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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02547922
Recruitment Status : Completed
First Posted : September 14, 2015
Results First Posted : November 24, 2021
Last Update Posted : November 24, 2021
Sponsor:
Collaborator:
Parexel
Information provided by (Responsible Party):
AstraZeneca

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).

Condition or disease Intervention/treatment Phase
Lupus Nephritis Biological: Anifrolumab Drug: Placebo Phase 2

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).

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 147 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
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
Actual Study Start Date : November 4, 2015
Actual Primary Completion Date : November 26, 2019
Actual Study Completion Date : January 18, 2021

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Safety

Arm Intervention/treatment
Experimental: Anifrolumab - Lower Dose
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
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




Primary Outcome Measures :
  1. Change From Baseline in 24-hour Urine Protein to Creatinine Ratio (UPCR) [ Time Frame: From Week 1 (Baseline) up to Week 52 ]

    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.



Secondary Outcome Measures :
  1. Proportion of Subjects Achieving the Composite Endpoint Complete Renal Response (CRR) [ Time Frame: Week 52 ]

    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.


Other Outcome Measures:
  1. Number of Subjects With Adverse Events [ Time Frame: From screening (Day-30 to -1) period until the follow-up period (Week 112) ]

    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.


  2. Number of Subjects With Suicidal Ideation and Behavior and Suicide Attempts Via Columbia-Suicide Severity Rating Scale (C-SSRS) [ Time Frame: Baseline, treatment and follow up (an average of 60 weeks) ]
    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.

  3. Total Score of Personal Health Questionnaire Depression Scale-8 (PHQD-8) [ Time Frame: Baseline, Week 12, Week 24, Week 36, Week 52, Week 60 ]
    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.

  4. Extra-renal Flares Using Systemic Lupus Erythematosus (SLE) Disease Activity Index 2000 (SLEDAI 2K) Based Flare Assessment Instrument [ Time Frame: From baseline up to week 112 ]

    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.




Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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).

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02547922


Locations
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Sponsors and Collaborators
AstraZeneca
Parexel
Investigators
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Study Director: AstraZeneca AB AstraZeneca
  Study Documents (Full-Text)

Documents provided by AstraZeneca:
Study Protocol  [PDF] December 13, 2017
Statistical Analysis Plan  [PDF] March 24, 2020

Additional Information:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: AstraZeneca
ClinicalTrials.gov Identifier: NCT02547922    
Other Study ID Numbers: D3461C00007
First Posted: September 14, 2015    Key Record Dates
Results First Posted: November 24, 2021
Last Update Posted: November 24, 2021
Last Verified: October 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
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:
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Time Frame: AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles.
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.
URL: https://astrazenecagroup-dt.pharmacm.com/DT/Home

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by AstraZeneca:
lupus, nephritis, randomized, placebo, anifrolumab, safety, efficacy, adult
Additional relevant MeSH terms:
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Nephritis
Lupus Nephritis
Kidney Diseases
Urologic Diseases
Glomerulonephritis
Lupus Erythematosus, Systemic
Connective Tissue Diseases
Autoimmune Diseases
Immune System Diseases