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Atacicept in Combination With Rituximab in Subjects With Rheumatoid Arthritis (August III) (August III)

Primary Purpose

Rheumatoid Arthritis

Status
Completed
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
Rituximab
Atacicept
Placebo matched to atacicept
Sponsored by
Merck KGaA, Darmstadt, Germany
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Rheumatoid Arthritis

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Male and female subjects
  • Greater than and equal to (>=) 18 years of age at the time of Informed Consent
  • Who have rheumatoid arthritis satisfying American College of Rheumatology (ACR) criteria with a disease history of at least 12 months
  • Subjects must have active disease defined by DAS28 >3.2
  • Subjects must have received previous treatment with rituximab and must be candidates for re-treatment with rituximab
  • Female subjects of childbearing potential must be willing to avoid pregnancy by using an adequate method of contraception for 4 weeks before study day 1 (SD1), during the treatment period and for 12 months after the last dose of rituximab, and must have a negative urine pregnancy test at the screening visit and SD1
  • Other protocol defined inclusion criteria could apply

Exclusion Criteria:

  • Current neurological disease excluding migraine
  • Inflammatory joint disease other than rheumatoid arthritis
  • Any contraindication to rituximab as per national label
  • Use of disease-modifying anti-rheumatic drugs (DMARDs; including methotrexate) for less than 3 months or change in dosing regimen within 28 days before SD1, or methotrexate dose regimen >25 mg/week
  • Participation in any interventional clinical trial within 1 month before SD1 (or within 5 half-lives of the investigated compound before SD1, whichever is longer)
  • Prednisone dose regimen >10 mg/day (or equivalent), or change in steroid dosing regimen within 28 days before SD1
  • Active or latent tuberculosis within the year before screening or major infection requiring hospitalization or intravenous anti-infectives within 28 days before SD1
  • Serum Immunoglobulin G (IgG) below 6 gram per liter (g/L)
  • Known hypersensitivity to atacicept or to any of the components of the formulated atacicpet
  • Known hypersensitivity to rituximab, to any of the components of the formulated rituximab or to murine proteins
  • Breastfeeding or pregnancy
  • Other protocol defined exclusion criteria could apply

Sites / Locations

  • Research Site
  • Research Site
  • Research Site
  • Research Site
  • Research Site
  • Research Site
  • Research Site
  • Research Site

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Rituximab Plus Atacicept

Rituximab Plus Placebo

Arm Description

Rituximab will be administered as an intravenous infusion at a dose of 1000 mg at Weeks 1 and 3, followed by atacicept 150 mg subcutaneously once a week from Week 7 to 32.

Rituximab will be administered as an intravenous infusion at a dose of 1000 mg at Weeks 1 and 3, followed by placebo matched to atacicept subcutaneously once a week from Week 7 to 32.

Outcomes

Primary Outcome Measures

Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
An AE was defined as any new untoward medical occurrences/worsening of pre-existing medical condition without regard to possibility of causal relationship. An SAE was defined as 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.
Percentage of Participants With Immunoglobulin G (IgG) Level Less Than 3 Gram Per Liter (g/L)
Percent Change From Baseline in Vital Signs and Routine Safety Lab Parameters at Week 32
Vital signs assessed included blood pressure (systolic and diastolic), pulse and body temperature. Routine safety lab parameters evaluated included red blood cell (RBC), hemoglobin, hematocrit, platelets, mean cellular hemoglobin (MCH), MCH concentration, MCH volume, white blood cell (WBC), lymphocytes, monocytes, eosinophils, basophils, neutrophils, gamma glutamyl transferase (GGT), alanine aminotransferase (ALT), albumin, alkaline phosphatase (AP), aspartate aminotransferase (AST), bilirubin, calcium, creatinine, glucose, potassium, total protein, sodium, uric acid, and blood urea nitrogen. Percent change from baseline was calculated as ([Week 32 value minus baseline value] multiplied by 100) divided by baseline value.
Percent Change From Baseline in Anti-tetanus and Anti-diphteria Immunization Titer at Week 32
Percent change from baseline was calculated as ([Week 32 value minus baseline value] multiplied by 100) divided by baseline value.
Percent Change From Baseline in Anti-pneumococcus Titer at Week 32
Percent change from baseline was calculated as ([Week 32 value minus baseline value] multiplied by 100) divided by baseline value.

Secondary Outcome Measures

Percentage of Participants Achieving American College of Rheumatology 20 Response Based on C-reactive Protein (ACR20-CRP), ACR50-CRP and ACR70-CRP at Week 32
ACR20-CRP response: greater than or equal to (>=) 20 percent (%) improvement in both tender joint counts (based on a total of 68 joints) and swollen joint counts (based on a total of 66 joints) together with >=20% improvement in at least 3 of the following: 1) participant's assessment of pain; 2) participant's global assessment of disease activity; 3) physician's global assessment of disease activity; 4) participant's assessment of physical function; and 5) acute-phase marker (CRP). ACR50-CRP and ACR70-CRP response are defined as >=50% and >=70% improvement in both tender joint counts (based on a total of 68 joints) and swollen joint counts (based on a total of 66 joints) respectively together with >=50% and >=70% improvement in at least 3 of the following respectively: 1) participant's assessment of pain; 2) participant's global assessment of disease activity; 3) physician's global assessment of disease activity; 4) participant's assessment of physical function; and 5) CRP.
Change From Baseline in Disease Activity Score in 28 Joints (DAS28) Based on CRP (DAS28-CRP) at Week 32
DAS28-CRP incorporates non-graded joint counts for tenderness and swelling based on a total of 28 joints, CRP as a marker of inflammation, and a general health assessment using a 100 mm visual analog scale (the participant's global assessment of disease activity). DAS28 score ranges between 0 and 10 representing current disease activity. A value above 5.1 represents high disease activity, a value below 3.2 represents low disease activity, and a value below 2.6 represents remission.
Median Percentage Change From Baseline in Levels of Total, Mature and Memory B Cells
Flow cytometric analysis of lymphocyte populations using four-color fluorescence-activated cell sorting was performed for the analysis of total, mature and memory B cell levels.

Full Information

First Posted
April 21, 2008
Last Updated
November 4, 2016
Sponsor
Merck KGaA, Darmstadt, Germany
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1. Study Identification

Unique Protocol Identification Number
NCT00664521
Brief Title
Atacicept in Combination With Rituximab in Subjects With Rheumatoid Arthritis (August III)
Acronym
August III
Official Title
A Randomized, Double-blind, Placebo Controlled, Multi-centre, Exploratory, Pilot, Phase II Trial of 150mg Atacicept Given Subcutaneously in Combination With Rituximab in Subjects With Rheumatoid Arthritis.
Study Type
Interventional

2. Study Status

Record Verification Date
November 2016
Overall Recruitment Status
Completed
Study Start Date
March 2008 (undefined)
Primary Completion Date
October 2010 (Actual)
Study Completion Date
October 2010 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Merck KGaA, Darmstadt, Germany

4. Oversight

5. Study Description

Brief Summary
The primary objective of this study is to assess the safety and tolerability of combined treatment with atacicept and rituximab in subjects with active rheumatoid arthritis (RA) receiving re-treatment with rituximab.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Rheumatoid Arthritis

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
27 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Rituximab Plus Atacicept
Arm Type
Experimental
Arm Description
Rituximab will be administered as an intravenous infusion at a dose of 1000 mg at Weeks 1 and 3, followed by atacicept 150 mg subcutaneously once a week from Week 7 to 32.
Arm Title
Rituximab Plus Placebo
Arm Type
Placebo Comparator
Arm Description
Rituximab will be administered as an intravenous infusion at a dose of 1000 mg at Weeks 1 and 3, followed by placebo matched to atacicept subcutaneously once a week from Week 7 to 32.
Intervention Type
Biological
Intervention Name(s)
Rituximab
Intervention Description
Rituximab will be administered as an intravenous infusion at a dose of 1000 mg at Weeks 1 and 3.
Intervention Type
Drug
Intervention Name(s)
Atacicept
Intervention Description
Atacicept will be administered at a dose of 150 mg subcutaneously once a week from Week 7 to 32.
Intervention Type
Drug
Intervention Name(s)
Placebo matched to atacicept
Intervention Description
Placebo matched to atacicept will be administered subcutaneously once a week from Week 7 to 32.
Primary Outcome Measure Information:
Title
Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
Description
An AE was defined as any new untoward medical occurrences/worsening of pre-existing medical condition without regard to possibility of causal relationship. An SAE was defined as 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.
Time Frame
Baseline up to Week 64
Title
Percentage of Participants With Immunoglobulin G (IgG) Level Less Than 3 Gram Per Liter (g/L)
Time Frame
Week 64
Title
Percent Change From Baseline in Vital Signs and Routine Safety Lab Parameters at Week 32
Description
Vital signs assessed included blood pressure (systolic and diastolic), pulse and body temperature. Routine safety lab parameters evaluated included red blood cell (RBC), hemoglobin, hematocrit, platelets, mean cellular hemoglobin (MCH), MCH concentration, MCH volume, white blood cell (WBC), lymphocytes, monocytes, eosinophils, basophils, neutrophils, gamma glutamyl transferase (GGT), alanine aminotransferase (ALT), albumin, alkaline phosphatase (AP), aspartate aminotransferase (AST), bilirubin, calcium, creatinine, glucose, potassium, total protein, sodium, uric acid, and blood urea nitrogen. Percent change from baseline was calculated as ([Week 32 value minus baseline value] multiplied by 100) divided by baseline value.
Time Frame
Baseline, Week 32
Title
Percent Change From Baseline in Anti-tetanus and Anti-diphteria Immunization Titer at Week 32
Description
Percent change from baseline was calculated as ([Week 32 value minus baseline value] multiplied by 100) divided by baseline value.
Time Frame
Baseline, Week 32
Title
Percent Change From Baseline in Anti-pneumococcus Titer at Week 32
Description
Percent change from baseline was calculated as ([Week 32 value minus baseline value] multiplied by 100) divided by baseline value.
Time Frame
Baseline, Week 32
Secondary Outcome Measure Information:
Title
Percentage of Participants Achieving American College of Rheumatology 20 Response Based on C-reactive Protein (ACR20-CRP), ACR50-CRP and ACR70-CRP at Week 32
Description
ACR20-CRP response: greater than or equal to (>=) 20 percent (%) improvement in both tender joint counts (based on a total of 68 joints) and swollen joint counts (based on a total of 66 joints) together with >=20% improvement in at least 3 of the following: 1) participant's assessment of pain; 2) participant's global assessment of disease activity; 3) physician's global assessment of disease activity; 4) participant's assessment of physical function; and 5) acute-phase marker (CRP). ACR50-CRP and ACR70-CRP response are defined as >=50% and >=70% improvement in both tender joint counts (based on a total of 68 joints) and swollen joint counts (based on a total of 66 joints) respectively together with >=50% and >=70% improvement in at least 3 of the following respectively: 1) participant's assessment of pain; 2) participant's global assessment of disease activity; 3) physician's global assessment of disease activity; 4) participant's assessment of physical function; and 5) CRP.
Time Frame
Week 32
Title
Change From Baseline in Disease Activity Score in 28 Joints (DAS28) Based on CRP (DAS28-CRP) at Week 32
Description
DAS28-CRP incorporates non-graded joint counts for tenderness and swelling based on a total of 28 joints, CRP as a marker of inflammation, and a general health assessment using a 100 mm visual analog scale (the participant's global assessment of disease activity). DAS28 score ranges between 0 and 10 representing current disease activity. A value above 5.1 represents high disease activity, a value below 3.2 represents low disease activity, and a value below 2.6 represents remission.
Time Frame
Baseline, Week 32
Title
Median Percentage Change From Baseline in Levels of Total, Mature and Memory B Cells
Description
Flow cytometric analysis of lymphocyte populations using four-color fluorescence-activated cell sorting was performed for the analysis of total, mature and memory B cell levels.
Time Frame
Baseline, Week 3, 7, 12, 16, 26 and 32

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Male and female subjects Greater than and equal to (>=) 18 years of age at the time of Informed Consent Who have rheumatoid arthritis satisfying American College of Rheumatology (ACR) criteria with a disease history of at least 12 months Subjects must have active disease defined by DAS28 >3.2 Subjects must have received previous treatment with rituximab and must be candidates for re-treatment with rituximab Female subjects of childbearing potential must be willing to avoid pregnancy by using an adequate method of contraception for 4 weeks before study day 1 (SD1), during the treatment period and for 12 months after the last dose of rituximab, and must have a negative urine pregnancy test at the screening visit and SD1 Other protocol defined inclusion criteria could apply Exclusion Criteria: Current neurological disease excluding migraine Inflammatory joint disease other than rheumatoid arthritis Any contraindication to rituximab as per national label Use of disease-modifying anti-rheumatic drugs (DMARDs; including methotrexate) for less than 3 months or change in dosing regimen within 28 days before SD1, or methotrexate dose regimen >25 mg/week Participation in any interventional clinical trial within 1 month before SD1 (or within 5 half-lives of the investigated compound before SD1, whichever is longer) Prednisone dose regimen >10 mg/day (or equivalent), or change in steroid dosing regimen within 28 days before SD1 Active or latent tuberculosis within the year before screening or major infection requiring hospitalization or intravenous anti-infectives within 28 days before SD1 Serum Immunoglobulin G (IgG) below 6 gram per liter (g/L) Known hypersensitivity to atacicept or to any of the components of the formulated atacicpet Known hypersensitivity to rituximab, to any of the components of the formulated rituximab or to murine proteins Breastfeeding or pregnancy Other protocol defined exclusion criteria could apply
Facility Information:
Facility Name
Research Site
City
Nice
Country
France
Facility Name
Research Site
City
Paris
Country
France
Facility Name
Research Site
City
Strasbourg
Country
France
Facility Name
Research Site
City
Amsterdam
Country
Netherlands
Facility Name
Research Site
City
Malmö
Country
Sweden
Facility Name
Research Site
City
Stockholm
Country
Sweden
Facility Name
Research Site
City
Newcastle
Country
United Kingdom
Facility Name
Research Site
City
Norwich
Country
United Kingdom

12. IPD Sharing Statement

Citations:
PubMed Identifier
26137975
Citation
van Vollenhoven RF, Wax S, Li Y, Tak PP. Safety and efficacy of atacicept in combination with rituximab for reducing the signs and symptoms of rheumatoid arthritis: a phase II, randomized, double-blind, placebo-controlled pilot trial. Arthritis Rheumatol. 2015 Nov;67(11):2828-36. doi: 10.1002/art.39262.
Results Reference
result

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Atacicept in Combination With Rituximab in Subjects With Rheumatoid Arthritis (August III)

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