Active Systemic Lupus Erythematosus
Conditions
Keywords
Lupus Erythematosus, Systemic Autoimmune Diseases, Connective Tissue Diseases,Immune System Diseases
Brief summary
The purpose of this study is to characterise long-term safety and tolerability of intravenous anifrolumab.
Detailed description
This is a Phase 3, multicentre, multinational, randomised, double-blind, placebo-controlled extension study to characterising the long term safety and tolerability of of an intravenous treatment regimen of anifrolumab versus placebo in subjects with moderately to severely active systemic lupus erythematosus who completed a Phase 3 study (D3461C00004 or D3461C00005) through the 52-week double-blind treatment period.
Interventions
BIOLOGICALAnifrolumab
Anifrolumab IV administration every 4 weeks from Week 0 to Week 152 for a total of 39 doses
DRUGPlacebo
Placebo IV administration every 4 weeks from Week 0 to Week 152 for a total of 39 doses
Sponsors
PRA Health Sciences
AstraZeneca
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 70 Years
Healthy volunteers
No
Inclusion criteria
1. Subjects who have qualified for and received investigational product (anifrolumab or placebo) and completed the treatment period in Studies D3461C00004 or D3461C00005 (through Week 52) 2. Adequate peripheral venous access 3. Females with an intact cervix should have documentation of a Pap smear with no documented malignancy within 90 days before Day 1/Visit 1 or 30 days following Day 1/Visit 1. Since access to a Pap smear may vary by country, the Sponsor recommends that local guidelines for obtaining Pap smears in subjects who have received immunomodulators or immunosuppressive treatment be followed. 4. Meets the following TB criteria: 1. Negative QuantiFERON®-TB Gold \[QFT-G\] test result for TB obtained from the study central laboratory at Week 52 of Studies D3461C00004 or D3461C00005; OR 2. Newly positive QFT-G test result at Week 52 of Studies D3461C00004 or D3461C00005 from the study central laboratory. A chest x-ray must be performed. If the chest x-ray shows no evidence of active TB, and the subject has no symptoms or medical history consistent with active TB, the subject must have a retest. If the retest is positive, the subject must start on prophylaxis within 30 days of randomisation but prior to the second dose of investigational product (Visit 2/Week 4); OR 3. Positive but not newly positive QFT-G test at Week 52 of Studies D3461C00004 or D3461C00005. The subject must have been diagnosed with latent TB and must have documentation confirming initiation of appropriate treatment OR initiate treatment for latent TB within 30 days of randomization, but prior to the second dose of investigational product administration (Visit 2/Week 4) 4. Newly indeterminate (confirmed on retest unless prior positive QFT G was documented, along with completed treatment for latent TB) or indeterminate but not newly indeterminate QFT-G test result at Week 52 of Studies D3461C00004 or D3461C00005 from the study central laboratory with ongoing QFT-G testing for TB according to the Study Plan 5. In the opinion of the Investigator, subject must be able to comprehend the ICF and all protocol related assessments
Exclusion criteria
1. Receipt of any of the following within the last 60 days: 1. Azathioprine \>200 mg/day 2. Mycophenolate mofetil \>2.0 g/day /mycophenolic acid \>1.44 g/day 3. Oral, subcutaneous, or intramuscular methotrexate \>25 mg/week 4. Mizoribine \>150 mg/day 2. Receipt of any investigational product (small molecule or biologic agent other than anifrolumab) within 4 weeks or 5 half-lives prior to Day 1/Visit 1, whichever is greater 3. Receipt of any of the following: 1. Any live or attenuated vaccine within 8 weeks prior to Day 1/Visit 1 (administration of killed vaccines is acceptable, the Sponsor recommends Investigators ensure all subjects are up to date on required vaccinations, including influenza \[inactivated/recombinant\] vaccine prior to study entry) 2. Bacillus Calmette-Guerin (BCG) vaccine between the end of Studies D3461C00004 or D3461C00005 and Day 1/Visit 1 4. Active severe SLE-driven renal or neuropsychiatric disease 5. Any underlying condition that predisposes the subject to infection, including history of/current human immunodeficiency virus (HIV) infection 6. Subjects with Hepatitis B core antibody (HBcAb) positivity at enrolment of Studies D3461C00004 or D3461C00005 will be tested every 3 months for Hepatitis B virus (HBV) DNA. To remain eligible in the LTE study, subject HBV DNA levels must remain below the lower limit of quantitation as per the central laboratory. 7. Opportunistic infection requiring hospitalisation or parenteral antimicrobial treatment within 3 years of Day 1/Visit 1
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Exposure-adjusted Incidence Rates (EAIRs) of Adverse Events of Special Interest (AESIs) | Up to a maximum of 1114 days | The event rate per 100 participant years was defined as the number of participants with an event divided by the sum of exposure time during the LTE study (including follow-up) in days for all participants in the analysis set multiplied by 365.25 days/year multiplied by 100. The exposure in a time period for each participant was calculated as end of period - start of period + 1. EAIRs of AESIs are presented as event rate per 100 participant years. The following AESIs were pre-defined: * Non-opportunistic serious infections * Opportunistic infections * Anaphylaxis * Malignancy * Herpes zoster * Tuberculosis (TB) (including latent TB) * Influenza * Vasculitis (non-systemic lupus erythematosus \[SLE\]) * Major cardiovascular events as according to the Cardiovascular Event Adjudication Committee. |
| EAIRs of Serious Adverse Events (SAEs) | Up to a maximum of 1114 days | EAIRs of SAEs are presented as event rate per 100 participant years. An SAE was an AE occurring during any study phase that fulfils 1 or more of the following criteria: * Results in death * Is immediately life-threatening * Requires in-patient hospitalisation or prolongation of existing hospitalisation * Results in persistent or significant disability/incapacity or substantial disruption of the ability to conduct normal life functions * Is a congenital abnormality or birth defect * Is an important medical event that may jeopardise the participant or may require medical intervention to prevent one of the outcomes listed above. |
Countries
Argentina, Australia, Bulgaria, Canada, Chile, Colombia, France, Germany, Hungary, Israel, Japan, Lithuania, Mexico, Peru, Poland, Romania, Russia, South Africa, South Korea, Spain, Taiwan, Ukraine, United Kingdom, United States
Participant flow
Recruitment details
This long-term extension (LTE) study was conducted at 176 study centres in 24 countries.
Pre-assignment details
The LTE population was comprised of participants who had completed the 52-week double-blind treatment period in one of the Phase III feeder studies (D3461C00004 \[NCT02446899\] or D3461C00005 \[NCT02446912\]), met all LTE eligibility criteria, and were willing to continue into the extension study.
Participants by arm
| Arm | Count |
|---|---|
| Randomised Anifrolumab 300 mg Anifrolumab (300 mg) administered via an IV infusion every 4 weeks for up to 152 weeks (39 doses).
Participants were previously administered anifrolumab (300 mg) in a feeder study. | 257 |
| Placebo Feeder + Placebo LTE Placebo administered via an IV infusion every 4 weeks for up to 152 weeks (39 doses).
Participants were previously administered placebo in a feeder study. | 112 |
| Placebo Feeder + Anifrolumab 300 mg LTE Anifrolumab (300 mg) administered via an IV infusion every 4 weeks for up to 152 weeks (39 doses).
Participants were previously administered placebo in a feeder study. | 111 |
| Anifrolumab 150 mg Feeder + Anifrolumab 300 mg LTE Anifrolumab (300 mg) administered via an IV infusion every 4 weeks for up to 152 weeks (39 doses).
Participants were previously administered anifrolumab (150 mg) in a feeder study. | 67 |
| Total | 547 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 11 | 4 | 5 | 8 |
| Overall Study | Condition Under Investigation Improved | 1 | 0 | 0 | 0 |
| Overall Study | Condition Under Investigation Worsened | 0 | 2 | 1 | 0 |
| Overall Study | Death | 2 | 1 | 2 | 0 |
| Overall Study | Development of Study-specific Withdrawal Criteria | 1 | 0 | 0 | 1 |
| Overall Study | Due to COVID-19 Pandemic | 7 | 2 | 4 | 0 |
| Overall Study | Failure to Meet Randomisation Criteria | 0 | 0 | 1 | 0 |
| Overall Study | Lack of Efficacy | 10 | 6 | 3 | 3 |
| Overall Study | Lost to Follow-up | 5 | 6 | 3 | 1 |
| Overall Study | Missing | 1 | 0 | 0 | 0 |
| Overall Study | Other - Not Due to COVID-19 Pandemic | 2 | 6 | 2 | 1 |
| Overall Study | Severe Non-compliance to Protocol | 1 | 2 | 1 | 0 |
| Overall Study | Withdrawal by Subject | 38 | 29 | 20 | 12 |
Baseline characteristics
| Characteristic | Randomised Anifrolumab 300 mg | Placebo Feeder + Placebo LTE | Placebo Feeder + Anifrolumab 300 mg LTE | Anifrolumab 150 mg Feeder + Anifrolumab 300 mg LTE | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 10 Participants | 1 Participants | 4 Participants | 2 Participants | 17 Participants |
| Age, Categorical Between 18 and 65 years | 247 Participants | 111 Participants | 107 Participants | 65 Participants | 530 Participants |
| Age, Continuous | 43.4 Years STANDARD_DEVIATION 11.51 | 41.4 Years STANDARD_DEVIATION 11.46 | 42.2 Years STANDARD_DEVIATION 12.24 | 42.4 Years STANDARD_DEVIATION 11.7 | 42.6 Years STANDARD_DEVIATION 11.67 |
| Race/Ethnicity, Customized American Indian or Alaska Native | 3 Participants | 1 Participants | 0 Participants | 0 Participants | 4 Participants |
| Race/Ethnicity, Customized Asian | 33 Participants | 10 Participants | 12 Participants | 6 Participants | 61 Participants |
| Race/Ethnicity, Customized Black or African American | 28 Participants | 11 Participants | 17 Participants | 10 Participants | 66 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 54 Participants | 28 Participants | 22 Participants | 14 Participants | 118 Participants |
| Race/Ethnicity, Customized Missing | 5 Participants | 2 Participants | 2 Participants | 0 Participants | 9 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 198 Participants | 82 Participants | 87 Participants | 53 Participants | 420 Participants |
| Race/Ethnicity, Customized Other | 15 Participants | 11 Participants | 10 Participants | 6 Participants | 42 Participants |
| Race/Ethnicity, Customized White | 173 Participants | 77 Participants | 70 Participants | 45 Participants | 365 Participants |
| Sex: Female, Male Female | 237 Participants | 103 Participants | 102 Participants | 63 Participants | 505 Participants |
| Sex: Female, Male Male | 20 Participants | 9 Participants | 9 Participants | 4 Participants | 42 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 | 3 / 257 | 1 / 112 | 3 / 111 | 2 / 67 |
| other Total, other adverse events | 195 / 257 | 79 / 112 | 81 / 111 | 53 / 67 |
| serious Total, serious adverse events | 56 / 257 | 27 / 112 | 26 / 111 | 14 / 67 |
Outcome results
Primary
EAIRs of Serious Adverse Events (SAEs)
EAIRs of SAEs are presented as event rate per 100 participant years. An SAE was an AE occurring during any study phase that fulfils 1 or more of the following criteria: * Results in death * Is immediately life-threatening * Requires in-patient hospitalisation or prolongation of existing hospitalisation * Results in persistent or significant disability/incapacity or substantial disruption of the ability to conduct normal life functions * Is a congenital abnormality or birth defect * Is an important medical event that may jeopardise the participant or may require medical intervention to prevent one of the outcomes listed above.
Time frame: Up to a maximum of 1114 days
Population: FAS - LTE Study: consisted of all participants who were randomised and received at least 1 dose of investigational product in the LTE Study.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Randomised Anifrolumab 300 mg | EAIRs of Serious Adverse Events (SAEs) | 8.5 Events per 100 participant years |
| Placebo Feeder + Placebo LTE | EAIRs of Serious Adverse Events (SAEs) | 11.2 Events per 100 participant years |
| Placebo Feeder + Anifrolumab 300 mg LTE | EAIRs of Serious Adverse Events (SAEs) | 10.1 Events per 100 participant years |
| Anifrolumab 150 mg Feeder + Anifrolumab 300 mg LTE | EAIRs of Serious Adverse Events (SAEs) | 10.7 Events per 100 participant years |
Primary
Exposure-adjusted Incidence Rates (EAIRs) of Adverse Events of Special Interest (AESIs)
The event rate per 100 participant years was defined as the number of participants with an event divided by the sum of exposure time during the LTE study (including follow-up) in days for all participants in the analysis set multiplied by 365.25 days/year multiplied by 100. The exposure in a time period for each participant was calculated as end of period - start of period + 1. EAIRs of AESIs are presented as event rate per 100 participant years. The following AESIs were pre-defined: * Non-opportunistic serious infections * Opportunistic infections * Anaphylaxis * Malignancy * Herpes zoster * Tuberculosis (TB) (including latent TB) * Influenza * Vasculitis (non-systemic lupus erythematosus \[SLE\]) * Major cardiovascular events as according to the Cardiovascular Event Adjudication Committee.
Time frame: Up to a maximum of 1114 days
Population: FAS - LTE Study: consisted of all participants who were randomised and received at least 1 dose of investigational product in the LTE Study.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Randomised Anifrolumab 300 mg | Exposure-adjusted Incidence Rates (EAIRs) of Adverse Events of Special Interest (AESIs) | 11.0 Events per 100 participant years |
| Placebo Feeder + Placebo LTE | Exposure-adjusted Incidence Rates (EAIRs) of Adverse Events of Special Interest (AESIs) | 9.6 Events per 100 participant years |
| Placebo Feeder + Anifrolumab 300 mg LTE | Exposure-adjusted Incidence Rates (EAIRs) of Adverse Events of Special Interest (AESIs) | 12.9 Events per 100 participant years |
| Anifrolumab 150 mg Feeder + Anifrolumab 300 mg LTE | Exposure-adjusted Incidence Rates (EAIRs) of Adverse Events of Special Interest (AESIs) | 12.5 Events per 100 participant years |