability to comply with study procedures for the duration of the study.
Voluntary provision of written informed consent (including, for the USA, subject authorization under the Health Insurance Portability and Accountability Act (HIPAA)), given before any study-related procedure that is not part of normal medical care and with the understanding that the subject may withdraw consent at any time without prejudice to his or her future medical care.

Exclusion Criteria:

Premature discontinuation of core study 28063.
Subjects who meet criteria listed below will receive IMP in study 28851:
- Subjects who are eligible for participation in extension study 28851 but do not meet these criteria will not be treated with IMP but will undergo scheduled visits, irrespective of their treatment.
All subjects must satisfy the following criteria before Extension Study Day 1 (D1-EXT; defined as the first day of dosing in the extension study) to be eligible for treatment with IMP:
- Eligibility for participation in extension study 28851.
- For women of childbearing potential, a negative urine pregnancy test at eligibility assessment.
- Female subjects of childbearing potential must be willing to avoid pregnancy by using an adequate method of contraception for four (4) weeks before the first dose administered within the extension study, during the study and for twelve (12) weeks after the last dose of trial medication. Adequate contraception is defined as two barrier methods, or one barrier method with spermicide, or an intrauterine device, or use of a combined oral female hormonal contraceptive (or the definitions requested by health authorities and locally amended in the core study 28063). For the purposes of this trial, women of childbearing potential are defined as: "All female subjects after puberty unless they are post-menopausal for at least two years or are surgically sterile" (For Germany Only: Female subjects of childbearing potential must be willing to avoid pregnancy by using highly effective methods of contraception for approximately four (4) weeks prior to D1-EXT, during and for twelve (12) weeks after the last dose of trial medication. This requirement does not apply to surgically sterile subjects or to subjects who are postmenopausal for at least 2 years. Highly effective contraception is defined as any method or combination of methods which result in a low failure rate (i.e. less than (<) 1% per year) when used consistently and correctly, such as implants, injectables, combined oral contraceptives, sexual abstinence, vasectomized partner, 2 barrier methods, or 1 barrier method with spermicide)
Willingness and ability to comply with study procedures for the duration of the study.
To be eligible for treatment with investigational medicinal product (IMP) in study 28851, the subjects must not meet any of the following criteria:
Non-eligibility for participation in extension study 28851 (premature discontinuation of core study 28063).
Major protocol violation or non-compliance in the core study.
Use of prohibited immunomodulatory / immunosuppressive therapies
Serum immunoglobulin G (IgG) level <3 gram per liter (g/L) if the subject received atacicept in the core study, or serum IgG level <6 g/L if the subject received placebo in the core study (to protect the blinding of the core study, the IgG level will be communicated to the treating physician only if it is too low for extension study participation and only after all Week 36 assessments performed within the core study have been completed).
Any condition, including laboratory findings that, in the opinion of the Investigator, constitutes a risk or a contraindication for participation in the extension study, or that could interfere with the study objectives, conduct or evaluation.
Known active clinically significant acute or chronic infection, or any major episode of infection requiring hospitalization or treatment with parenteral anti-infectives.
Investigator judgement that treatment of the subject with atacicept in the extension study is not appropriate.
Aspartate aminotransferase (AST), or alanine aminotransferase (ALT), or alkaline phosphatase (AP) level greater than (>)2.5 x upper limit of normal (ULN), or total bilirubin >1.5 x ULN at eligibility assessment.
Clinically significant abnormality in any hematological test (e.g. hemoglobin <100 g/L (6.21 millimoles per liter [mmol/L]), white blood cells <3 x 10^9 per liter (/L), platelets <100 x 10^9/L) at eligibility assessment.
Clinically significant abnormality on electrocardiogram (ECG) performed at eligibility assessment.
Presence of uncontrolled or New York Health Association (NYHA) class 3 or 4 congestive heart failure at Week 36 of the core study.
Moderate to severe renal impairment (creatinine clearance <50 milliliter per minute (mL/min) according to Cockcroft-Gault equation).
Allergy or hypersensitivity to gadolinium (Gd).
Allergy or hypersensitivity to atacicept or to any of the components of the formulated atacicept.
Diagnosis or family history of Creutzfeldt-Jakob disease (CJD).

Name	Affiliation	Role
Daniel Mikol, MD, PhD	EMD Serono	Study Director

Facility	Status	City	State	ZIP	Country	Contacts
Research Site		Phoenix	Arizona		United States
Research Site

PubMed Identifier	Type	Citation	Retractions
24613349	Derived	Kappos L, Hartung HP, Freedman MS, Boyko A, Radu EW, Mikol DD, Lamarine M, Hyvert Y, Freudensprung U, Plitz T, van Beek J; ATAMS Study Group. Atacicept in multiple sclerosis (ATAMS): a randomised, placebo-controlled, double-blind, phase 2 trial. Lancet Neurol. 2014 Apr;13(4):353-63. doi: 10.1016/S1474-4422(14)70028-6. Epub 2014 Mar 6.

ID	Title	Description
FG000	Atacicept 25 mg (With Loading)	Subjects who received atacicept 25 milligram (mg) subcutaneously (SC) as loading dose twice weekly for first 4 weeks, followed by atacicept 25 mg SC for 32 weeks, in 28063 study were continued with atacicept 25 mg SC once weekly up to 5 years or up to early termination of treatment or early termination of the study.

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

Number of Subjects With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, Injection Site Reactions, Infections, and Malignancies by Severity

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®).

Double-blind safety analysis set included all the subjects who received at least 1 dose of trial medication in the ATAMS extension study.

Posted

Number

Subjects

From the first dose of study drug administration up to Week 24

ID	Title	Description
OG000	Atacicept 25 mg (With Loading)	Subjects who received atacicept 25 mg SC as loading dose twice weekly for first 4 weeks, followed by atacicept 25 mg SC for 32 weeks, in 28063 study were continued with atacicept 25 mg SC once weekly up to 5 years or up to early termination of treatment or early termination of the study.
OG001	Atacicept 75 mg (With Loading)	Subjects who received atacicept 75 mg SC as loading dose twice weekly for first 4 weeks, followed by atacicept 75 mg SC for 32 weeks, in 28063 study were continued with atacicept 75 mg SC once weekly up to 5 years or up to early termination of treatment or early termination of the study.
OG002	Atacicept 150 mg (With Loading)	Subjects who received atacicept 150 mg SC as loading dose twice weekly for first 4 weeks, followed by atacicept 150 mg SC for 32 weeks, in 28063 study were continued with atacicept 150 mg SC once weekly up to 5 years or up to early termination of treatment or early termination of the study.
OG003	Atacicept 150 mg (Without Loading)	Subjects who received placebo SC twice weekly for first 4 weeks, followed by placebo SC for 32 weeks, in 28063 study were 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.

Units	Counts
Participants	OG00016 OG00117 OG00215 OG003

Title

Denominators

Categories

Mild TEAEs

Title	Measurements
	OG0005 OG0018 OG0028 OG003

Primary

Change From Baseline in Vital Signs: Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP)

Blood pressure (systolic and diastolic) was measured after at least 3 minutes resting, with the subject in the seated position.

Double-blind safety analysis set included all the subjects who received at least 1 dose of trial medication in the ATAMS extension study. Here 'n' signifies those subjects who were evaluable for the specified category.

Posted

Mean

Standard Deviation

millimeter of mercury (mmHg)

Baseline, Week 2, 4, 8, 12, 16, 20, 24 and 36

ID	Title	Description
OG000	Atacicept 25 mg (With Loading)	Subjects who received atacicept 25 mg SC as loading dose twice weekly for first 4 weeks, followed by atacicept 25 mg SC for 32 weeks, in 28063 study were continued with atacicept 25 mg SC once weekly up to 5 years or up to early termination of treatment or early termination of the study.
OG001	Atacicept 75 mg (With Loading)	Subjects who received atacicept 75 mg SC as loading dose twice weekly for first 4 weeks, followed by atacicept 75 mg SC for 32 weeks, in 28063 study were continued with atacicept 75 mg SC once weekly up to 5 years or up to early termination of treatment or early termination of the study.
OG002	Atacicept 150 mg (With Loading)

Primary

Change From Baseline in Vital Signs: Pulse Rate

Posted

Mean

Standard Deviation

beats per minute (beats/min)

Baseline, Week 2, 4, 8, 12, 16, 20, 24 and 36

ID	Title	Description
OG000	Atacicept 25 mg (With Loading)	Subjects who received atacicept 25 mg SC as loading dose twice weekly for first 4 weeks, followed by atacicept 25 mg SC for 32 weeks, in 28063 study were continued with atacicept 25 mg SC once weekly up to 5 years or up to early termination of treatment or early termination of the study.
OG001	Atacicept 75 mg (With Loading)	Subjects who received atacicept 75 mg SC as loading dose twice weekly for first 4 weeks, followed by atacicept 75 mg SC for 32 weeks, in 28063 study were continued with atacicept 75 mg SC once weekly up to 5 years or up to early termination of treatment or early termination of the study.
OG002	Atacicept 150 mg (With Loading)	Subjects who received atacicept 150 mg SC as loading dose twice weekly for first 4 weeks, followed by atacicept 150 mg SC for 32 weeks, in 28063 study were continued with atacicept 150 mg SC once weekly up to 5 years or up to early termination of treatment or early termination of the study.

Primary

Change From Baseline in Vital Signs: Temperature

Posted

Mean

Standard Deviation

Degree Celsius

Baseline, Week 2, 4, 8, 12, 16, 20, 24 and 36

ID	Title	Description
OG000	Atacicept 25 mg (With Loading)	Subjects who received atacicept 25 mg SC as loading dose twice weekly for first 4 weeks, followed by atacicept 25 mg SC for 32 weeks, in 28063 study were continued with atacicept 25 mg SC once weekly up to 5 years or up to early termination of treatment or early termination of the study.
OG001	Atacicept 75 mg (With Loading)	Subjects who received atacicept 75 mg SC as loading dose twice weekly for first 4 weeks, followed by atacicept 75 mg SC for 32 weeks, in 28063 study were continued with atacicept 75 mg SC once weekly up to 5 years or up to early termination of treatment or early termination of the study.
OG002	Atacicept 150 mg (With Loading)	Subjects who received atacicept 150 mg SC as loading dose twice weekly for first 4 weeks, followed by atacicept 150 mg SC for 32 weeks, in 28063 study were continued with atacicept 150 mg SC once weekly up to 5 years or up to early termination of treatment or early termination of the study.

Primary

Change From Baseline in Electrocardiogram (ECGs)

No summary tables were prepared for ECG parameters, and ECG data were not formally analyzed. However, a qualitative assessment of ECG morphology and rhythm was made by the Investigator and recorded in the electronic case report form (eCRF). ECG abnormalities considered significant by the investigator were reported as AEs.

Posted

Baseline, Week 12 and 36

ID	Title	Description
OG000	Atacicept 25 mg (With Loading)	Subjects who received atacicept 25 mg SC as loading dose twice weekly for first 4 weeks, followed by atacicept 25 mg SC for 32 weeks, in 28063 study were continued with atacicept 25 mg SC once weekly up to 5 years or up to early termination of treatment or early termination of the study.
OG001	Atacicept 75 mg (With Loading)	Subjects who received atacicept 75 mg SC as loading dose twice weekly for first 4 weeks, followed by atacicept 75 mg SC for 32 weeks, in 28063 study were continued with atacicept 75 mg SC once weekly up to 5 years or up to early termination of treatment or early termination of the study.
OG002	Atacicept 150 mg (With Loading)	Subjects who received atacicept 150 mg SC as loading dose twice weekly for first 4 weeks, followed by atacicept 150 mg SC for 32 weeks, in 28063 study were continued with atacicept 150 mg SC once weekly up to 5 years or up to early termination of treatment or early termination of the study.

Primary

Number of Subjects With Worsened Post Baseline Shift in Immunoglobulin A (IgA), IgG and IgM Levels

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.

Intent-to-treat (ITT) population included all randomized subjects.

Posted

Number

Subjects

Baseline up to Week 36

ID	Title	Description
OG000	Atacicept 25 mg (With Loading)	Subjects who received atacicept 25 mg SC as loading dose twice weekly for first 4 weeks, followed by atacicept 25 mg SC for 32 weeks, in 28063 study were continued with atacicept 25 mg SC once weekly up to 5 years or up to early termination of treatment or early termination of the study.
OG001	Atacicept 75 mg (With Loading)	Subjects who received atacicept 75 mg SC as loading dose twice weekly for first 4 weeks, followed by atacicept 75 mg SC for 32 weeks, in 28063 study were continued with atacicept 75 mg SC once weekly up to 5 years or up to early termination of treatment or early termination of the study.

Secondary

Number of Subjects With Clinical Attacks/Relapses

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.

Intent-to-treat (ITT) population included all randomized subjects.

Posted

Number

Subjects

Baseline up to Week 24

ID	Title	Description
OG000	Atacicept 25 mg (With Loading)	Subjects who received atacicept 25 mg SC as loading dose twice weekly for first 4 weeks, followed by atacicept 25 mg SC for 32 weeks, in 28063 study were continued with atacicept 25 mg SC once weekly up to 5 years or up to early termination of treatment or early termination of the study.
OG001	Atacicept 75 mg (With Loading)	Subjects who received atacicept 75 mg SC as loading dose twice weekly for first 4 weeks, followed by atacicept 75 mg SC for 32 weeks, in 28063 study were continued with atacicept 75 mg SC once weekly up to 5 years or up to early termination of treatment or early termination of the study.

Secondary

Change From Baseline in Expanded Disability Status Scale (EDSS) Scores at Week 12

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.

Intent-to-treat (ITT) population included all randomized subjects. "N" signifies (total number of subjects analyzed) the number of evaluable subjects for this outcome measure.

Posted

Mean

Standard Deviation

Units on a scale

Baseline, Week 12

ID	Title	Description
OG000	Atacicept 25 mg (With Loading)	Subjects who received atacicept 25 mg SC as loading dose twice weekly for first 4 weeks, followed by atacicept 25 mg SC for 32 weeks, in 28063 study were continued with atacicept 25 mg SC once weekly up to 5 years or up to early termination of treatment or early termination of the study.
OG001	Atacicept 75 mg (With Loading)	Subjects who received atacicept 75 mg SC as loading dose twice weekly for first 4 weeks, followed by atacicept 75 mg SC for 32 weeks, in 28063 study were continued with atacicept 75 mg SC once weekly up to 5 years or up to early termination of treatment or early termination of the study.

Secondary

Change in Multiple Sclerosis Functional Composite (MSFC) Score at Week 12

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).

Intent-to-treat (ITT) population included all randomized subjects. "N" signifies number of evaluable subjects for this outcome measure.

Posted

Mean

Standard Deviation

z-score

Week 12

ID	Title	Description
OG000	Atacicept 25 mg (With Loading)	Subjects who received atacicept 25 mg SC as loading dose twice weekly for first 4 weeks, followed by atacicept 25 mg SC for 32 weeks, in 28063 study were continued with atacicept 25 mg SC once weekly up to 5 years or up to early termination of treatment or early termination of the study.
OG001	Atacicept 75 mg (With Loading)

Secondary

Magnetic Resonance Imaging (MRI) Parameters: Number of T1 Gadolinium (Gd)-Enhancing Lesions Per Subject

Intent-to-treat (ITT) population included all randomized subjects. "n" signifies the number of evaluable subjects for this outcome measure.

Posted

Mean

Standard Deviation

Number of lesions per subject

Baseline, Week 12 and 24

ID	Title	Description
OG000	Atacicept 25 mg (With Loading)	Subjects who received atacicept 25 mg SC as loading dose twice weekly for first 4 weeks, followed by atacicept 25 mg SC for 32 weeks, in 28063 study were continued with atacicept 25 mg SC once weekly up to 5 years or up to early termination of treatment or early termination of the study.
OG001	Atacicept 75 mg (With Loading)	Subjects who received atacicept 75 mg SC as loading dose twice weekly for first 4 weeks, followed by atacicept 75 mg SC for 32 weeks, in 28063 study were continued with atacicept 75 mg SC once weekly up to 5 years or up to early termination of treatment or early termination of the study.
OG002	Atacicept 150 mg (With Loading)	Subjects who received atacicept 150 mg SC as loading dose twice weekly for first 4 weeks, followed by atacicept 150 mg SC for 32 weeks, in 28063 study were continued with atacicept 150 mg SC once weekly up to 5 years or up to early termination of treatment or early termination of the study.

Secondary

Magnetic Resonance Imaging (MRI) Parameters: Volume of T2 Lesions (New or Enlarging T2 Lesions) Per Subject

Posted

Mean

Standard Deviation

Cubic millimeter

Baseline, Week 12 and Week 24

ID	Title	Description
OG000	Atacicept 25 mg (With Loading)	Subjects who received atacicept 25 mg SC as loading dose twice weekly for first 4 weeks, followed by atacicept 25 mg SC for 32 weeks, in 28063 study were continued with atacicept 25 mg SC once weekly up to 5 years or up to early termination of treatment or early termination of the study.
OG001	Atacicept 75 mg (With Loading)	Subjects who received atacicept 75 mg SC as loading dose twice weekly for first 4 weeks, followed by atacicept 75 mg SC for 32 weeks, in 28063 study were continued with atacicept 75 mg SC once weekly up to 5 years or up to early termination of treatment or early termination of the study.
OG002	Atacicept 150 mg (With Loading)	Subjects who received atacicept 150 mg SC as loading dose twice weekly for first 4 weeks, followed by atacicept 150 mg SC for 32 weeks, in 28063 study were continued with atacicept 150 mg SC once weekly up to 5 years or up to early termination of treatment or early termination of the study.
OG003

Secondary

Concentrations of Free and Total Atacicept

This outcome measure was not assessed due to lack of a valid assay during the usable time period of the samples.

Posted

Baseline and Week 12

ID	Title	Description
OG000	Atacicept 25 mg (With Loading)	Subjects who received atacicept 25 mg SC as loading dose twice weekly for first 4 weeks, followed by atacicept 25 mg SC for 32 weeks, in 28063 study were continued with atacicept 25 mg SC once weekly up to 5 years or up to early termination of treatment or early termination of the study.
OG001	Atacicept 75 mg (With Loading)	Subjects who received atacicept 75 mg SC as loading dose twice weekly for first 4 weeks, followed by atacicept 75 mg SC for 32 weeks, in 28063 study were continued with atacicept 75 mg SC once weekly up to 5 years or up to early termination of treatment or early termination of the study.
OG002	Atacicept 150 mg (With Loading)	Subjects who received atacicept 150 mg SC as loading dose twice weekly for first 4 weeks, followed by atacicept 150 mg SC for 32 weeks, in 28063 study were continued with atacicept 150 mg SC once weekly up to 5 years or up to early termination of treatment or early termination of the study.

Secondary

Free B-Lymphocyte Stimulator (BLyS) and Free A Proliferation-Inducing Ligand (APRIL) Serum Concentrations.

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.

This outcome measure was not assessed due to lack of a valid assay for measuring BLyS and APRIL.

Posted

Baseline, Week 12 and 36

ID	Title	Description
OG000	Atacicept 25 mg (With Loading)	Subjects who received atacicept 25 mg SC as loading dose twice weekly for first 4 weeks, followed by atacicept 25 mg SC for 32 weeks, in 28063 study were continued with atacicept 25 mg SC once weekly up to 5 years or up to early termination of treatment or early termination of the study.
OG001	Atacicept 75 mg (With Loading)	Subjects who received atacicept 75 mg SC as loading dose twice weekly for first 4 weeks, followed by atacicept 75 mg SC for 32 weeks, in 28063 study were continued with atacicept 75 mg SC once weekly up to 5 years or up to early termination of treatment or early termination of the study.
OG002	Atacicept 150 mg (With Loading)

Secondary

Pharmacogenetics/Pharmacogenomics Analysis

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 .

Genetic/genomic analysis was not performed as the trial was terminated early.

Posted

Day 1 and Week 36

ID	Title	Description
OG000	Atacicept 25 mg (With Loading)	Subjects who received atacicept 25 mg SC as loading dose twice weekly for first 4 weeks, followed by atacicept 25 mg SC for 32 weeks, in 28063 study were continued with atacicept 25 mg SC once weekly up to 5 years or up to early termination of treatment or early termination of the study.
OG001	Atacicept 75 mg (With Loading)	Subjects who received atacicept 75 mg SC as loading dose twice weekly for first 4 weeks, followed by atacicept 75 mg SC for 32 weeks, in 28063 study were continued with atacicept 75 mg SC once weekly up to 5 years or up to early termination of treatment or early termination of the study.
OG002

Primary

Number of Subjects With Positive Neutralizing Antibody (NAb)

Appropriate method/test was not established to identify the positive neutralizing antibodies for atacicept. Hence, this outcome measure was not assessed.

Posted

Baseline, Week 12 and 36

ID	Title	Description
OG000	Atacicept 25 mg (With Loading)	Subjects who received atacicept 25 mg SC as loading dose twice weekly for first 4 weeks, followed by atacicept 25 mg SC for 32 weeks, in 28063 study were continued with atacicept 25 mg SC once weekly up to 5 years or up to early termination of treatment or early termination of the study.
OG001	Atacicept 75 mg (With Loading)	Subjects who received atacicept 75 mg SC as loading dose twice weekly for first 4 weeks, followed by atacicept 75 mg SC for 32 weeks, in 28063 study were continued with atacicept 75 mg SC once weekly up to 5 years or up to early termination of treatment or early termination of the study.
OG002	Atacicept 150 mg (With Loading)	Subjects who received atacicept 150 mg SC as loading dose twice weekly for first 4 weeks, followed by atacicept 150 mg SC for 32 weeks, in 28063 study were continued with atacicept 150 mg SC once weekly up to 5 years or up to early termination of treatment or early termination of the study.

Other Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Injection site reaction	General disorders	MedDRA 11.1	Non-systematic Assessment	EG0002 affected16 at risk EG0012 affected17 at risk EG0025 affected15 at risk EG0037 affected22 at risk
Fatigue	General disorders	MedDRA 11.1	Non-systematic Assessment	EG0000 affected16 at risk EG0012 affected17 at risk EG0020 affected15 at risk EG003
Nasopharyngitis	Infections and infestations	MedDRA 11.1	Non-systematic Assessment	EG0000 affected16 at risk EG0011 affected17 at risk EG0023 affected15 at risk EG003
Arthralgia	Musculoskeletal and connective tissue disorders	MedDRA 11.1	Non-systematic Assessment	EG0000 affected16 at risk EG0010 affected17 at risk EG0022 affected15 at risk EG003
Injection site pruritus	General disorders	MedDRA 11.1	Non-systematic Assessment	EG0000 affected16 at risk EG0011 affected17 at risk EG0020 affected15 at risk EG003
Influenza	Infections and infestations	MedDRA 11.1	Non-systematic Assessment	EG0000 affected16 at risk EG0011 affected17 at risk EG0020 affected15 at risk EG003
Viral upper respiratory tract infection	Infections and infestations	MedDRA 11.1	Non-systematic Assessment	EG0001 affected16 at risk EG0010 affected17 at risk EG0020 affected15 at risk EG003
Acute sinusitis	Infections and infestations	MedDRA 11.1	Non-systematic Assessment	EG0000 affected16 at risk EG0010 affected17 at risk EG0021 affected15 at risk EG003
Acute tonsillitis	Infections and infestations	MedDRA 11.1	Non-systematic Assessment	EG0000 affected16 at risk EG0010 affected17 at risk EG0021 affected15 at risk EG003
Ear infection	Infections and infestations	MedDRA 11.1	Non-systematic Assessment	EG0000 affected16 at risk EG0011 affected17 at risk EG0020 affected15 at risk EG003
Herpes zoster	Infections and infestations	MedDRA 11.1	Non-systematic Assessment	EG0000 affected16 at risk EG0010 affected17 at risk EG0021 affected15 at risk EG003
Respiratory tract infection viral	Infections and infestations	MedDRA 11.1	Non-systematic Assessment	EG0000 affected16 at risk EG0011 affected17 at risk EG0020 affected15 at risk EG003
Rhinitis	Infections and infestations	MedDRA 11.1	Non-systematic Assessment	EG0000 affected16 at risk EG0010 affected17 at risk EG0021 affected15 at risk EG003
Vaginitis bacterial	Infections and infestations	MedDRA 11.1	Non-systematic Assessment	EG0001 affected16 at risk EG0010 affected17 at risk EG0020 affected15 at risk EG003
Headache	Nervous system disorders	MedDRA 11.1	Non-systematic Assessment	EG0000 affected16 at risk EG0013 affected17 at risk EG0021 affected15 at risk EG003
Dizziness	Nervous system disorders	MedDRA 11.1	Non-systematic Assessment	EG0000 affected16 at risk EG0011 affected17 at risk EG0021 affected15 at risk EG003
Dysgeusia	Nervous system disorders	MedDRA 11.1	Non-systematic Assessment	EG0000 affected16 at risk EG0011 affected17 at risk EG0020 affected15 at risk EG003
Lumbar radiculopathy	Nervous system disorders	MedDRA 11.1	Non-systematic Assessment	EG0001 affected16 at risk EG0010 affected17 at risk EG0020 affected15 at risk EG003
Sinus headache	Nervous system disorders	MedDRA 11.1	Non-systematic Assessment	EG0000 affected16 at risk EG0010 affected17 at risk EG0021 affected15 at risk EG003
Trigeminal neuralgia	Nervous system disorders	MedDRA 11.1	Non-systematic Assessment	EG0000 affected16 at risk EG0011 affected17 at risk EG0020 affected15 at risk EG003
Neck pain	Musculoskeletal and connective tissue disorders	MedDRA 11.1	Non-systematic Assessment	EG0000 affected16 at risk EG0011 affected17 at risk EG0020 affected15 at risk EG003
Osteoarthritis	Musculoskeletal and connective tissue disorders	MedDRA 11.1	Non-systematic Assessment	EG0000 affected16 at risk EG0011 affected17 at risk EG0021 affected15 at risk EG003
Back pain	Musculoskeletal and connective tissue disorders	MedDRA 11.1	Non-systematic Assessment	EG0000 affected16 at risk EG0011 affected17 at risk EG0020 affected15 at risk EG003
Bursitis	Musculoskeletal and connective tissue disorders	MedDRA 11.1	Non-systematic Assessment	EG0001 affected16 at risk EG0010 affected17 at risk EG0020 affected15 at risk EG003
Intervertebral disc degeneration	Musculoskeletal and connective tissue disorders	MedDRA 11.1	Non-systematic Assessment	EG0001 affected16 at risk EG0010 affected17 at risk EG0020 affected15 at risk EG003
Myalgia	Musculoskeletal and connective tissue disorders	MedDRA 11.1	Non-systematic Assessment	EG0001 affected16 at risk EG0010 affected17 at risk EG0020 affected15 at risk EG003
Spinal column stenosis	Musculoskeletal and connective tissue disorders	MedDRA 11.1	Non-systematic Assessment	EG0001 affected16 at risk EG0010 affected17 at risk EG0020 affected15 at risk EG003
Weight increased	Investigations	MedDRA 11.1	Non-systematic Assessment	EG0000 affected16 at risk EG0010 affected17 at risk EG0021 affected15 at risk EG003
Bilirubin urine	Investigations	MedDRA 11.1	Non-systematic Assessment	EG0000 affected16 at risk EG0010 affected17 at risk EG0021 affected15 at risk EG003
Body temperature increased	Investigations	MedDRA 11.1	Non-systematic Assessment	EG0000 affected16 at risk EG0011 affected17 at risk EG0020 affected15 at risk EG003
Creatinine renal clearance increased	Investigations	MedDRA 11.1	Non-systematic Assessment	EG0000 affected16 at risk EG0010 affected17 at risk EG0021 affected15 at risk EG003
Electrocardiogram T wave abnormal	Investigations	MedDRA 11.1	Non-systematic Assessment	EG0000 affected16 at risk EG0010 affected17 at risk EG0021 affected15 at risk EG003
Electrocardiogram repolarisation abnormality	Investigations	MedDRA 11.1	Non-systematic Assessment	EG0001 affected16 at risk EG0010 affected17 at risk EG0020 affected15 at risk EG003
Gamma-glutamyltransferase increased	Investigations	MedDRA 11.1	Non-systematic Assessment	EG0000 affected16 at risk EG0010 affected17 at risk EG0021 affected15 at risk EG003
White blood cells urine positive	Investigations	MedDRA 11.1	Non-systematic Assessment	EG0000 affected16 at risk EG0010 affected17 at risk EG0021 affected15 at risk EG003
Depression	Psychiatric disorders	MedDRA 11.1	Non-systematic Assessment	EG0000 affected16 at risk EG0011 affected17 at risk EG0021 affected15 at risk EG003
Libido decreased	Psychiatric disorders	MedDRA 11.1	Non-systematic Assessment	EG0000 affected16 at risk EG0011 affected17 at risk EG0020 affected15 at risk EG003
Tic	Psychiatric disorders	MedDRA 11.1	Non-systematic Assessment	EG0000 affected16 at risk EG0011 affected17 at risk EG0020 affected15 at risk EG003
Leukocytosis	Blood and lymphatic system disorders	MedDRA 11.1	Non-systematic Assessment	EG0001 affected16 at risk EG0010 affected17 at risk EG0021 affected15 at risk EG003
Leukopenia	Blood and lymphatic system disorders	MedDRA 11.1	Non-systematic Assessment	EG0001 affected16 at risk EG0010 affected17 at risk EG0020 affected15 at risk EG003
Lymphopenia	Blood and lymphatic system disorders	MedDRA 11.1	Non-systematic Assessment	EG0001 affected16 at risk EG0010 affected17 at risk EG0020 affected15 at risk EG003
Neutropenia	Blood and lymphatic system disorders	MedDRA 11.1	Non-systematic Assessment	EG0001 affected16 at risk EG0010 affected17 at risk EG0020 affected15 at risk EG003
Neutrophilia	Blood and lymphatic system disorders	MedDRA 11.1	Non-systematic Assessment	EG0001 affected16 at risk EG0010 affected17 at risk EG0020 affected15 at risk EG003
Hypertension	Vascular disorders	MedDRA 11.1	Non-systematic Assessment	EG0000 affected16 at risk EG0011 affected17 at risk EG0020 affected15 at risk EG003
Hot flush	Vascular disorders	MedDRA 11.1	Non-systematic Assessment	EG0000 affected16 at risk EG0010 affected17 at risk EG0021 affected15 at risk EG003
Cardiomyopathy	Cardiac disorders	MedDRA 11.1	Non-systematic Assessment	EG0001 affected16 at risk EG0010 affected17 at risk EG0020 affected15 at risk EG003
Sinus bradycardia	Cardiac disorders	MedDRA 11.1	Non-systematic Assessment	EG0000 affected16 at risk EG0010 affected17 at risk EG0021 affected15 at risk EG003
Flatulence	Gastrointestinal disorders	MedDRA 11.1	Non-systematic Assessment	EG0000 affected16 at risk EG0011 affected17 at risk EG0021 affected15 at risk EG003
Teething	Gastrointestinal disorders	MedDRA 11.1	Non-systematic Assessment	EG0000 affected16 at risk EG0010 affected17 at risk EG0021 affected15 at risk EG003
Vertigo positional	Ear and labyrinth disorders	MedDRA 11.1	Non-systematic Assessment	EG0000 affected16 at risk EG0010 affected17 at risk EG0021 affected15 at risk EG003
Rib fracture	Injury, poisoning and procedural complications	MedDRA 11.1	Non-systematic Assessment	EG0000 affected16 at risk EG0010 affected17 at risk EG0021 affected15 at risk EG003
Vitamin D deficiency	Metabolism and nutrition disorders	MedDRA 11.1	Non-systematic Assessment	EG0000 affected16 at risk EG0010 affected17 at risk EG0021 affected15 at risk EG003
Uterine leiomyoma	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA 11.1	Non-systematic Assessment	EG0001 affected16 at risk EG0010 affected17 at risk EG0020 affected15 at risk EG003
Erectile dysfunction	Reproductive system and breast disorders	MedDRA 11.1	Non-systematic Assessment	EG0000 affected16 at risk EG0011 affected17 at risk EG0020 affected15 at risk EG003
Dermatitis atopic	Skin and subcutaneous tissue disorders	MedDRA 11.1	Non-systematic Assessment	EG0000 affected16 at risk EG0011 affected17 at risk EG0020 affected15 at risk EG003

ID	Title	Description
BG000	Atacicept 25 mg (With Loading)	Subjects who received atacicept 25 mg SC as loading dose twice weekly for first 4 weeks, followed by atacicept 25 mg SC for 32 weeks, in 28063 study were continued with atacicept 25 mg SC once weekly up to 5 years or up to early termination of treatment or early termination of the study.
BG001	Atacicept 75 mg (With Loading)	Subjects who received atacicept 75 mg SC as loading dose twice weekly for first 4 weeks, followed by atacicept 75 mg SC for 32 weeks, in 28063 study were continued with atacicept 75 mg SC once weekly up to 5 years or up to early termination of treatment or early termination of the study.
BG002	Atacicept 150 mg (With Loading)	Subjects who received atacicept 150 mg SC as loading dose twice weekly for first 4 weeks, followed by atacicept 150 mg SC for 32 weeks, in 28063 study were continued with atacicept 150 mg SC once weekly up to 5 years or up to early termination of treatment or early termination of the study.
BG003	Atacicept 150 mg (Without Loading)	Subjects who received placebo SC twice weekly for first 4 weeks, followed by placebo SC for 32 weeks, in 28063 study were 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.
BG004	Total	Total of all reporting groups

ID	Title	Description	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Atacicept 25 mg (With Loading)	Subjects who received atacicept 25 mg SC as loading dose twice weekly for first 4 weeks, followed by atacicept 25 mg SC for 32 weeks, in 28063 study were continued with atacicept 25 mg SC once weekly up to 5 years or up to early termination of treatment or early termination of the study.	0	16	6	16
EG001	Atacicept 75 mg (With Loading)	Subjects who received atacicept 75 mg SC as loading dose twice weekly for first 4 weeks, followed by atacicept 75 mg SC for 32 weeks, in 28063 study were continued with atacicept 75 mg SC once weekly up to 5 years or up to early termination of treatment or early termination of the study.	1	17	9	17
EG002	Atacicept 150 mg (With Loading)	Subjects who received atacicept 150 mg SC as loading dose twice weekly for first 4 weeks, followed by atacicept 150 mg SC for 32 weeks, in 28063 study were continued with atacicept 150 mg SC once weekly up to 5 years or up to early termination of treatment or early termination of the study.	0	15	8	15
EG003	Atacicept 150 mg (Without Loading)	Subjects who received placebo SC as loading dose twice weekly for first 4 weeks, followed by placebo SC for 32 weeks, in 28063 study were 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.	0	22	12	22