Rheumatoid Arthritis
Conditions
Keywords
atacicept, arthritis
Brief summary
This was a double-blind, placebo-controlled, parallel-arm, multicentre, prospective dose-finding trial of the safety and efficacy of atacicept in subjects with active rheumatoid arthritis who had failed a three month therapeutic trial with a tumor necrosis factor alpha (TNFa) antagonist due to lack of efficacy.
Interventions
DRUGAtacicept
Atacicept was administered subcutaneously at a dose of 25 milligram (mg) twice a week for initial 4 weeks as loading dose, followed by 25 mg once a week for subsequent 21 weeks.
Placebo matched to atacicept was administered subcutaneously twice a week for initial 4 weeks, followed by once a week for subsequent 21 weeks.
Sponsors
Merck KGaA, Darmstadt, Germany
EMD Serono
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Rheumatoid arthritis (RA) satisfying American College of Rheumatology (ACR) diagnostic criteria with a disease history of at least one year 2. Male or female greater than or equal to (\>=)18-years of age at time of informed consent 3. Active RA as defined by: * \>=8 swollen joints (66-joint count), * \>=8 tender joints (68-joint count), and * C-reactive protein (CRP) \>=10 milligram per liter (mg/L) (central laboratory) and/or erythrocyte sedimentation rate (ESR) \>= to 28 millimeter per hour (mm/h) 4. Failure of at least one TNFa antagonist therapy (previously or at the time of screening) as specified in the protocol 5. Other protocol defined inclusion criteria could apply
Exclusion criteria
1. Any condition, including laboratory findings or findings in the medical history or pre-trial assessments, that in the opinion of the Investigator constitutes a risk or a contraindication for the subject's participation in the trial or that could interfere with the trial objectives, conduct or evaluation 2. Treatment with biologics aiming at B cell modulation such as rituximab or belimumab within 2 years before study Day 1 3. Any previous treatment with anakinra (Kineret), abatacept (Orencia) or tocilizumab within 3 months before study Day 1 4. Use of etanercept (Enbrel) within 28 days before study Day 1, or of infliximab (Remicade) or adalimumab (Humira) within 60 days before study Day 1 5. Participation in any interventional clinical trial with an unapproved investigational therapy within the 3 months before the start of this study (or within 5 half-lives of the investigated compound before study Day 1, whichever is longer) 6. Other protocol defined
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Achieving American College of Rheumatology 20 Response Based on C-reactive Protein (ACR20-CRP) at Week 26 | Week 26 | ACR20-CRP response is defined as 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 5 measures: 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). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Achieving American College of Rheumatology 70 Response Based on CRP (ACR70-CRP) at Week 26 | Week 26 | ACR70-CRP response is defined as \>=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) together with \>=70% improvement in at least 3 of the following 5 measures: 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). |
| Percentage of Participants Achieving Disease Activity Score in 28 Joints (DAS28) Based on CRP (DAS28-CRP) of Less Than or Equal to (<=) 3.2 at Week 26 | Week 26 | 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-millimeter (mm) visual analog scale (the participant's global assessment of disease activity). DAS28 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. |
| Percentage of Participants Achieving Disease Activity Score in 28 Joints (DAS28) Based on CRP (DAS28-CRP) of <=2.6 at Week 26 | Week 26 | 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 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. |
| Percentage of Participants Achieving American College of Rheumatology 50 Response Based on CRP (ACR50-CRP) at Week 26 | Week 26 | ACR50-CRP response is defined as \>=50% 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 \>=50% improvement in at least 3 of the following 5 measures: 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). |
| Percentage of Participants With Good or Moderate European League Against Rheumatism (EULAR) Response at Week 26 | Week 26 | The EULAR response criteria evaluate change in DAS28 scores represented as good response, moderate response, or no response considering both the current DAS28 score and the observed improvement from baseline. Participants were considered to have good or moderate EULAR response if at the time of assessment, their DAS28 score was \<=5.1 and the improvement from baseline in their DAS28 score was greater than (\>) 0.6; or if at the time of assessment, their DAS28 score was \>5.1 and improvement from baseline in their DAS28 score was \>1.2. |
| Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Baseline up to Week 38 | 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 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 Achieving Improvement in Health Assessment Questionnaire Disability Index (HAQ-DI) of at Least 0.3 From Baseline at Week 26 | Week 26 | The HAQ-DI is a participant-reported assessment of ability to perform tasks in 8 categories of daily living activities: dress/groom; arise; eat; walk; reach; grip; hygiene; and common activities over past week. Each item was scored on 4-point scale from 0 to 3: 0 = no difficulty; 1 = some difficulty; 2 = much difficulty; 3 = unable to do. Overall score was computed as the sum of domain scores and divided by the number of domains answered. Total possible score range is 0 to 3 where 0 = least difficulty and 3 = extreme difficulty. Percentage of participants achieving improvement in HAQ-DI of at least 0.3 from baseline at Week 26 was reported. |
Countries
Canada, United States
Participant flow
Pre-assignment details
A total of 456 subjects were screened, of whom 256 were enrolled and randomized of which 254 received the trial medication and included in Intention to Treat (ITT) population.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Placebo matched to atacicept was administered subcutaneously twice a week for initial 4 weeks, followed by once a week for subsequent 21 weeks. | 62 |
| Atacicept 25 mg Atacicept was administered subcutaneously at a dose of 25 mg twice a week for initial 4 weeks as loading dose, followed by 25 mg once a week for subsequent 21 weeks. | 66 |
| Atacicept 75 mg Atacicept was administered subcutaneously at a dose of 75 mg twice a week for initial 4 weeks as loading dose, followed by 75 mg once a week for subsequent 21 weeks. | 62 |
| Atacicept 150 mg Atacicept was administered subcutaneously at a dose of 150 mg twice a week for initial 4 weeks as loading dose, followed by 150 mg once a week for subsequent 21 weeks. | 64 |
| Total | 254 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 2 | 3 | 2 | 0 |
| Overall Study | Death | 0 | 0 | 1 | 0 |
| Overall Study | Disease Progression | 1 | 1 | 0 | 0 |
| Overall Study | Lost to Follow-up | 0 | 1 | 4 | 0 |
| Overall Study | Other | 8 | 2 | 5 | 4 |
| Overall Study | Protocol Violation | 1 | 0 | 1 | 0 |
| Overall Study | Randomized but not Treated | 2 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Total | Placebo | Atacicept 25 mg | Atacicept 75 mg | Atacicept 150 mg |
|---|---|---|---|---|---|
| Age, Continuous | 53.8 years STANDARD_DEVIATION 11.9 | 53.1 years STANDARD_DEVIATION 12.5 | 53.4 years STANDARD_DEVIATION 13.1 | 55.3 years STANDARD_DEVIATION 12 | 53.5 years STANDARD_DEVIATION 10.1 |
| Sex: Female, Male Female | 211 Participants | 51 Participants | 54 Participants | 53 Participants | 53 Participants |
| Sex: Female, Male Male | 43 Participants | 11 Participants | 12 Participants | 9 Participants | 11 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 15 / 62 | 25 / 66 | 16 / 62 | 26 / 64 |
| serious Total, serious adverse events | 3 / 62 | 9 / 66 | 8 / 62 | 5 / 64 |
Outcome results
Primary
Percentage of Participants Achieving American College of Rheumatology 20 Response Based on C-reactive Protein (ACR20-CRP) at Week 26
ACR20-CRP response is defined as 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 5 measures: 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).
Time frame: Week 26
Population: ITT population included all randomized participants who received at least 1 treatment dose.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants Achieving American College of Rheumatology 20 Response Based on C-reactive Protein (ACR20-CRP) at Week 26 | 29.0 percentage of participants |
| Atacicept 25 mg | Percentage of Participants Achieving American College of Rheumatology 20 Response Based on C-reactive Protein (ACR20-CRP) at Week 26 | 30.3 percentage of participants |
| Atacicept 75 mg | Percentage of Participants Achieving American College of Rheumatology 20 Response Based on C-reactive Protein (ACR20-CRP) at Week 26 | 27.4 percentage of participants |
| Atacicept 150 mg | Percentage of Participants Achieving American College of Rheumatology 20 Response Based on C-reactive Protein (ACR20-CRP) at Week 26 | 39.1 percentage of participants |
Secondary
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 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 38
Population: Safety population included all randomized participants who received at least 1 treatment dose and had safety data following their first dose.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs | 41 participants |
| Placebo | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAEs | 3 participants |
| Atacicept 25 mg | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs | 49 participants |
| Atacicept 25 mg | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAEs | 9 participants |
| Atacicept 75 mg | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAEs | 8 participants |
| Atacicept 75 mg | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs | 42 participants |
| Atacicept 150 mg | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs | 46 participants |
| Atacicept 150 mg | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAEs | 5 participants |
Secondary
Percentage of Participants Achieving American College of Rheumatology 50 Response Based on CRP (ACR50-CRP) at Week 26
ACR50-CRP response is defined as \>=50% 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 \>=50% improvement in at least 3 of the following 5 measures: 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).
Time frame: Week 26
Population: ITT population included all randomized participants who received at least 1 treatment dose.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants Achieving American College of Rheumatology 50 Response Based on CRP (ACR50-CRP) at Week 26 | 6.5 percentage of participants |
| Atacicept 25 mg | Percentage of Participants Achieving American College of Rheumatology 50 Response Based on CRP (ACR50-CRP) at Week 26 | 13.6 percentage of participants |
| Atacicept 75 mg | Percentage of Participants Achieving American College of Rheumatology 50 Response Based on CRP (ACR50-CRP) at Week 26 | 11.3 percentage of participants |
| Atacicept 150 mg | Percentage of Participants Achieving American College of Rheumatology 50 Response Based on CRP (ACR50-CRP) at Week 26 | 10.9 percentage of participants |
Secondary
Percentage of Participants Achieving American College of Rheumatology 70 Response Based on CRP (ACR70-CRP) at Week 26
ACR70-CRP response is defined as \>=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) together with \>=70% improvement in at least 3 of the following 5 measures: 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).
Time frame: Week 26
Population: ITT population included all randomized participants who received at least 1 treatment dose.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants Achieving American College of Rheumatology 70 Response Based on CRP (ACR70-CRP) at Week 26 | 0.0 percentage of participants |
| Atacicept 25 mg | Percentage of Participants Achieving American College of Rheumatology 70 Response Based on CRP (ACR70-CRP) at Week 26 | 6.1 percentage of participants |
| Atacicept 75 mg | Percentage of Participants Achieving American College of Rheumatology 70 Response Based on CRP (ACR70-CRP) at Week 26 | 4.8 percentage of participants |
| Atacicept 150 mg | Percentage of Participants Achieving American College of Rheumatology 70 Response Based on CRP (ACR70-CRP) at Week 26 | 0.0 percentage of participants |
Secondary
Percentage of Participants Achieving Disease Activity Score in 28 Joints (DAS28) Based on CRP (DAS28-CRP) of <=2.6 at Week 26
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 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: Week 26
Population: ITT population included all randomized participants who received at least 1 treatment dose.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants Achieving Disease Activity Score in 28 Joints (DAS28) Based on CRP (DAS28-CRP) of <=2.6 at Week 26 | 1.6 percentage of participants |
| Atacicept 25 mg | Percentage of Participants Achieving Disease Activity Score in 28 Joints (DAS28) Based on CRP (DAS28-CRP) of <=2.6 at Week 26 | 6.1 percentage of participants |
| Atacicept 75 mg | Percentage of Participants Achieving Disease Activity Score in 28 Joints (DAS28) Based on CRP (DAS28-CRP) of <=2.6 at Week 26 | 4.8 percentage of participants |
| Atacicept 150 mg | Percentage of Participants Achieving Disease Activity Score in 28 Joints (DAS28) Based on CRP (DAS28-CRP) of <=2.6 at Week 26 | 4.7 percentage of participants |
Secondary
Percentage of Participants Achieving Disease Activity Score in 28 Joints (DAS28) Based on CRP (DAS28-CRP) of Less Than or Equal to (<=) 3.2 at Week 26
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-millimeter (mm) visual analog scale (the participant's global assessment of disease activity). DAS28 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: Week 26
Population: ITT population included all randomized participants who received at least 1 treatment dose.
| Arm | Measure | Value (NUMBER) | Dispersion |
|---|---|---|---|
| Placebo | Percentage of Participants Achieving Disease Activity Score in 28 Joints (DAS28) Based on CRP (DAS28-CRP) of Less Than or Equal to (<=) 3.2 at Week 26 | 9.7 percentage of participants | 0.95 |
| Atacicept 25 mg | Percentage of Participants Achieving Disease Activity Score in 28 Joints (DAS28) Based on CRP (DAS28-CRP) of Less Than or Equal to (<=) 3.2 at Week 26 | 10.6 percentage of participants | 0.84 |
| Atacicept 75 mg | Percentage of Participants Achieving Disease Activity Score in 28 Joints (DAS28) Based on CRP (DAS28-CRP) of Less Than or Equal to (<=) 3.2 at Week 26 | 9.7 percentage of participants | 0.88 |
| Atacicept 150 mg | Percentage of Participants Achieving Disease Activity Score in 28 Joints (DAS28) Based on CRP (DAS28-CRP) of Less Than or Equal to (<=) 3.2 at Week 26 | 12.5 percentage of participants | 0.84 |
Secondary
Percentage of Participants Achieving Improvement in Health Assessment Questionnaire Disability Index (HAQ-DI) of at Least 0.3 From Baseline at Week 26
The HAQ-DI is a participant-reported assessment of ability to perform tasks in 8 categories of daily living activities: dress/groom; arise; eat; walk; reach; grip; hygiene; and common activities over past week. Each item was scored on 4-point scale from 0 to 3: 0 = no difficulty; 1 = some difficulty; 2 = much difficulty; 3 = unable to do. Overall score was computed as the sum of domain scores and divided by the number of domains answered. Total possible score range is 0 to 3 where 0 = least difficulty and 3 = extreme difficulty. Percentage of participants achieving improvement in HAQ-DI of at least 0.3 from baseline at Week 26 was reported.
Time frame: Week 26
Population: ITT population included all randomized participants who received at least 1 treatment dose. Here, 'N' (number of participants analyzed) signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants Achieving Improvement in Health Assessment Questionnaire Disability Index (HAQ-DI) of at Least 0.3 From Baseline at Week 26 | 47.4 percentage of participants |
| Atacicept 25 mg | Percentage of Participants Achieving Improvement in Health Assessment Questionnaire Disability Index (HAQ-DI) of at Least 0.3 From Baseline at Week 26 | 48.8 percentage of participants |
| Atacicept 75 mg | Percentage of Participants Achieving Improvement in Health Assessment Questionnaire Disability Index (HAQ-DI) of at Least 0.3 From Baseline at Week 26 | 55.9 percentage of participants |
| Atacicept 150 mg | Percentage of Participants Achieving Improvement in Health Assessment Questionnaire Disability Index (HAQ-DI) of at Least 0.3 From Baseline at Week 26 | 37.5 percentage of participants |
Secondary
Percentage of Participants With Good or Moderate European League Against Rheumatism (EULAR) Response at Week 26
The EULAR response criteria evaluate change in DAS28 scores represented as good response, moderate response, or no response considering both the current DAS28 score and the observed improvement from baseline. Participants were considered to have good or moderate EULAR response if at the time of assessment, their DAS28 score was \<=5.1 and the improvement from baseline in their DAS28 score was greater than (\>) 0.6; or if at the time of assessment, their DAS28 score was \>5.1 and improvement from baseline in their DAS28 score was \>1.2.
Time frame: Week 26
Population: ITT population included all randomized participants who received at least 1 treatment dose.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants With Good or Moderate European League Against Rheumatism (EULAR) Response at Week 26 | 41.9 percentage of participants |
| Atacicept 25 mg | Percentage of Participants With Good or Moderate European League Against Rheumatism (EULAR) Response at Week 26 | 31.8 percentage of participants |
| Atacicept 75 mg | Percentage of Participants With Good or Moderate European League Against Rheumatism (EULAR) Response at Week 26 | 35.5 percentage of participants |
| Atacicept 150 mg | Percentage of Participants With Good or Moderate European League Against Rheumatism (EULAR) Response at Week 26 | 53.1 percentage of participants |