Clinical trial NCT02547922: Safety and Efficacy of Two Doses of Anifrolumab Compared to Placebo in Adult Subjects With Active Proliferative Lupus Nephritis
Official title: A Multicentre, Randomised, Double-blind, Placebo-controlled, Phase 2 Study Evaluating the Efficacy and Safety of Anifrolumab in Adult Subjects With Active Proliferative Lupus Nephritis
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Lupus Nephritis
Keywords: lupus, nephritis, randomized, placebo, anifrolumab, safety, efficacy, adult
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
Collaborators: name: Parexel
First posted: 2015-09-14
Enrollment: 147
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to evaluate the efficacy and safety of an intravenous treatment regimen of two doses of anifrolumab versus placebo in adult subjects with active proliferative lupus nephritis (LN).

Detailed description: This is a Phase 2, multicentre, multinational, randomised, double-blind, placebo-controlled study to evaluate the efficacy and safety of two intravenous (IV) treatment regimens of anifrolumab versus placebo while taking standard of care (SOC) treatment with mycophenolate mofetil (MMF) and corticosteroids in adult subjects with active proliferative lupus nephritis (LN).

Eligibility criteria: Main Inclusion Criteria:

1. Age 18 through 70 years at the time of screening
2. Fulfils at least 4 of the 11 criteria of the revised 1982 ACR classification criteria for SLE, at least one of which must be:

   1. Positive antinuclear antibody (ANA) test (1:40 or higher) or
   2. Elevated anti-dsDNA antibodies at screening (reported as equivocal or positive results), as per the centrallaboratory; or
   3. Anti-Smith antibody at screening elevated to above normal (ie, positive or equivocal results) as per the central laboratory
3. Class III (±Class V) or Class IV (±Class V) LN according to the World Health Organisation (WHO) or 2003 ISN/RPS classification based on a renal biopsy obtained within 12 weeks prior to signing the ICF or during the screening period:
4. Urine protein to creatinine ratio \>1 gm/gm (113.17 mg/mmol), obtained on a 24-hour urine collection at screening
5. Estimated glomerular filtration rate ≥35 mL/min/1.73 m2
6. Must not have active or latent TB on either chest radiograph or by Quantiferon gold test
7. Women of childbearing potential must have a negative serum beta-hCG test at screening and negative urine pregnancy test prior to the first dose of sponsor-provided MMF.

Main Exclusion Criteria:

1. Receipt of any investigational product (small molecule or biologic) or commercially available biologic agent within four weeks or 5 half lives prior to signing of the ICF, whichever is greater
2. Pure Class V membranous LN on a renal biopsy obtained within 12 weeks prior to signing ICF or during the screening period
3. Known intolerance to ≤1.0 gm/day of MMF
4. History of dialysis within 12 months prior to signing the ICF or expected need for renal replacement therapy (dialysis or renal transplant) within a 6 month period after enrolment
5. Subjects, who at the time of signing the ICF, received any of the following immunosuppressive therapies after their qualifying biopsy

   1. Oral corticosteroids \>0.5 mg/kg/day for more than 8 weeks or
   2. Oral or IV pulse methylprednisolone \>3.0 gm (cumulative dose) or
   3. IV cyclophosphamide \>2 pulses of high-dose (≥0.5 gm/m2) or \>4 doses of low dose (500 mg every 2 weeks) or
   4. Average MMF \>2.5 gm/day (\>1800 mg/day of enteric-coated mycophenolate sodium) for more than 8 weeks or
   5. Tacrolimus \>4 mg/day for more than 8 weeks
6. Major surgery within 8 weeks before signing the ICF or major surgery planned during the study period
7. History of any non-SLE disease that has required treatment with oral or parenteral corticosteroids for more than a total of 2 weeks within the last 24 weeks prior to signing the ICF
8. Confirmed positive test for hepatitis B or hepatitis C
9. Any severe herpes infection at any time prior to randomization
10. Opportunistic infection requiring hospitalisation or parenteral antimicrobial treatment within 3 years prior to randomization (vaginal, oral and skin candidiasis is not an exclusionreason).
11. History of cancer, apart from:

    1. Squamous or basal cell carcinoma of the skin that has been successfully treated
    2. Cervical cancer in situ that has been successfully treated
12. Concurrent enrolment in another clinical study with an IP within 4 weeks prior to ICF signing or within 5 half-lives of the IP used in that clinical study, whichever is longer.
13. During screening (within 30 days before Day 1 \[Week 0 visit\]), any of the following:

    1. Aspartate transaminase (AST) \>2.5×upper limit of normal (ULN)
    2. Alanine transaminase (ALT) \>2.5×ULN
    3. Total bilirubin \>ULN (unless due to Gilbert's syndrome \[based on Investigator's judgement\])
    4. Glycosylated haemoglobin (HbA1c) \>8% (or \>0.08) at screening (diabetic subjects only)
    5. Neutrophil count \<1x103/μL (or \<1.0 GI/L)
    6. Platelet count \<25x103/μL (or \<25 GI/L)
    7. Haemoglobin \<8 g/dL (or \<80 g/L).

Primary outcomes:
measure: Change From Baseline in 24-hour Urine Protein to Creatinine Ratio (UPCR)
timeFrame: From Week 1 (Baseline) up to Week 52
Secondary outcomes:
measure: Proportion of Subjects Achieving the Composite Endpoint Complete Renal Response (CRR)
timeFrame: Week 52
Other outcomes:
measure: Number of Subjects With Adverse Events
timeFrame: From screening (Day-30 to -1) period until the follow-up period (Week 112)
measure: Number of Subjects With Suicidal Ideation and Behavior and Suicide Attempts Via Columbia-Suicide Severity Rating Scale (C-SSRS)
timeFrame: Baseline, treatment and follow up (an average of 60 weeks)
measure: Total Score of Personal Health Questionnaire Depression Scale-8 (PHQD-8)
timeFrame: Baseline, Week 12, Week 24, Week 36, Week 52, Week 60
measure: Extra-renal Flares Using Systemic Lupus Erythematosus (SLE) Disease Activity Index 2000 (SLEDAI 2K) Based Flare Assessment Instrument
timeFrame: From baseline up to week 112
Locations:
city: Glendale
country: United States
facility: Research Site
state: Arizona
city: Phoenix
country: United States
facility: Research Site
state: Arizona
city: La Jolla
country: United States
facility: Research Site
state: California
city: Los Angeles
country: United States
facility: Research Site
state: California
city: Thousand Oaks
country: United States
facility: Research Site
state: California
city: Aurora
country: United States
facility: Research Site
state: Colorado
city: DeBary
country: United States
facility: Research Site
state: Florida
city: Boston
country: United States
facility: Research Site
state: Massachusetts
city: Newark
country: United States
facility: Research Site
state: New Jersey
city: Bronx
country: United States
facility: Research Site
state: New York
city: Great Neck
country: United States
facility: Research Site
state: New York
city: New Hyde Park
country: United States
facility: Research Site
state: New York
city: New York
country: United States
facility: Research Site
state: New York
city: New York
country: United States
facility: Research Site
state: New York
city: Columbus
country: United States
facility: Research Site
state: Ohio
city: Oklahoma City
country: United States
facility: Research Site
state: Oklahoma
city: Memphis
country: United States
facility: Research Site
state: Tennessee
city: Buenos Aires
country: Argentina
facility: Research Site
city: Cordoba
country: Argentina
facility: Research Site
city: Rosario
country: Argentina
facility: Research Site
city: Adelaide
country: Australia
facility: Research Site
city: Clayton
country: Australia
facility: Research Site
city: Parkville
country: Australia
facility: Research Site
city: Westmead
country: Australia
facility: Research Site
city: Brussels
country: Belgium
facility: Research Site
city: Bruxelles
country: Belgium
facility: Research Site
city: Leuven
country: Belgium
facility: Research Site
city: Liege
country: Belgium
facility: Research Site
city: Bordeaux Cedex
country: France
facility: Research Site
city: Marseille
country: France
facility: Research Site
city: Paris Cedex 14
country: France
facility: Research Site
city: Strasbourg
country: France
facility: Research Site
city: Toulouse
country: France
facility: Research Site
city: Berlin
country: Germany
facility: Research Site
city: Kiel
country: Germany
facility: Research Site
city: Budapest
country: Hungary
facility: Research Site
city: Debrecen
country: Hungary
facility: Research Site
city: Kaposvár
country: Hungary
facility: Research Site
city: Szeged
country: Hungary
facility: Research Site
city: Milano
country: Italy
facility: Research Site
city: Padova
country: Italy
facility: Research Site
city: Pisa
country: Italy
facility: Research Site
city: Reggio Emilia
country: Italy
facility: Research Site
city: Gwangju
country: Korea, Republic of
facility: Research Site
city: Seoul
country: Korea, Republic of
facility: Research Site
city: Seoul
country: Korea, Republic of
facility: Research Site
city: Suwon-si
country: Korea, Republic of
facility: Research Site
city: Chihuahua
country: Mexico
facility: Research Site
city: Guadalajara
country: Mexico
facility: Research Site
city: Guadalajara
country: Mexico
facility: Research Site
city: Mexico
country: Mexico
facility: Research Site
city: San Luis Potosí
country: Mexico
facility: Research Site
city: Arequipa
country: Peru
facility: Research Site
city: Lima
country: Peru
facility: Research Site
city: Lima
country: Peru
facility: Research Site
city: Lima
country: Peru
facility: Research Site
city: Lima
country: Peru
facility: Research Site
city: Lima
country: Peru
facility: Research Site
city: Lima
country: Peru
facility: Research Site
city: Lima
country: Peru
facility: Research Site
city: Lima
country: Peru
facility: Research Site
city: Krakow
country: Poland
facility: Research Site
city: Warszawa
country: Poland
facility: Research Site
city: Łódź
country: Poland
facility: Research Site
city: Orenburg
country: Russian Federation
facility: Research Site
city: Saint Petersburg
country: Russian Federation
facility: Research Site
city: Saint Petersburg
country: Russian Federation
facility: Research Site
city: Belgrade
country: Serbia
facility: Research Site
city: Belgrade
country: Serbia
facility: Research Site
city: Nis
country: Serbia
facility: Research Site
city: Novi Sad
country: Serbia
facility: Research Site
city: Barcelona
country: Spain
facility: Research Site
city: Barcelona
country: Spain
facility: Research Site
city: Changhua City
country: Taiwan
facility: Research Site
city: Kaohsiung
country: Taiwan
facility: Research Site
city: Taichung
country: Taiwan
facility: Research Site
city: Taichung
country: Taiwan
facility: Research Site
city: Taipei
country: Taiwan
facility: Research Site
city: Taoyuan City
country: Taiwan
facility: Research Site
city: London
country: United Kingdom
facility: Research Site
Study officials:
affiliation: AstraZeneca
name: AstraZeneca AB
role: STUDY_DIRECTOR
References:
citation: Jayne D, Rovin B, Mysler EF, Furie RA, Houssiau FA, Trasieva T, Knagenhjelm J, Schwetje E, Chia YL, Tummala R, Lindholm C. Phase II randomised trial of type I interferon inhibitor anifrolumab in patients with active lupus nephritis. Ann Rheum Dis. 2022 Apr;81(4):496-506. doi: 10.1136/annrheumdis-2021-221478. Epub 2022 Feb 10.