Safety and Efficacy of Two Doses of Anifrolumab Compared to Placebo in Adult Subjects With Active Proliferative Lupus Nephritis

Lupus Nephritis Clinical Trial

— TULIP-LN1  

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02547922
• Other study ID #: D3461C00007
• Status: Completed
• Phase: Phase 2
• Start date: November 4, 2015
• Est. completion date: January 18, 2021

Study information

• Verified date: October 2021
• Source: AstraZeneca
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

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).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 147
• Est. completion date: January 18, 2021
• Est. primary completion date: November 26, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 70 Years

Eligibility

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).

Related Conditions & MeSH terms

• Lupus Nephritis
• Nephritis

Intervention

Biological:
• Anifrolumab
Administration every 4 week from Week 0 to Week 100 in addition to SOC which will continue until Week 112

Drug:
• Placebo
Administration every 4 week from Week 0 to Week 100 in addition to SOC which will continue until Week 112

Locations

Country	Name	City	State
Argentina	Research Site	Buenos Aires
Argentina	Research Site	Cordoba
Argentina	Research Site	Rosario
Australia	Research Site	Adelaide
Australia	Research Site	Clayton
Australia	Research Site	Parkville
Australia	Research Site	Westmead
Belgium	Research Site	Brussels
Belgium	Research Site	Bruxelles
Belgium	Research Site	Leuven
Belgium	Research Site	Liege
France	Research Site	Bordeaux Cedex
France	Research Site	Marseille
France	Research Site	Paris Cedex 14
France	Research Site	Strasbourg
France	Research Site	Toulouse
Germany	Research Site	Berlin
Germany	Research Site	Kiel
Hungary	Research Site	Budapest
Hungary	Research Site	Debrecen
Hungary	Research Site	Kaposvár
Hungary	Research Site	Szeged
Italy	Research Site	Milano
Italy	Research Site	Padova
Italy	Research Site	Pisa
Italy	Research Site	Reggio Emilia
Korea, Republic of	Research Site	Gwangju
Korea, Republic of	Research Site	Seoul
Korea, Republic of	Research Site	Seoul
Korea, Republic of	Research Site	Suwon-si
Mexico	Research Site	Chihuahua
Mexico	Research Site	Guadalajara
Mexico	Research Site	Guadalajara
Mexico	Research Site	Mexico
Mexico	Research Site	San Luis Potosí
Peru	Research Site	Arequipa
Peru	Research Site	Lima
Peru	Research Site	Lima
Peru	Research Site	Lima
Peru	Research Site	Lima
Peru	Research Site	Lima
Peru	Research Site	Lima
Peru	Research Site	Lima
Peru	Research Site	Lima
Poland	Research Site	Krakow
Poland	Research Site	Lódz
Poland	Research Site	Warszawa
Russian Federation	Research Site	Orenburg
Russian Federation	Research Site	Saint Petersburg
Russian Federation	Research Site	Saint Petersburg
Serbia	Research Site	Belgrade
Serbia	Research Site	Belgrade
Serbia	Research Site	Nis
Serbia	Research Site	Novi Sad
Spain	Research Site	Barcelona
Spain	Research Site	Barcelona
Taiwan	Research Site	Changhua City
Taiwan	Research Site	Kaohsiung
Taiwan	Research Site	Taichung
Taiwan	Research Site	Taichung
Taiwan	Research Site	Taipei
Taiwan	Research Site	Taoyuan City
United Kingdom	Research Site	London
United States	Research Site	Aurora	Colorado
United States	Research Site	Boston	Massachusetts
United States	Research Site	Bronx	New York
United States	Research Site	Columbus	Ohio
United States	Research Site	DeBary	Florida
United States	Research Site	Glendale	Arizona
United States	Research Site	Great Neck	New York
United States	Research Site	La Jolla	California
United States	Research Site	Los Angeles	California
United States	Research Site	Memphis	Tennessee
United States	Research Site	New Hyde Park	New York
United States	Research Site	New York	New York
United States	Research Site	New York	New York
United States	Research Site	Newark	New Jersey
United States	Research Site	Oklahoma City	Oklahoma
United States	Research Site	Phoenix	Arizona
United States	Research Site	Thousand Oaks	California

Sponsors (2)

Lead Sponsor	Collaborator
AstraZeneca	Parexel

Countries where clinical trial is conducted

United States,  Argentina,  Australia,  Belgium,  France,  Germany,  Hungary,  Italy,  Korea, Republic of,  Mexico,  Peru,  Poland,  Russian Federation,  Serbia,  Spain,  Taiwan,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	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)
Other	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)
Other	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
Other	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
Primary	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	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

External Links

•   CSR Synopsis
•   Protocol
•   SAP