Long-term Safety and Tolerability of Atacicept (Long-term Follow-Up of Participant Who Participated in ADDRESS II)

Lupus Erythematosus, Systemic Clinical Trial

Official title:

A Phase IIb, Multi-Center, Long-Term Extension Trial to Evaluate the Safety and Tolerability of Atacicept in Subjects With Systemic Lupus Erythematosus (SLE) Who Completed Protocol EMR-700461-023 (ADDRESS II)

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT02070978
• Other study ID #: 700461-024
• Secondary ID: 2013-002758-62
• Status: Terminated
• Phase: Phase 2
• Start date: July 29, 2014
• Est. completion date: February 9, 2018

Study information

• Verified date: March 2019
• Source: EMD Serono
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This is a multicenter, double-blind, Phase 2b, long-term extension (LTE) to the ADDRESS II core trial (EMR 700461-023) (NCT01972568), to evaluate long-term safety and tolerability of atacicept in participants with systemic lupus erythematosus (SLE). Participants who completed the 24-week core study ADDRESS II core study (NCT01972568) and thus not met any of the discontinuation criteria were invited to enter this long-term extension (LTE) study NCT02070978.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 253
• Est. completion date: February 9, 2018
• Est. primary completion date: April 5, 2016
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Participants who had completed the 24-week treatment period of study EMR-700461-023 (ADDRESS II core trial)

• Women of childbearing potential who had a negative pregnancy test

• Other protocol defined inclusion criteria were applied

Exclusion Criteria:

• Active neurological symptoms of SLE that were deemed severe or progressive

• Diagnosis of any demyelinating disease, such as, but not restricted to, multiple sclerosis (MS) or optic neuritis

• Pregnancy

• Active clinically significant viral, bacterial, or fungal infection, or any major episode of infection that in the investigator's opinion makes the participants unsuitable to continued participation in the study

• Other protocol defined exclusion criteria were applied

Related Conditions & MeSH terms

• Lupus Erythematosus, Systemic

Intervention

Drug:
• Atacicept 75 mg
Participants who received atacicept 75 milligram (mg) as once-weekly subcutaneous injection in the core study ADDRESS II continued to receive this dose during this LTE study. Participants in this reporting arm received the medication up to a maximum of 143.7 weeks.
• Atacicept 150 mg
Participants who received placebo in the core study ADDRESS II switched to receive atacicept 150 mg as once-weekly subcutaneous injection for up to a maximum of 97.7 weeks during this LTE study.
• Atacicept 150 mg
Participants who received atacicept 150 mg in core study ADDRESS II continued to receive atacicept 150 mg as once-weekly subcutaneous injection during this LTE study up to a maximum of 97.9 weeks.

Locations

Country	Name	City	State
Argentina	APRILLUS	Ciudad Autonoma Buenos aires
Argentina	Atencion Integral en Reumatologia (AIR)	Ciudad Autonoma Buenos Aires
Argentina	Organizacion Medica de Investigacion (OMI)	Ciudad Autonoma Buenos Aires
Argentina	Hospital Privado Centro Medico de Cordoba	Cordoba
Argentina	Instituto CAICI	Rosario	Santa Fe
Argentina	Cordis S.A.	Salta
Argentina	Centro Polivalente de Asistencia e Inv. Clinica CER	San Juan
Argentina	Centro Medico Privado de Reumatologia	San Miguel de Tucuman	Tucuman
Argentina	Investigaciones Clinicas Tucuman	San Miguel de Tucuman	Tucuman
Argentina	Centro Integral de Reumatologia	San Miguel de Tucumán	Tucuman
Brazil	Centro de Pesquisas em Diabetes Ltda.	Porto Alegre	Rio Grande Do Sul
Bulgaria	MHAT "Eurohospital" - Plovdiv, OOD	Plovdiv
Bulgaria	Medical Center "Teodora", EOOD	Ruse
Bulgaria	MHAT - Ruse, AD	Ruse
Bulgaria	DCC "Sveta Anna", EOOD	Sofia
Bulgaria	UMHAT "Sv. Ivan Rilski", EAD	Sofia
Bulgaria	Medical Center "Nov Rehabilitatsionen Tsentar", EOOD	Stara Zagora
Bulgaria	MHAT-Targovishte, AD	Targovishte
Chile	Corporacion de Beneficencia Osorno	Osorno
Chile	Quantum Research Santiago	Puerto Varas
Chile	Biomedica	Santiago
Chile	Centro de Estudios Reumatologicos	Santiago
Chile	Centro Medico Prosalud	Santiago
Chile	CINVEC - Centro de Investigacion Clinica V Region	Viña del Mar
Czechia	Revmatologicky Ustav	Praha 2
Czechia	Revmatologicka ambulance	Uherske Hradiste
Germany	Charite Universitaetsmedizin Berlin - Campus Charite Mitte	Berlin
Germany	Universitaetsmedizin der Johannes Gutenberg-Universitaet Mainz	Mainz	Rheinland Pfalz
Italy	Fondazione IRCCS CA' Granda Ospedale Maggiore Policlinico	Milano
Korea, Republic of	Konkuk University Medical Center	Seoul
Korea, Republic of	Seoul National University Hospital	Seoul	Gyeonggi-do
Korea, Republic of	Ajou University Hospital	Suwon-si	Gyeonggi-do
Mexico	Investigacion y Biomedicina de Chihuahua, S.C.	Chihuahua
Mexico	Icle S.C.	Guadalajara	Jalisco
Mexico	Unidad de Investigacion en Enfermedades Cronico Degenerativas SC	Guadalajara	Jalisco
Mexico	Morales Vargas Centro de Investigacion, S.C.	Leon	Guanajuato
Mexico	Centro Multidisciplinario para el desarrollo Especializado de la Investigacion Clinica en Yucatan	Merida	Yucatán
Mexico	Clinstile, S.A. de C.V.	Mexico	Distrito Federal
Mexico	Accelerium S. de R.L. de C.V.	Monterrey	Nuevo León
Mexico	Clinica de Enfermedades Cronicas y de Procedimientos Especiales, S.C.	Morelia	Michoacán
Mexico	Hospital Universitario de Saltillo "Dr. Gonzalo Valdés Valdés"	Saltillo	Coahuila
Peru	Hogar Clínica San Juan de Dios - Arequipa	Arequipa
Peru	Clinica Medica Cayetano Heredia	Lima
Peru	Invest Clinicas Sac Inst de Ginecologia y Reproduccion	Lima
Philippines	Angeles University Foundation Medical Center	Angeles City, Pampanga
Philippines	Mary Mediatrix Medical Center	Batangas
Philippines	Davao Doctors Hospital	Davao
Philippines	Iloilo Doctors Hospital	Iloilo
Poland	Szpital Uniwersytecki nr 2 im.dr J. Biziela	Bydgoszcz
Russian Federation	FSBEI HE " First Moscow State Medical University n.a. I.M. Sechenov" of the MoH of the RF	Moscow
Russian Federation	SBIH of Republic Kareliya "Republican Hospital n.a. V.A. Baranov"	Petrozavodsk
Russian Federation	SPb SBIH "Clinical Rheumatological Hospital # 25"	Saint-Petersburg
Russian Federation	SIH "Saratov City Clinical Hospital # 12"	Saratov
Russian Federation	SBIH of Vladimir region "Regional Clinical Hospital"	Vladimir
Russian Federation	SBHI of Yaroslavl Region "Clinical Hospital # 8"	Yaroslavl
South Africa	Naidoo, A	Durban	KwaZulu-Natal
South Africa	Winelands Medical Research Centre	Stellenbosch	Western Cape
Spain	Hospital Clinico Universitario de Valladolid	Valladolid
United Kingdom	Guy's Hospital	London	Greater London
United Kingdom	University College London Hospitals	London	Greater London
United Kingdom	Queen's Hospital	Romford	Essex
United States	Pinnacle Research Group LLC	Anniston	Alabama
United States	Austin Regional Clinic, P.A.	Austin	Texas
United States	Wallace Rheumatic Study Center	Beverly Hills	California
United States	University of Alabama at Birmingham - (UAB)	Birmingham	Alabama
United States	Medical University of South Carolina (MUSC)	Charleston	South Carolina
United States	DJL Clinical Research, PLLC	Charlotte	North Carolina
United States	Clinical Research of West Florida - Corporate	Clearwater	Florida
United States	MetroHealth System	Cleveland	Ohio
United States	Southern California Permenent Medical Group	Fontana	California
United States	AA MRC LLC Ahmed Arif Medical Research Center	Grand Blanc	Michigan
United States	The Feinstein Institute for Medical Research	Manhasset	New York
United States	Hospital for Special Surgery	New York	New York
United States	Rutgers New Jersey Medical School	Newark	New Jersey
United States	Arthritis & Rheumatology Center of Oklahoma	Oklahoma City	Oklahoma
United States	OMRF	Oklahoma City	Oklahoma
United States	Mayo Clinic	Rochester	Minnesota
United States	Clayton Medical Associates, P.C.	Saint Louis	Missouri
United States	Washington University	Saint Louis	Missouri
United States	East Bay Rheumatology Medical Group, Inc.	San Leandro	California
United States	Clinical Research of West Florida, Inc.	Tampa	Florida
United States	McIlwain Medical Group, PA	Tampa	Florida
United States	Little River Arthritis & Osteoporosis Clinic	Waco	Texas
United States	Clinical Research Center of Reading LLC	Wyomissing	Pennsylvania

Sponsors (1)

Lead Sponsor	Collaborator
EMD Serono

Countries where clinical trial is conducted

United States,  Argentina,  Brazil,  Bulgaria,  Chile,  Czechia,  Germany,  Italy,  Korea, Republic of,  Mexico,  Peru,  Philippines,  Poland,  Russian Federation,  South Africa,  Spain,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of Participants With at Least One Serious Adverse Event (SAE) During the Treatment Period	An Adverse event (AE) was defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease associated with the use of study drug, whether or not considered related to the study drug or worsening of pre-existing medical condition, whether or not related to study drug. A serious adverse event (SAE) was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. An AE was considered as 'treatment emergent' if it occurred after the first drug administration of each period or if it was present prior to drug administration but exacerbated after the drug administration. Treatment- Emergent adverse events (TEAEs) during the treatment period exclude those ongoing at the time of study entry into 024 LTE Day 1 and exclude the safety follow-up period.	Baseline (LTE Day 1) up to maximum treatment duration of 143.7 weeks
Primary	Number of Participants Who Prematurely Discontinued the Treatment Due to Adverse Event (AE)	An Adverse event (AE) was defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease associated with the use of study drug, whether or not considered related to the study drug or worsening of pre-existing medical condition, whether or not related to study drug. TEAEs were defined as events with an onset date on or after the date of first dose of study treatment in the core study and ongoing at the 024 LTE study entry, occurring during the 024 LTE study and the Safety follow-up Period.	Baseline (Day 1 of Core study) up to maximum duration of 167.7 weeks
Secondary	Change From Baseline in Systemic Lupus International Collaborating Clinics/American College of Rheumatology (SLICC/ACR) Damage Index Organ Damage Scores	SLICC/ACR score or damage index evaluates cumulative damage in Systemic Lupus Erythematosus (SLE). These changes may or may not be related to SLE. Most items are scored only if they have been present for at least 6 months. Scores range from 0 to 47 points, with higher scores indicating greater cumulative damage. Baseline was defined as Day 1 of Core study.	Baseline: Day 1 (Core Study), Day 1 (LTE Study), Week 24, Week 48, Week 72 and Week 96
Secondary	Change From Baseline in Disease Activity as Measured by British Isles Lupus Assessment Group (BILAG) 2004 Score	BILAG Disease Activity Index evaluates systemic lupus erythematosus (SLE) activity in 8 organ system domains: General, mucocutaneous, neurological, musculoskeletal, cardiorespiratory, vasculitis, renal, and hematologic using a separate alphabetic score (A to E) assigned to each organ system defined as follows. BILAG A: Severe disease activity; BILAG B: moderate disease activity; BILAG C: mild disease; BILAG D: system previously affected but now inactive; BILAG E: system never involved. BILAG evaluated by scoring each of a list of signs and symptoms as: improving (1); same (2); worse (3); new (4); not present (0); not done (ND). The total BILAG score is the sum of the scores of the 8 domains where A=9, B=3, C=1, D=0, and E=0. The total score ranges from 0 to 72 with a higher score indicating greater lupus activity.	Baseline: Core study Screening, LTE Day 1, Week 24, Week 48, Week 72 and Week 96
Secondary	Change From Baseline in Disease Activity as Measured by Systemic Lupus Erythematosus Disease Activity Index-2000 (SLEDAI-2K) Score	SLEDAI-2K is an activity index that measures disease activity and records feature of active lupus as present or not present. SLEDAI-2K uses a weighted checklist to assign a numerical score based on the presence or absence of 24 symptoms. Each symptom present is assigned between 1 and 8 points based on its usual clinical importance, yielding a total score that ranges from 0 points (no symptoms) to 105 points (presence of all defined symptoms). Baseline was defined as core study screening visit.	Baseline: Screening Visit (Core Study); LTE Day 1, Week 24, Week 48, Week 72 and Week 96
Secondary	Change From Baseline in Disease Activity as Measured by SLEDAI-2K Responder Index-50 (SRI-50) Score	SRI-50 index was derived from SLEDAI-2K and could capture 50% or better improvement in each descriptor between any 2 visits in systemic lupus erythematosus (SLE) participants when there was incomplete resolution. The new assigned scores for the descriptors of SRI-50 were derived by dividing the score of each SLEDAI-2K descriptor by 2. SLEDAI-2K was an activity index that measured disease activity and records feature of active lupus as present or not present. SLEDAI-2K used a weighted checklist to assign a numerical score based on the presence or absence of 24 symptoms. Each symptom present was assigned between 1 and 8 points based on its usual clinical importance, yielding a total score that ranged from 0 points (no symptoms) to 105 points (presence of all defined symptoms).	Baseline: Screening Visit (Core Study); LTE Day 1, Week 24, Week 48, Week 72 and Week 96
Secondary	Change From Baseline in Disease Activity as Measured by Physician's Global Assessment (PGA) Score	The PGA was used to quantify disease activity and was measured using an anchored visual analog scale (VAS). The participant's current disease activity assessed by investigator in the score range of 0 to 3. Where 0=none; 1=mild; 2=moderate; 3=severe. The assessment made relative not to the participant's most severe state, but the most severe state of systemic lupus erythematosus (SLE) per the investigator's assessment. Baseline was defined as core study screening visit.	Baseline: Screening Visit (Core Study); LTE Day1, Week 24, Week 48, Week 72 and Week 96
Secondary	Number of Participants Who Achieved SLE Responder Index (SRI-4) Response (a Disease Activity Composite Index)	SRI-4 response was defined as greater than or equal to 4-point reduction in Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) total score, no new British Isles Lupus Assessment Group (BILAG) A and no more than 1 new BILAG B domain score and no worsening (less than 10 percent increase) from baseline Physician's Global Assessment of Disease Activity (PGA). SLEDAI-2K is an activity index that measures disease activity and records feature of active lupus as present or not present. SLEDAI-2K uses a weighted checklist to assign a numerical score based on the presence or absence of 24 symptoms. Each symptom present is assigned between 1 and 8 points based on its usual clinical importance, yielding a total score that ranges from 0 points (no symptoms) to 105 points (presence of all defined symptoms).	Baseline: Core study Screening; LTE Day 1, Week 24, Week 48, Week 72 and Week 96
Secondary	Number of Participants Who Achieved BILAG-based Combined Lupus Assessment (BICLA) Response (a Disease Activity Composite Index)	The BICLA response was defined as BILAG-2004 improvement (all screening visit BILAG A improving to B/C/D, all screening visit BILAG B to C/D, and less than or equal to (<=1) new BILAG B and no new BILAG A); no deterioration in SLEDAI total score; PGA increase by less than (<) 0 percentage (%) (defined as less then (<)0.3 point increase for the statistical analyses) and no non-permitted medication/treatment. Baseline was defined as core study screening visit.	Baseline: Core study Screening; LTE Day 1, Week 24, Week 48, Week 72 and Week 96
Secondary	Percent Change From Baseline in Prednisone-equivalent Corticosteroid Dose		Baseline: Screening Visit (Core Study); LTE Day 1, Week 24, Week 48, Week 72 and Week 96
Secondary	Change From Baseline in the Short-Form (SF-36) Health Survey Physical Component Score and Mental Component Score	The 36-Item Short-Form Health Survey (SF-36) is a standardized survey evaluating 8 aspects of functional health and well-being. These eight subscales were summarized as relating to either physical health or mental health. Physical component summary (PCS) is based primarily on physical functioning, role-physical, bodily pain, and general health scales and mental component summary (MCS) encompasses vitality, social functioning, role-emotional, and mental health scales. Score from mental health, role emotional, social functioning, and vitality domains were averaged to calculate MCS. Total score range for MCS was 0-100 (100=highest level of mental functioning). Score from physical function, role physical, bodily pain, and general health domains were averaged to calculate PCS. Total score range for PCS was 0-100 (100=highest level of physical functioning).	Baseline (Core Study Day 1); LTE Day 1, Week 24, Week 48, Week 72 and Week 96
Secondary	Change From Baseline in Lupus Quality of Life (LupusQoL) Questionnaire Score	The LupusQoL was a lupus-specific health related QoL (HRQoL) questionnaire consisting of 34 items grouped in 8 domains: physical health, pain, planning, intimate relationships, burden to others, emotional health, body image, and fatigue. Participants indicate their responses on a 5-point Likert response format, where 4 = never, 3 = occasionally, 2 = a good bit of the time, 1 = most of the time, and 0 = all of the time. Summary scores can be calculated for all 8 domains. A LupusQoL score for each domain was reported on a 0 to 100 scale, with greater values indicating better HRQoL. Baseline was defined as Day 1 of core study.	Baseline (Core Study Day 1); LTE Day 1, Week 24, Week 48, Week 72, and Week 96
Secondary	Number of Participants With Patient Global Impression of Change (PGIC)	The PGIC is self-rated scale that asks the participant to describe the change in activity limitations, symptoms, emotions, and overall Quality of life (QoL) related to the participant's painful condition on the following scale: 1 (very much improved), 2 (much improved), 3 (minimally improved), 4 (no change), 5 (minimally worse), 6 (much worse) and 7 (very much worse). Number of participants in the PGIC categories of very much improved (1) and much improved (2) are reported.	Baseline (Core Study Day 1); LTE Day 1, Week 24, Week 48, Week 72 and Week 96
Secondary	Change From Baseline in EuroQoL 5 Dimension Instrument (EQ-5D) Score	EQ-5D questionnaire comprised of 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression measured on 3 levels; 1=no problem, 2=moderate problems, 3=extreme problems. This part, called the EQ-5D descriptive system, provides a 5-dimensional description of health status. 5 dimensional 3-level system was converted into single index utility score. Possible values for single index utility score ranged from -0.594 (severe problems in all dimensions) to 1.0 (no problem in all dimensions) on scale where 1 represented best possible health state. Baseline was defined as Day 1 of Core study.	Baseline: Day 1 (Core Study), LTE Day 1, Week 24, Week 48, Week 72 and Week 96
Secondary	Change From Baseline in EQ-5D Visual Analogue Scale (VAS) Scores	EQ-5D is a participant rated questionnaire to assess health-related QoL in terms of a single index value. The VAS component rates current health state on a scale from 0 millimeters (mm) (worst imaginable health state) to 100 mm (best imaginable health state); higher scores indicate a better health state. Baseline defined as Day 1 of core study.	Baseline: Day 1 (Core Study), LTE Day 1, Week 24, Week 48, Week 72 and Week 96
Secondary	Change From Baseline in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue Score	The FACIT-Fatigue score was calculated according to a 13-item questionnaire that assesses self-reported fatigue and its impact upon daily activities and function. It uses a 5-point Likert-type scale (0 = not at all; 1 = a little bit; 2 = somewhat; 3 = quite a bit; 4 = very much). The sum of all responses resulted in the FACIT-Fatigue score for a total possible score of 0 (worse possible score) to 52 (best score). A higher score reflected an improvement in the participant's health status.	Baseline: Day 1 (Core study); LTE Day 1, Week 24, Week 48, Week 72 and Week 96
Secondary	Number of Participants With at Least One Adverse Event	An Adverse event (AE) was defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease associated with the use of study drug, whether or not considered related to the study drug or worsening of pre-existing medical condition, whether or not related to study drug. Treatment-Emergent adverse events (TEAEs) are defined as events with an onset date on or after the date of first dose of study treatment in the core study and ongoing at LTE study entry, or occurring during LTE study.	Baseline (Day 1 of Core study) up to maximum duration of 167.7 weeks
Secondary	Number of Participants With Columbia-Suicide Severity Rating Scale (C-SSRS) Score	The C-SSRS assesses the suicidal behavior and suicidal ideation in participants. Occurrence of suicidal behavior after study entry is defined as having answered "yes" to a least 1 of the 4 suicidal behavior subcategories (actual attempt, interrupted attempt, aborted attempt, and preparatory acts or behavior). Occurrence of suicidal ideation is defined as having answered "yes" to at least 1 of the suicidal ideation sub-categories (1) wish to be dead, (2) nonspecific active suicidal thoughts, (3) active suicidal ideation with any methods (no plan) without intent to act, (4) active suicidal ideation with some intent to act (without specific plan), and (5) active suicidal ideation with specific plan and intent).	LTE Day 1, Week 24, Week 48, Week 72 and Week 98