Lupus Erythematosus, Systemic
Conditions
Keywords
Atacicept 75 and 150 mg, Placebo
Brief summary
This study is to evaluate the efficacy and safety of atacicept compared to placebo in preventing new flares in subjects with systemic lupus erythematosus (SLE) and to confirm the optimal dose of atacicept for treatment of subjects with SLE and gain information on the effect of atacicept on markers specific to its mechanism of action (MoA) and their correlation to disease activity/progression. Study medication will be administered through subcutaneous (under the skin) injections, beginning with twice weekly injections for the first 4 weeks, followed by once weekly doses for 48 weeks. Following the last treatment, a safety follow-up period of 24 weeks will be conducted.
Interventions
DRUGAtacicept 75 mg
75 milligram (mg) atacicept injection will be administered subcutaneously twice weekly during initial loading period for 4 weeks followed by once weekly during maintenance period for subsequent 48 weeks.
DRUGAtacicept 150 mg
150 mg atacicept injection will be administered subcutaneously twice weekly during initial loading period for 4 weeks followed by once weekly during maintenance period for subsequent 48 weeks.
OTHERPlacebo Comparator
Placebo matched to atacicept injection will be administered subcutaneously twice weekly during initial loading period for 4 weeks followed by once weekly during maintenance period for subsequent 48 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
16 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Male or female 16 years of age or older * Disease history of at least six months meeting at least 4 out of the 11 American College of Rheumatology (ACR) criteria for SLE * Active SLE with at least one British Isles Lupus Assessment Group (BILAG) flare A or B at screening requiring a change in the dose of corticosteroids * Positive antinuclear antibody (ANA) or anti-double-stranded deoxyribonucleic acid (dsDNA) at screening * Female subjects must be willing to avoid pregnancy by using an adequate method of contraception for 4 weeks prior to Study Day 1, during the trial and 24 weeks after the last dose of study medication * Other protocol defined inclusion criteria could apply
Exclusion criteria
* Active moderate to severe glomerulonephritis (kidney impairment) as defined in the protocol * Active central nervous system SLE deemed to be severe/progressive and/or associated with significant cognitive impairment leading to inability to provide informed consent and/or comply with the protocol * Previous treatment with rituximab, abatacept, or belimumab * History of demyelinating disease such as multiple sclerosis (MS) or optic neuritis * Other protocol defined
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Experiencing a New Flare as Defined by British Isles Lupus Assessment Group (BILAG) Score A or B | From screening up to Week 52 | A flare was defined as having an adjudicated BILAG A or B score in any of the 8 organ systems during treatment, or imputed for participants who had premature treatment discontinuation. Discontinuations due to sponsor termination of the atacicept 150 mg group were not imputed as flares in this analysis. The BILAG disease activity index evaluates systemic lupus erythematosus (SLE) activity in 8 organ systems, using a separate alphabetic score (A to E) assigned to each organ system defined as follows. BILAG A: Disease sufficiently active requiring disease-modifying treatment (prednisone greater than 20 mg daily or immunosuppressants); BILAG B: Disease less active than in A, mild reversible problems requiring only symptomatic therapy such as antimalarials, non-steroidal anti-inflammatory drugs (NSAIDs), or prednisone less than 20 mg day; BILAG C: Stable mild disease; BILAG D: System previously affected but now inactive; BILAG E: System never involved. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to First New Flare as Defined by BILAG Score A or B | From screening up to Week 52 | A flare was defined as having an adjudicated BILAG A or B score in any of the 8 organ systems during treatment. Analysis was right-censored at Week 52. The hazard ratios and 95% confidence intervals were obtained from the Cox proportional hazards model. The 25th Percentile of time to new flare was reported using Kaplan-Meier estimates (Median was not reached). The BILAG disease activity index evaluates SLE activity in 8 organ systems, using a separate alphabetic score (A to E) assigned to each organ system defined as follows. BILAG A: Disease sufficiently active requiring disease-modifying treatment (prednisone greater than 20 mg daily or immunosuppressants); BILAG B: Disease less active than in A, mild reversible problems requiring only symptomatic therapy such as antimalarials, NSAIDs, or prednisone less than 20 mg day; BILAG C: Stable mild disease; BILAG D: System previously affected but now inactive; BILAG E: System never involved. |
| Percentage of Participants Experiencing a New Flare as Defined by BILAG Score A or B During Initial 24 Weeks | From screening up to Week 24 | A flare was defined as having an adjudicated BILAG A or B score in any of the 8 organ systems during treatment, or imputed for participants who had premature treatment discontinuation. The BILAG disease activity index evaluates SLE activity in 8 organ systems, using a separate alphabetic score (A to E) assigned to each organ system defined as follows. BILAG A: Disease sufficiently active requiring disease-modifying treatment (prednisone greater than 20 mg daily or immunosuppressants); BILAG B: Disease less active than in A, mild reversible problems requiring only symptomatic therapy such as antimalarials, NSAIDs, or prednisone less than 20 mg day; BILAG C: Stable mild disease; BILAG D: System previously affected but now inactive; BILAG E: System never involved. |
| Percentage of Participants Within Ordinal Response Categories for British Isles Lupus Assessment Group (BILAG) Flares | Week 52 | Ordinal response categories have been defined as: 1) No BILAG A, no BILAG B, and completed treatment, 2) No BILAG A, at least 1 BILAG B during treatment period, and 3) At least 1 BILAG A during treatment period. The BILAG disease activity index evaluates SLE activity in 8 organ systems, using a separate alphabetic score (A to E) assigned to each organ system defined as follows. BILAG A: Disease sufficiently active requiring disease-modifying treatment (prednisone greater than 20 mg daily or immunosuppressants); BILAG B: Disease less active than in A, mild reversible problems requiring only symptomatic therapy such as antimalarials, NSAIDs, or prednisone less than 20 mg day; BILAG C: Stable mild disease; BILAG D: System previously affected but now inactive; BILAG E: System never involved. |
| Mean Cumulative Corticosteroid Dose | Randomization up to Week 52 | — |
Countries
Argentina, Australia, Austria, Bulgaria, Croatia, Czechia, France, Germany, Greece, India, Israel, Latvia, Lebanon, Lithuania, Malaysia, Mexico, Netherlands, Philippines, Poland, Russia, Serbia, South Africa, South Korea, Spain, Switzerland, Taiwan, Ukraine, United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Atacicept 75 mg 75 mg atacicept injection was administered subcutaneously twice weekly during initial loading period for 4 weeks followed by once weekly during maintenance period for subsequent 48 weeks. | 159 |
| Atacicept 150 mg 150 mg atacicept injection was administered subcutaneously twice weekly during initial loading period for 4 weeks followed by once weekly during maintenance period for subsequent 48 weeks. | 145 |
| Placebo Placebo matched to atacicept injection was administered subcutaneously twice weekly during initial loading period for 4 weeks followed by once weekly during maintenance period for subsequent 48 weeks. | 157 |
| Total | 461 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 14 | 14 | 18 |
| Overall Study | Death | 0 | 2 | 0 |
| Overall Study | Immunoglobulin less than 3gram per liter | 1 | 0 | 0 |
| Overall Study | Lack of Efficacy | 11 | 3 | 14 |
| Overall Study | Lost to Follow-up | 1 | 0 | 0 |
| Overall Study | Other | 15 | 5 | 9 |
| Overall Study | Protocol Violation | 3 | 3 | 2 |
| Overall Study | Randomized but not treated | 2 | 1 | 3 |
| Overall Study | Termination of 150 mg group by Sponsor | 0 | 55 | 0 |
Baseline characteristics
| Characteristic | Atacicept 75 mg | Atacicept 150 mg | Placebo | Total |
|---|---|---|---|---|
| Age, Continuous | 39.1 years STANDARD_DEVIATION 12 | 39.0 years STANDARD_DEVIATION 12.8 | 39.0 years STANDARD_DEVIATION 12.1 | 39.0 years STANDARD_DEVIATION 12.2 |
| Sex: Female, Male Female | 148 Participants | 134 Participants | 148 Participants | 430 Participants |
| Sex: Female, Male Male | 11 Participants | 11 Participants | 9 Participants | 31 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 129 / 157 | 120 / 144 | 118 / 154 |
| serious Total, serious adverse events | 30 / 157 | 23 / 144 | 27 / 154 |
Outcome results
Primary
Percentage of Participants Experiencing a New Flare as Defined by British Isles Lupus Assessment Group (BILAG) Score A or B
A flare was defined as having an adjudicated BILAG A or B score in any of the 8 organ systems during treatment, or imputed for participants who had premature treatment discontinuation. Discontinuations due to sponsor termination of the atacicept 150 mg group were not imputed as flares in this analysis. The BILAG disease activity index evaluates systemic lupus erythematosus (SLE) activity in 8 organ systems, using a separate alphabetic score (A to E) assigned to each organ system defined as follows. BILAG A: Disease sufficiently active requiring disease-modifying treatment (prednisone greater than 20 mg daily or immunosuppressants); BILAG B: Disease less active than in A, mild reversible problems requiring only symptomatic therapy such as antimalarials, non-steroidal anti-inflammatory drugs (NSAIDs), or prednisone less than 20 mg day; BILAG C: Stable mild disease; BILAG D: System previously affected but now inactive; BILAG E: System never involved.
Time frame: From screening up to Week 52
Population: Modified intent-to-treat (MITT) population included all the randomized participants who received study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Atacicept 75 mg | Percentage of Participants Experiencing a New Flare as Defined by British Isles Lupus Assessment Group (BILAG) Score A or B | 57.32 percentage of participants |
| Atacicept 150 mg | Percentage of Participants Experiencing a New Flare as Defined by British Isles Lupus Assessment Group (BILAG) Score A or B | 36.11 percentage of participants |
| Placebo | Percentage of Participants Experiencing a New Flare as Defined by British Isles Lupus Assessment Group (BILAG) Score A or B | 53.25 percentage of participants |
p-value: 0.51895% CI: [0.74, 1.82]Regression, Logistic
p-value: 0.00395% CI: [0.31, 0.78]Regression, Logistic
Secondary
Mean Cumulative Corticosteroid Dose
Time frame: Randomization up to Week 52
Population: MITT population included all the randomized participants who received study treatment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Atacicept 75 mg | Mean Cumulative Corticosteroid Dose | 2456.79 mg | Standard Deviation 1029.87 |
| Atacicept 150 mg | Mean Cumulative Corticosteroid Dose | 2018.87 mg | Standard Deviation 1062.61 |
| Placebo | Mean Cumulative Corticosteroid Dose | 2624.02 mg | Standard Deviation 812.44 |
Secondary
Percentage of Participants Experiencing a New Flare as Defined by BILAG Score A or B During Initial 24 Weeks
A flare was defined as having an adjudicated BILAG A or B score in any of the 8 organ systems during treatment, or imputed for participants who had premature treatment discontinuation. The BILAG disease activity index evaluates SLE activity in 8 organ systems, using a separate alphabetic score (A to E) assigned to each organ system defined as follows. BILAG A: Disease sufficiently active requiring disease-modifying treatment (prednisone greater than 20 mg daily or immunosuppressants); BILAG B: Disease less active than in A, mild reversible problems requiring only symptomatic therapy such as antimalarials, NSAIDs, or prednisone less than 20 mg day; BILAG C: Stable mild disease; BILAG D: System previously affected but now inactive; BILAG E: System never involved.
Time frame: From screening up to Week 24
Population: MITT population included all the randomized participants who received study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Atacicept 75 mg | Percentage of Participants Experiencing a New Flare as Defined by BILAG Score A or B During Initial 24 Weeks | 40.13 percentage of participants |
| Atacicept 150 mg | Percentage of Participants Experiencing a New Flare as Defined by BILAG Score A or B During Initial 24 Weeks | 28.47 percentage of participants |
| Placebo | Percentage of Participants Experiencing a New Flare as Defined by BILAG Score A or B During Initial 24 Weeks | 35.06 percentage of participants |
p-value: 0.41295% CI: [0.76, 1.94]Regression, Logistic
p-value: 0.19895% CI: [0.44, 1.19]Regression, Logistic
Secondary
Percentage of Participants Within Ordinal Response Categories for British Isles Lupus Assessment Group (BILAG) Flares
Ordinal response categories have been defined as: 1) No BILAG A, no BILAG B, and completed treatment, 2) No BILAG A, at least 1 BILAG B during treatment period, and 3) At least 1 BILAG A during treatment period. The BILAG disease activity index evaluates SLE activity in 8 organ systems, using a separate alphabetic score (A to E) assigned to each organ system defined as follows. BILAG A: Disease sufficiently active requiring disease-modifying treatment (prednisone greater than 20 mg daily or immunosuppressants); BILAG B: Disease less active than in A, mild reversible problems requiring only symptomatic therapy such as antimalarials, NSAIDs, or prednisone less than 20 mg day; BILAG C: Stable mild disease; BILAG D: System previously affected but now inactive; BILAG E: System never involved.
Time frame: Week 52
Population: MITT population included all the randomized participants who received study treatment. 'N' (number of participants analyzed) signifies participants who were evaluable for this measure.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Atacicept 75 mg | Percentage of Participants Within Ordinal Response Categories for British Isles Lupus Assessment Group (BILAG) Flares | No BILAG A, at least 1 BILAG B in treatment period | 39.8 percentage of participants |
| Atacicept 75 mg | Percentage of Participants Within Ordinal Response Categories for British Isles Lupus Assessment Group (BILAG) Flares | No BILAG A, no BILAG B, and completed treatment | 52.3 percentage of participants |
| Atacicept 75 mg | Percentage of Participants Within Ordinal Response Categories for British Isles Lupus Assessment Group (BILAG) Flares | At least 1 BILAG A in treatment period | 7.8 percentage of participants |
| Atacicept 150 mg | Percentage of Participants Within Ordinal Response Categories for British Isles Lupus Assessment Group (BILAG) Flares | No BILAG A, at least 1 BILAG B in treatment period | 28.9 percentage of participants |
| Atacicept 150 mg | Percentage of Participants Within Ordinal Response Categories for British Isles Lupus Assessment Group (BILAG) Flares | No BILAG A, no BILAG B, and completed treatment | 60.5 percentage of participants |
| Atacicept 150 mg | Percentage of Participants Within Ordinal Response Categories for British Isles Lupus Assessment Group (BILAG) Flares | At least 1 BILAG A in treatment period | 10.5 percentage of participants |
| Placebo | Percentage of Participants Within Ordinal Response Categories for British Isles Lupus Assessment Group (BILAG) Flares | No BILAG A, no BILAG B, and completed treatment | 52.9 percentage of participants |
| Placebo | Percentage of Participants Within Ordinal Response Categories for British Isles Lupus Assessment Group (BILAG) Flares | At least 1 BILAG A in treatment period | 8.8 percentage of participants |
| Placebo | Percentage of Participants Within Ordinal Response Categories for British Isles Lupus Assessment Group (BILAG) Flares | No BILAG A, at least 1 BILAG B in treatment period | 38.2 percentage of participants |
Secondary
Time to First New Flare as Defined by BILAG Score A or B
A flare was defined as having an adjudicated BILAG A or B score in any of the 8 organ systems during treatment. Analysis was right-censored at Week 52. The hazard ratios and 95% confidence intervals were obtained from the Cox proportional hazards model. The 25th Percentile of time to new flare was reported using Kaplan-Meier estimates (Median was not reached). The BILAG disease activity index evaluates SLE activity in 8 organ systems, using a separate alphabetic score (A to E) assigned to each organ system defined as follows. BILAG A: Disease sufficiently active requiring disease-modifying treatment (prednisone greater than 20 mg daily or immunosuppressants); BILAG B: Disease less active than in A, mild reversible problems requiring only symptomatic therapy such as antimalarials, NSAIDs, or prednisone less than 20 mg day; BILAG C: Stable mild disease; BILAG D: System previously affected but now inactive; BILAG E: System never involved.
Time frame: From screening up to Week 52
Population: MITT population included all the randomized participants who received study treatment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Atacicept 75 mg | Time to First New Flare as Defined by BILAG Score A or B | 143 days |
| Atacicept 150 mg | Time to First New Flare as Defined by BILAG Score A or B | 310 days |
| Placebo | Time to First New Flare as Defined by BILAG Score A or B | 142 days |
p-value: 0.92995% CI: [0.69, 1.4]Regression, Cox
p-value: 0.00995% CI: [0.36, 0.87]Regression, Cox