Safety and Efficacy of Two Doses of Anifrolumab Compared to Placebo in Adult Subjects With Active Proliferative Lupus Nephritis (TULIP-LN1)

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

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).

Study Overview

• Status: Completed
• Conditions: Lupus Nephritis
• Intervention / Treatment: Biological: Anifrolumab; Drug: Placebo

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).

• Study Type: Interventional
• Enrollment (Actual): 147
• Phase: Phase 2

Contacts and Locations

Study Locations

• Argentina
  • Buenos Aires, Argentina, C1015ABO
    • Research Site
  • Cordoba, Argentina, 5016
    • Research Site
  • Rosario, Argentina, S2000PBJ
    • Research Site
• Australia
  • Adelaide, Australia, 5000
    • Research Site
  • Clayton, Australia, VIC 3168
    • Research Site
  • Parkville, Australia, 3050
    • Research Site
  • Westmead, Australia, 2145
    • Research Site
• Belgium
  • Brussels, Belgium, 1070
    • Research Site
  • Bruxelles, Belgium, 1200
    • Research Site
  • Leuven, Belgium, 3000
    • Research Site
  • Liege, Belgium, B-4000
    • Research Site
• France
  • Bordeaux Cedex, France, 33076
    • Research Site
  • Marseille, France, 13005
    • Research Site
  • Paris Cedex 14, France, 75013
    • Research Site
  • Strasbourg, France, 67098
    • Research Site
  • Toulouse, France, 31059
    • Research Site
• Germany
  • Berlin, Germany, 10117
    • Research Site
  • Kiel, Germany, 24105
    • Research Site
• Hungary
  • Budapest, Hungary, 1097
    • Research Site
  • Debrecen, Hungary, 4032
    • Research Site
  • Kaposvár, Hungary, 7400
    • Research Site
  • Szeged, Hungary, 6725
    • Research Site
• Italy
  • Milano, Italy, 20132
    • Research Site
  • Padova, Italy, 35128
    • Research Site
  • Pisa, Italy, 56126
    • Research Site
  • Reggio Emilia, Italy, 42100
    • Research Site
• Korea, Republic of
  • Gwangju, Korea, Republic of, 501-757
    • Research Site
  • Seoul, Korea, Republic of, 05505
    • Research Site
  • Seoul, Korea, Republic of, 150-713
    • Research Site
  • Suwon-si, Korea, Republic of, 16499
    • Research Site
• Mexico
  • Chihuahua, Mexico, 31000
    • Research Site
  • Guadalajara, Mexico, 44280
    • Research Site
  • Guadalajara, Mexico, 44160
    • Research Site
  • Mexico, Mexico, 14080
    • Research Site
  • San Luis Potosí, Mexico, 78213
    • Research Site
• Peru
  • Arequipa, Peru, AREQUIPA54
    • Research Site
  • Lima, Peru
    • Research Site
  • Lima, Peru, LIMA 01
    • Research Site
  • Lima, Peru, LIMA 31
    • Research Site
  • Lima, Peru, Lima 32
    • Research Site
  • Lima, Peru, LIMA 33
    • Research Site
  • Lima, Peru, L14
    • Research Site
  • Lima, Peru, L34
    • Research Site
  • Lima, Peru, Lima-1
    • Research Site
• Poland
  • Krakow, Poland, 31-066
    • Research Site
  • Warszawa, Poland, 02-637
    • Research Site
  • Łódź, Poland, 92-213
    • Research Site
• Russian Federation
  • Orenburg, Russian Federation, 460018
    • Research Site
  • Saint Petersburg, Russian Federation, 197022
    • Research Site
  • Saint Petersburg, Russian Federation, 197089
    • Research Site
• Serbia
  • Belgrade, Serbia, 11000
    • Research Site
  • Belgrade, Serbia, 1100
    • Research Site
  • Nis, Serbia, 18000
    • Research Site
  • Novi Sad, Serbia, 21000
    • Research Site
• Spain
  • Barcelona, Spain, 08035
    • Research Site
  • Barcelona, Spain, 08036
    • Research Site
• Taiwan
  • Changhua City, Taiwan, 50006
    • Research Site
  • Kaohsiung, Taiwan, 80756
    • Research Site
  • Taichung, Taiwan, 40705
    • Research Site
  • Taichung, Taiwan, 40447
    • Research Site
  • Taipei, Taiwan, 100
    • Research Site
  • Taoyuan City, Taiwan, 333
    • Research Site
• United Kingdom
  • London, United Kingdom, E1 1BB
    • Research Site
• United States
  • Arizona
    • Glendale, Arizona, United States, 85306
      • Research Site
    • Phoenix, Arizona, United States, 85032
      • Research Site
  • California
    • La Jolla, California, United States, 92037-0706
      • Research Site
    • Los Angeles, California, United States, 90095-1670
      • Research Site
    • Thousand Oaks, California, United States, 91360
      • Research Site
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Research Site
  • Florida
    • DeBary, Florida, United States, 32713
      • Research Site
  • Massachusetts
    • Boston, Massachusetts, United States, 02118
      • Research Site
  • New Jersey
    • Newark, New Jersey, United States, 07103-2499
      • Research Site
  • New York
    • Bronx, New York, United States, 10457
      • Research Site
    • Great Neck, New York, United States, 11021
      • Research Site
    • New Hyde Park, New York, United States, 11042
      • Research Site
    • New York, New York, United States, 10016
      • Research Site
    • New York, New York, United States, 10029
      • Research Site
  • Ohio
    • Columbus, Ohio, United States, 43210
      • Research Site
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • Research Site
  • Tennessee
    • Memphis, Tennessee, United States, 38119
      • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Anifrolumab - Lower Dose	Biological: Anifrolumab; Administration every 4 week from Week 0 to Week 100 in addition to SOC which will continue until Week 112
Experimental: Anifrolumab - Higher Dose	Biological: Anifrolumab; Administration every 4 week from Week 0 to Week 100 in addition to SOC which will continue until Week 112
Placebo Comparator: Placebo; Placebo IV Q4W plus SOC	Drug: Placebo; Administration every 4 week from Week 0 to Week 100 in addition to SOC which will continue until Week 112

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in 24-hour Urine Protein to Creatinine Ratio (UPCR)	To evaluate the efficacy of anifrolumab plus SOC (combination of mycophenolate mofetil and corticosteroids) compared with placebo plus SOC in subjects with active proliferative lupus nephritis (LN). Geometric mean ratio of 24-hour UPCR at week 52 over baseline. Values <1 indicate improvement from baseline.	From Week 1 (Baseline) up to Week 52

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of Subjects Achieving the Composite Endpoint Complete Renal Response (CRR)	CRR was defined as meeting all of the following: Estimated glomerular filtration rate (eGFR) is ≥60 mL/min/1.73 m^2 or no confirmed decrease of eGFR from baseline of ≥20%; 24-hour UPCR ≤ 0.7 mg/mg; No discontinuation of investigational product (IP) or use of restricted medication beyond the protocol allowed threshold before assessment; eGFR was based on Modification of Diet in Renal Disease (MDRD) formula. Subjects treated with restricted medication beyond the protocol allowed threshold, or discontinuing study treatment for other reasons, were regarded as non-responders.	Week 52

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Subjects With Adverse Events	To assess AEs (non-serious, serious and adverse event of special interest (AESI)) as variables of safety and tolerability of anifrolimab. The AESIs are serious infections, including non-opportunistic serious infections, opportunistic infections, anaphylaxis, malignancy, herpes zoster, TB (including latent TB), influenza, vasculitis (non-SLE), and MACE (including stroke, acute coronary syndrome, myocardial infarction, or cardiovascular death). Study period: During treatment and follow-up data are presented.	From screening (Day-30 to -1) period until the follow-up period (Week 112)
Number of Subjects With Suicidal Ideation and Behavior and Suicide Attempts Via Columbia-Suicide Severity Rating Scale (C-SSRS)	The C-SSRS was used to assess the suicidal ideation and behavior and suicide attempts on a graded scale from 1 to 5. 1 indicates as low suicidal and 5 as high suicidal behavior.	Baseline, treatment and follow up (an average of 60 weeks)
Total Score of Personal Health Questionnaire Depression Scale-8 (PHQD-8)	PHQ-8 is a 8-item self-report scale, all items are rated on a score of 0-3, for a total range of 0-24. PHQ-8 assesses symptoms of depression over the previous 2 weeks. Higher scores indicate more depressive symptoms.	Baseline, Week 12, Week 24, Week 36, Week 52, Week 60
Extra-renal Flares Using Systemic Lupus Erythematosus (SLE) Disease Activity Index 2000 (SLEDAI 2K) Based Flare Assessment Instrument	Flare will be defined as any one criterion present in either the Mild/Moderate Flare and/or Severe Flare categories. New or worsened manifestation should only be reported for manifestations of SLE. The SLEDAI-2K score range is 0 to 105 with higher scores representing increased disease activity. Mild/ Moderate flare defined as change in non-renal components of the SLEDAI-2K instrument score of ≥3 but <7 points compared to previous visit. Severe Flare defined as change in non-renal components of the SLEDAI-2K instrument score by ≥7 points compared to previous visit. The flare rate per subject year is defined as the number of subjects with a respective flare divided by the sum of exposure time in days for all subjects in the analysis set multiplied by 365.25.	From baseline up to week 112

Collaborators and Investigators

• Sponsor: AstraZeneca
• Collaborators: Parexel
• Investigators: Study Director: AstraZeneca AB, AstraZeneca

Publications and helpful links

General Publications

• 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.

Helpful Links

• Protocol
• SAP
• CSR Synopsis

Study record dates

Study Major Dates

• Study Start (Actual): November 4, 2015
• Primary Completion (Actual): November 26, 2019
• Study Completion (Actual): January 18, 2021

Study Registration Dates

• First Submitted: August 31, 2015
• First Submitted That Met QC Criteria: September 10, 2015
• First Posted (Estimate): September 14, 2015

Study Record Updates

• Last Update Posted (Actual): November 24, 2021
• Last Update Submitted That Met QC Criteria: October 28, 2021
• Last Verified: October 1, 2021

More Information

Terms related to this study

• Keywords: lupus, nephritis, randomized, placebo, anifrolumab, safety, efficacy, adult
• Additional Relevant MeSH Terms: Immune System Diseases; Autoimmune Diseases; Kidney Diseases; Urologic Diseases; Connective Tissue Diseases; Glomerulonephritis; Lupus Erythematosus, Systemic; Nephritis; Lupus Nephritis
• Other Study ID Numbers: D3461C00007

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All request will be evaluated as per the AZ disclosure commitment:
• IPD Sharing Time Frame: AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles.
• IPD Sharing Access Criteria: When a request has been approved AstraZeneca will provide access to the de-identified individual patient-level data in an approved sponsored tool . Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access.
• IPD Sharing Supporting Information Type: Study Protocol; Statistical Analysis Plan (SAP)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No