<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT04449991</url>
  </required_header>
  <id_info>
    <org_study_id>REBIOLUP</org_study_id>
    <nct_id>NCT04449991</nct_id>
  </id_info>
  <brief_title>Per-protocol Repeat Kidney Biopsy in Incident Cases of Lupus Nephritis</brief_title>
  <acronym>REBIOLUP</acronym>
  <official_title>Per-protocol Repeat Kidney Biopsy in Incident Cases of Lupus Nephritis</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Karolinska Institutet</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Université Catholique de Louvain</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Karolinska Institutet</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Lupus nephritis (LN) is one of the most severe complications of systemic lupus erythematosus&#xD;
      (SLE). Among people living with SLE, 35-60% will develop LN during the course of the disease.&#xD;
      This complication is one of the factors that contribute to deterioration of the renal&#xD;
      function.&#xD;
&#xD;
      Some centres perform kidney biopsies after completion of treatment for an episode of LN as a&#xD;
      part of the treatment evaluation. The term &quot;repeat biopsy&quot; is often used to describe these&#xD;
      biopsies. Several studies have reported that repeat kidney biopsies show activity at the&#xD;
      level of tissue, even in patients with normal routine blood and urine markers. The&#xD;
      investigators strongly believe that this information is important, and should be taken into&#xD;
      consideration during decision of treatment. To provide evidence for this, the investigators&#xD;
      have designed a collaborative project within the frame of the Lupus Nephritis Trials Network.&#xD;
      With this research project, the investigators want to contribute to an increased proportion&#xD;
      of patients with LN who achieve remission (inactivity) of LN, and a reduced proportion of&#xD;
      patients who worsen in renal function in the long term.&#xD;
&#xD;
      Patients with SLE who develop a first episode of LN will be asked to participate in this&#xD;
      project, and will receive treatment according to current guidelines. Half of the patients&#xD;
      will undergo a repeat biopsy 12 months later, and half of the patients will not. The&#xD;
      selection of patients who will undergo or not undergo repeat biopsy will be random. Patients&#xD;
      with high disease activity at the level of kidney tissue will receive more intense&#xD;
      immunosuppressive treatment. Patients who have not undergone repeat biopsy will continue to&#xD;
      be treated according to standard routine.&#xD;
&#xD;
      The investigators will compare the results of treatment between the group of patients who&#xD;
      underwent and the group of patients who did not undergo repeat biopsy, with regard to (i)&#xD;
      complete disease inactivity at month 24 and (ii) renal function at month 60 from treatment&#xD;
      initiation.&#xD;
&#xD;
      The investigators expect that significantly greater proportions of patients in the repeat&#xD;
      biopsy group will have inactive disease at month 24 and adequate levels of renal function at&#xD;
      month 60. This will provide support for performing repeat biopsies as a part of the treatment&#xD;
      evaluation, in order to optimise the therapeutic management and improve the long-term&#xD;
      prognosis of patients with LN.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Study rationale&#xD;
&#xD;
      Lupus nephritis (LN) affects 35-60% of patients with systemic lupus erythematosus (SLE), and&#xD;
      constitutes one of the most severe disease manifestations. Several factors contribute to&#xD;
      renal function impairment in LN, including genetic cargo, nephron endowment, disease&#xD;
      activity, drug-induced toxicity and renal flares. Five to 20% of the afflicted patients&#xD;
      develop end-stage kidney disease (ESKD) within ten years from the first LN episode. Available&#xD;
      therapies induce complete renal remission in only 20-30% of patients after six months of&#xD;
      treatment, and even patients who respond to therapy may relapse in 35% of the cases.&#xD;
&#xD;
      To date, clinical and laboratory tests cannot reliably reflect histopathological findings,&#xD;
      and kidney biopsy is indispensable for diagnosis, classification, and exclusion of mimickers.&#xD;
      The role of control biopsies after induction therapy is debatable, despite accumulating&#xD;
      evidence of discrepancies between clinical and histological responses. In the concrete,&#xD;
      several elegant post-treatment biopsy studies have demonstrated persistent activity at the&#xD;
      level of tissue despite adequate clinical response, suggesting that intensified&#xD;
      immunosuppression may be required in these patients. However, studies investigating the role&#xD;
      of repeat kidney biopsies in treatment evaluation and long-term renal outcome have to date&#xD;
      included limited numbers of patients, and varying definitions regarding treatment response&#xD;
      and renal outcome. Thus, the concept of a prospective multicentric per-protocol repeat biopsy&#xD;
      study to generate evidence for future recommendations for the diagnostic and therapeutic&#xD;
      management of LN gains increasing support.&#xD;
&#xD;
      Several studies have sought to identify predictors of long-term renal prognosis, including&#xD;
      routine clinical and serological markers. Proteinuria levels &lt; 0.7-0.8 g/day at month 12&#xD;
      after initiation of treatment have been validated in different cohorts as a readily available&#xD;
      predictor of favourable long-term renal outcome. However, while the positive predictive value&#xD;
      (PPV) of this target was high, the negative predictive value (NPV) was poor in two of three&#xD;
      studies, since most patients not achieving the proteinuria target still had a good long-term&#xD;
      outcome (Tamirou et al. 2015; Ugolini-Lopes et al. 2017). Associations between chronic tissue&#xD;
      damage in repeat biopsies and long-term renal function impairment have been demonstrated in&#xD;
      European and Hispanic LN populations (Piñeiro et al. 2016). It was recently demonstrated in a&#xD;
      retrospective study that a high grade of residual activity in per-protocol repeat biopsies&#xD;
      predicted subsequent renal relapse in patients with incident LN, and a high grade of chronic&#xD;
      damage in repeat biopsies predicted long-term renal function impairment. More specifically,&#xD;
      NIH activity index scores &gt; 3 predicted subsequent renal flares, whereas NIH chronicity index&#xD;
      scores &gt; 3 were associated with renal function deterioration in the long term. It is worth&#xD;
      noting that active lesions in glomeruli mostly accounted for the former association with&#xD;
      relapses, whereas chronic damage in the tubulointerstitial compartment were found to be a&#xD;
      more important contributor to the latter association with long-term renal function (Parodis&#xD;
      et al. 2020).&#xD;
&#xD;
      Study objectives&#xD;
&#xD;
      The objectives of the project will be&#xD;
&#xD;
        -  to determine the percentage of LN patients in histopathological remission after 12&#xD;
           months of standard of care immunosuppression;&#xD;
&#xD;
        -  to correlate histological and immunological (immune deposits) response to therapy with&#xD;
           clinical response;&#xD;
&#xD;
        -  to evaluate whether therapeutic decisions steered by the results of a per-protocol&#xD;
           repeat kidney biopsy improve renal outcomes compared with a matched control group of&#xD;
           patients who did not undergo repeat kidney biopsy.&#xD;
&#xD;
        -  to generate data on how to evaluate response to therapy in pure membranous LN (ISN/RPS&#xD;
           class V), as well as the value of the information retrieved from repeat kidney biopsies&#xD;
           in portending long-term renal prognosis in this LN subset.&#xD;
&#xD;
      Study design&#xD;
&#xD;
      Patients with an incident biopsy-proven proliferative or membranous LN, or combinations&#xD;
      thereof, selected to be initiated at standard of care immunosuppressive therapy with either&#xD;
      MMF or EURO-Lupus IV CYC (combined with GCs and ACE inhibitors/ARBs) will be enrolled in this&#xD;
      prospective study. Add-on therapies on the top of the aforementioned regimens will be&#xD;
      allowed. At baseline, patients will be randomised 1:1 to either undergo or not undergo a&#xD;
      per-protocol repeat kidney biopsy at month 12 from baseline. After randomisation, the&#xD;
      patients will be followed for one year within the frame of REBIOLUP Part I, which is&#xD;
      observational. Inclusion of patients participating in other investigator-initiated or&#xD;
      pharmaceutical industry-driven therapeutic trials will be made possible, provided that those&#xD;
      trials do not last more than 12 months. At month 12, REBIOLUP patients will enter into Part&#xD;
      II, which is interventional and an interval of ± 1 month is allowed.&#xD;
&#xD;
      In patients with 2003 ISN/RPS class III/IV (± V) at baseline and an NIH activity index score&#xD;
      &gt; 3 (cut-off based on a recent proof-of-concept retrospective analysis) in the repeat kidney&#xD;
      biopsy, the immunosuppressive therapy will be intensified based on the physician's and&#xD;
      patient's shared decision (see recommendations below). In cases of pure membranous nephritis&#xD;
      (ISN/RPS class V) at baseline which transformed to ISN/RPS class III/IV (± V) in the repeat&#xD;
      biopsy, the same algorithm will be applied.&#xD;
&#xD;
      In patients with pure membranous (2003 ISN/RPS class V) LN in the repeat biopsy, individual&#xD;
      assessment of the biopsy should steer the decision of treatment.&#xD;
&#xD;
      Patients who have not undergone a repeat biopsy will be treated according to standard&#xD;
      clinical parameters. Percentages of complete renal response at month 24 and renal impairment&#xD;
      at month 60 will be compared between the two study arms.&#xD;
&#xD;
      Patients randomised to the control arm (i.e. to not undergo per-protocol repeat biopsy) who&#xD;
      underwent a repeat kidney biopsy upon clinical indication approximately at month 12 from&#xD;
      baseline, e.g. due to primary non-response or worsening, will be analysed in the control arm&#xD;
      (as per intention) for the primary analysis, and, additionally, together with the patients in&#xD;
      the interventional arm in a secondary analysis.&#xD;
&#xD;
      Statistical power calculation and number of subjects needed&#xD;
&#xD;
      The anticipated frequency of CRR at month 24 in patients of the &quot;no repeat biopsy&quot; arm is&#xD;
      40%. The investigators consider that a difference of 20% in favour of the &quot;repeat biopsy&quot; arm&#xD;
      would be clinically meaningful (i.e. a frequency of 60% CRR at month 24). To detect such a&#xD;
      difference, with an α level of 0.05 and a power of 0.80, a number of 98 patients per arm is&#xD;
      required. In order to take an anticipated 5% drop-out proportion into account, 206 patients&#xD;
      with incident proliferative [2003 ISN/RPS class III/IV (A or A/C)] lupus nephritis will need&#xD;
      to be enrolled. Patients with incident active membranous LN (2003 ISN/RPS class V) will also&#xD;
      be enrolled in REBIOLUP; however, the target number of patients per arm will be based on&#xD;
      proliferative cases only, since power calculation has been based on data from studies of&#xD;
      proliferative LN.&#xD;
&#xD;
      Based on an anticipated yearly inclusion rate of 3-5 patients per year per centre, i.e. 6-10&#xD;
      patients during a 2-year period, approximately 20-30 centres of LN expertise will need to&#xD;
      participate in the study.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">January 5, 2022</start_date>
  <completion_date type="Anticipated">December 2028</completion_date>
  <primary_completion_date type="Anticipated">December 2028</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <intervention_model_description>At baseline, patients will be randomised 1:1 to either undergo or not undergo a per-protocol repeat kidney biopsy at month 12 from baseline.</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Complete Renal Response (CRR) at month 24 from baseline</measure>
    <time_frame>Month 24 from baseline</time_frame>
    <description>UPCR ≤ 0.5 g/g in two consecutive first-morning void urine specimens and no increase in serum creatinine by ≥ 25% from baseline.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Renal function impairment at month 60</measure>
    <time_frame>Month 60 from baseline</time_frame>
    <description>Sustained (i.e. observed in at least two consecutive measurements on different dates) increase in serum creatinine by ≥ 25% from baseline.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Renal relapse (proteinuric flare)</measure>
    <time_frame>Between month 12 and month 60 from baseline</time_frame>
    <description>Reappearance of UPCR &gt; 1.0 g/g from month 12 onwards, leading to intensification or change of immunosuppressive therapy. This increased proteinuria has to be sustained (i.e. observed in at least two consecutive measurements on different dates), occurring after an initial response to induction therapy (defined as sustained UPCR &lt; 0.5 g/g).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Reabsorption of immune deposits in repeat kidney biopsies</measure>
    <time_frame>Month 12 from baseline</time_frame>
    <description>≥ 50% decrease in intensity and amount of immune deposits in electron microscopy.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>End-stage kidney disease (ESKD)</measure>
    <time_frame>Between month 12 and month 60 from baseline</time_frame>
    <description>Chronic kidney disease stage 5 and/or dialysis will be used to assess ESKD.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Mortality rate</measure>
    <time_frame>Between month 12 and month 60 from baseline</time_frame>
    <description>The number of deaths during the study period.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">206</enrollment>
  <condition>Lupus Nephritis</condition>
  <arm_group>
    <arm_group_label>Intervention arm: Repeat kidney biopsy at M12</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients will undergo repeat kidney biopsy at month 12 from baseline.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Control arm: No repeat kidney biopsy</arm_group_label>
    <arm_group_type>No Intervention</arm_group_type>
    <description>Patients will not undergo repeat kidney biopsy at month 12 from baseline.</description>
  </arm_group>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Repeat kidney biopsy</intervention_name>
    <description>Intensification of immunosuppression if NIH AI &gt; 3</description>
    <arm_group_label>Intervention arm: Repeat kidney biopsy at M12</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Fulfilment of the EULAR/ACR classification criteria of SLE.&#xD;
&#xD;
          -  18 years of age or above.&#xD;
&#xD;
          -  Incident biopsy-proven proliferative or membranous LN, or combinations thereof (with&#xD;
             UPCR ≥ 1 g/g), i.e. 2003 ISN/RPS class III (A or A/C) ± V, class IV (A or A/C) ± V, or&#xD;
             class V.&#xD;
&#xD;
          -  Consent to the possibility of a repeat kidney biopsy at month 12 from baseline.&#xD;
&#xD;
          -  Initiation of the following treatment regimens:&#xD;
&#xD;
               -  intravenous pulses of methylprednisolone (total dose of 500-3000 mg);&#xD;
&#xD;
               -  oral prednisone or equivalent 0.3-0.5 mg/kg/day with tapering;&#xD;
&#xD;
               -  hydroxychloroquine unless contraindicated;&#xD;
&#xD;
               -  angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor&#xD;
                  blockers (ARBs);&#xD;
&#xD;
               -  either one of mycophenolate mofetil (MMF) equivalent dose 2-3 g/day, or IV&#xD;
                  cyclophosphamide (CYC) according to the Euro-Lupus regimen;&#xD;
&#xD;
               -  the NIH protocol for IV CYC (0.5-0.75 g/m2 monthly for six months) could be&#xD;
                  considered in severe cases;&#xD;
&#xD;
               -  add-on therapies (e.g. calcineurin inhibitors, biologics) to the above two&#xD;
                  regimens are optional.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Antiphospholipid syndrome nephropathy (APSN).&#xD;
&#xD;
          -  Pregnancy at baseline (pregnancy during follow-up will not lead to exclusion).&#xD;
&#xD;
          -  Medical contraindications to kidney biopsy, e.g. thrombocytopenia &lt; 50,000/μL,&#xD;
             uncontrolled hypertension or end-stage kidney disease (ESKD).&#xD;
&#xD;
          -  Anticipated non-adherence to therapy.&#xD;
&#xD;
          -  Medical conditions interfering with outcome evaluations.&#xD;
&#xD;
          -  Inability to read and/or sign the informed consent form.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Ioannis Parodis, MD PhD</last_name>
    <role>Study Chair</role>
    <affiliation>Karolinska Institutet</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Farah Tamirou, MD PhD</last_name>
    <role>Study Chair</role>
    <affiliation>Université Catholique de Louvain</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Julia Weinmann-Menke, MD PhD</last_name>
    <role>Study Chair</role>
    <affiliation>Johannes Gutenberg University Mainz</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Hans-Joachim Anders, Professor</last_name>
    <role>Study Chair</role>
    <affiliation>Ludwig-Maximilians - University of Munich</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Brad H Rovin, Professor</last_name>
    <role>Study Chair</role>
    <affiliation>Ohio State University</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Frédéric A Houssiau, Professor</last_name>
    <role>Study Chair</role>
    <affiliation>Université Catholique de Louvain</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Ioannis Parodis, MD PhD | Associate Professor</last_name>
    <phone>+46722321322</phone>
    <email>ioannis.parodis@ki.se</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Farah Tamirou, MD PhD</last_name>
    <phone>+32487586016</phone>
    <email>farah.tamirou@uclouvain.be</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Karolinska University Hospital</name>
      <address>
        <city>Stockholm</city>
        <zip>17676</zip>
        <country>Sweden</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Ioannis Parodis, MD PhD | Associate Professor</last_name>
      <phone>+46722321322</phone>
      <email>ioannis.parodis@ki.se</email>
    </contact>
  </location>
  <location_countries>
    <country>Sweden</country>
  </location_countries>
  <reference>
    <citation>Tamirou F, Lauwerys BR, Dall'Era M, Mackay M, Rovin B, Cervera R, Houssiau FA; MAINTAIN Nephritis Trial Investigators. A proteinuria cut-off level of 0.7 g/day after 12 months of treatment best predicts long-term renal outcome in lupus nephritis: data from the MAINTAIN Nephritis Trial. Lupus Sci Med. 2015 Nov 12;2(1):e000123. doi: 10.1136/lupus-2015-000123. eCollection 2015.</citation>
    <PMID>26629352</PMID>
  </reference>
  <reference>
    <citation>Ugolini-Lopes MR, Seguro LPC, Castro MXF, Daffre D, Lopes AC, Borba EF, Bonfa E. Early proteinuria response: a valid real-life situation predictor of long-term lupus renal outcome in an ethnically diverse group with severe biopsy-proven nephritis? Lupus Sci Med. 2017 Jun 12;4(1):e000213. doi: 10.1136/lupus-2017-000213. eCollection 2017.</citation>
    <PMID>29238603</PMID>
  </reference>
  <reference>
    <citation>Pineiro GJ, Arrizabalaga P, Sole M, Abellana RM, Espinosa G, Cervera R. Repeated Renal Biopsy - A Predictive Tool to Assess the Probability of Renal Flare in Lupus Nephritis. Am J Nephrol. 2016;44(6):439-446. doi: 10.1159/000452229. Epub 2016 Oct 28.</citation>
    <PMID>27788504</PMID>
  </reference>
  <reference>
    <citation>Parodis I, Adamichou C, Aydin S, Gomez A, Demoulin N, Weinmann-Menke J, Houssiau FA, Tamirou F. Per-protocol repeat kidney biopsy portends relapse and long-term outcome in incident cases of proliferative lupus nephritis. Rheumatology (Oxford). 2020 Nov 1;59(11):3424-3434. doi: 10.1093/rheumatology/keaa129.</citation>
    <PMID>32353879</PMID>
  </reference>
  <verification_date>June 2022</verification_date>
  <study_first_submitted>June 24, 2020</study_first_submitted>
  <study_first_submitted_qc>June 24, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">June 29, 2020</study_first_posted>
  <last_update_submitted>June 16, 2022</last_update_submitted>
  <last_update_submitted_qc>June 16, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">June 21, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Karolinska Institutet</investigator_affiliation>
    <investigator_full_name>Ioannis Parodis</investigator_full_name>
    <investigator_title>Principle Investigator</investigator_title>
  </responsible_party>
  <keyword>systemic lupus erythematosus</keyword>
  <keyword>lupus nephritis</keyword>
  <keyword>kidney biopsy</keyword>
  <keyword>renal function impairment</keyword>
  <keyword>long-term prognosis</keyword>
  <keyword>electron microscopy</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Nephritis</mesh_term>
    <mesh_term>Lupus Nephritis</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_description>Datasets needed for addressing research questions that have not been addressed in the original publications.</ipd_description>
    <ipd_info_type>Study Protocol</ipd_info_type>
    <ipd_info_type>Informed Consent Form (ICF)</ipd_info_type>
    <ipd_time_frame>Starting ten years after the baseline visit of the last study participant recruited.</ipd_time_frame>
    <ipd_access_criteria>The REBIOLUP steering committee will review all proposals and provide IPD to investigators upon reasonable request, however highly depending on the research questions to be addressed.</ipd_access_criteria>
    <ipd_url>http://rebiolup.com</ipd_url>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT04449991
org study id: REBIOLUP
nct id: NCT04449991
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
Lupus nephritis (LN) is one of the most severe complications of systemic lupus erythematosus
      (SLE). Among people living with SLE, 35-60% will develop LN during the course of the disease.
      This complication is one of the factors that contribute to deterioration of the renal
      function.

      Some centres perform kidney biopsies after completion of treatment for an episode of LN as a
      part of the treatment evaluation. The term "repeat biopsy" is often used to describe these
      biopsies. Several studies have reported that repeat kidney biopsies show activity at the
      level of tissue, even in patients with normal routine blood and urine markers. The
      investigators strongly believe that this information is important, and should be taken into
      consideration during decision of treatment. To provide evidence for this, the investigators
      have designed a collaborative project within the frame of the Lupus Nephritis Trials Network.
      With this research project, the investigators want to contribute to an increased proportion
      of patients with LN who achieve remission (inactivity) of LN, and a reduced proportion of
      patients who worsen in renal function in the long term.

      Patients with SLE who develop a first episode of LN will be asked to participate in this
      project, and will receive treatment according to current guidelines. Half of the patients
      will undergo a repeat biopsy 12 months later, and half of the patients will not. The
      selection of patients who will undergo or not undergo repeat biopsy will be random. Patients
      with high disease activity at the level of kidney tissue will receive more intense
      immunosuppressive treatment. Patients who have not undergone repeat biopsy will continue to
      be treated according to standard routine.

      The investigators will compare the results of treatment between the group of patients who
      underwent and the group of patients who did not undergo repeat biopsy, with regard to (i)
      complete disease inactivity at month 24 and (ii) renal function at month 60 from treatment
      initiation.

      The investigators expect that significantly greater proportions of patients in the repeat
      biopsy group will have inactive disease at month 24 and adequate levels of renal function at
      month 60. This will provide support for performing repeat biopsies as a part of the treatment
      evaluation, in order to optimise the therapeutic management and improve the long-term
      prognosis of patients with LN.
Study rationale

      Lupus nephritis (LN) affects 35-60% of patients with systemic lupus erythematosus (SLE), and
      constitutes one of the most severe disease manifestations. Several factors contribute to
      renal function impairment in LN, including genetic cargo, nephron endowment, disease
      activity, drug-induced toxicity and renal flares. Five to 20% of the afflicted patients
      develop end-stage kidney disease (ESKD) within ten years from the first LN episode. Available
      therapies induce complete renal remission in only 20-30% of patients after six months of
      treatment, and even patients who respond to therapy may relapse in 35% of the cases.

      To date, clinical and laboratory tests cannot reliably reflect histopathological findings,
      and kidney biopsy is indispensable for diagnosis, classification, and exclusion of mimickers.
      The role of control biopsies after induction therapy is debatable, despite accumulating
      evidence of discrepancies between clinical and histological responses. In the concrete,
      several elegant post-treatment biopsy studies have demonstrated persistent activity at the
      level of tissue despite adequate clinical response, suggesting that intensified
      immunosuppression may be required in these patients. However, studies investigating the role
      of repeat kidney biopsies in treatment evaluation and long-term renal outcome have to date
      included limited numbers of patients, and varying definitions regarding treatment response
      and renal outcome. Thus, the concept of a prospective multicentric per-protocol repeat biopsy
      study to generate evidence for future recommendations for the diagnostic and therapeutic
      management of LN gains increasing support.

      Several studies have sought to identify predictors of long-term renal prognosis, including
      routine clinical and serological markers. Proteinuria levels < 0.7-0.8 g/day at month 12
      after initiation of treatment have been validated in different cohorts as a readily available
      predictor of favourable long-term renal outcome. However, while the positive predictive value
      (PPV) of this target was high, the negative predictive value (NPV) was poor in two of three
      studies, since most patients not achieving the proteinuria target still had a good long-term
      outcome (Tamirou et al. 2015; Ugolini-Lopes et al. 2017). Associations between chronic tissue
      damage in repeat biopsies and long-term renal function impairment have been demonstrated in
      European and Hispanic LN populations (Piñeiro et al. 2016). It was recently demonstrated in a
      retrospective study that a high grade of residual activity in per-protocol repeat biopsies
      predicted subsequent renal relapse in patients with incident LN, and a high grade of chronic
      damage in repeat biopsies predicted long-term renal function impairment. More specifically,
      NIH activity index scores > 3 predicted subsequent renal flares, whereas NIH chronicity index
      scores > 3 were associated with renal function deterioration in the long term. It is worth
      noting that active lesions in glomeruli mostly accounted for the former association with
      relapses, whereas chronic damage in the tubulointerstitial compartment were found to be a
      more important contributor to the latter association with long-term renal function (Parodis
      et al. 2020).

      Study objectives

      The objectives of the project will be

        -  to determine the percentage of LN patients in histopathological remission after 12
           months of standard of care immunosuppression;

        -  to correlate histological and immunological (immune deposits) response to therapy with
           clinical response;

        -  to evaluate whether therapeutic decisions steered by the results of a per-protocol
           repeat kidney biopsy improve renal outcomes compared with a matched control group of
           patients who did not undergo repeat kidney biopsy.

        -  to generate data on how to evaluate response to therapy in pure membranous LN (ISN/RPS
           class V), as well as the value of the information retrieved from repeat kidney biopsies
           in portending long-term renal prognosis in this LN subset.

      Study design

      Patients with an incident biopsy-proven proliferative or membranous LN, or combinations
      thereof, selected to be initiated at standard of care immunosuppressive therapy with either
      MMF or EURO-Lupus IV CYC (combined with GCs and ACE inhibitors/ARBs) will be enrolled in this
      prospective study. Add-on therapies on the top of the aforementioned regimens will be
      allowed. At baseline, patients will be randomised 1:1 to either undergo or not undergo a
      per-protocol repeat kidney biopsy at month 12 from baseline. After randomisation, the
      patients will be followed for one year within the frame of REBIOLUP Part I, which is
      observational. Inclusion of patients participating in other investigator-initiated or
      pharmaceutical industry-driven therapeutic trials will be made possible, provided that those
      trials do not last more than 12 months. At month 12, REBIOLUP patients will enter into Part
      II, which is interventional and an interval of ± 1 month is allowed.

      In patients with 2003 ISN/RPS class III/IV (± V) at baseline and an NIH activity index score
      > 3 (cut-off based on a recent proof-of-concept retrospective analysis) in the repeat kidney
      biopsy, the immunosuppressive therapy will be intensified based on the physician's and
      patient's shared decision (see recommendations below). In cases of pure membranous nephritis
      (ISN/RPS class V) at baseline which transformed to ISN/RPS class III/IV (± V) in the repeat
      biopsy, the same algorithm will be applied.

      In patients with pure membranous (2003 ISN/RPS class V) LN in the repeat biopsy, individual
      assessment of the biopsy should steer the decision of treatment.

      Patients who have not undergone a repeat biopsy will be treated according to standard
      clinical parameters. Percentages of complete renal response at month 24 and renal impairment
      at month 60 will be compared between the two study arms.

      Patients randomised to the control arm (i.e. to not undergo per-protocol repeat biopsy) who
      underwent a repeat kidney biopsy upon clinical indication approximately at month 12 from
      baseline, e.g. due to primary non-response or worsening, will be analysed in the control arm
      (as per intention) for the primary analysis, and, additionally, together with the patients in
      the interventional arm in a secondary analysis.

      Statistical power calculation and number of subjects needed

      The anticipated frequency of CRR at month 24 in patients of the "no repeat biopsy" arm is
      40%. The investigators consider that a difference of 20% in favour of the "repeat biopsy" arm
      would be clinically meaningful (i.e. a frequency of 60% CRR at month 24). To detect such a
      difference, with an α level of 0.05 and a power of 0.80, a number of 98 patients per arm is
      required. In order to take an anticipated 5% drop-out proportion into account, 206 patients
      with incident proliferative [2003 ISN/RPS class III/IV (A or A/C)] lupus nephritis will need
      to be enrolled. Patients with incident active membranous LN (2003 ISN/RPS class V) will also
      be enrolled in REBIOLUP; however, the target number of patients per arm will be based on
      proliferative cases only, since power calculation has been based on data from studies of
      proliferative LN.

      Based on an anticipated yearly inclusion rate of 3-5 patients per year per centre, i.e. 6-10
      patients during a 2-year period, approximately 20-30 centres of LN expertise will need to
      participate in the study.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: At baseline, patients will be randomised 1:1 to either undergo or not undergo a per-protocol repeat kidney biopsy at month 12 from baseline.
primary purpose: Treatment
masking: None (Open Label)
measure: Complete Renal Response (CRR) at month 24 from baseline
time frame: Month 24 from baseline
description: UPCR ≤ 0.5 g/g in two consecutive first-morning void urine specimens and no increase in serum creatinine by ≥ 25% from baseline.
measure: Renal function impairment at month 60
time frame: Month 60 from baseline
description: Sustained (i.e. observed in at least two consecutive measurements on different dates) increase in serum creatinine by ≥ 25% from baseline.
measure: Renal relapse (proteinuric flare)
time frame: Between month 12 and month 60 from baseline
description: Reappearance of UPCR > 1.0 g/g from month 12 onwards, leading to intensification or change of immunosuppressive therapy. This increased proteinuria has to be sustained (i.e. observed in at least two consecutive measurements on different dates), occurring after an initial response to induction therapy (defined as sustained UPCR < 0.5 g/g).
measure: Reabsorption of immune deposits in repeat kidney biopsies
time frame: Month 12 from baseline
description: ≥ 50% decrease in intensity and amount of immune deposits in electron microscopy.
measure: End-stage kidney disease (ESKD)
time frame: Between month 12 and month 60 from baseline
description: Chronic kidney disease stage 5 and/or dialysis will be used to assess ESKD.
measure: Mortality rate
time frame: Between month 12 and month 60 from baseline
description: The number of deaths during the study period.
arm group label: Intervention arm: Repeat kidney biopsy at M12
arm group type: Experimental
description: Patients will undergo repeat kidney biopsy at month 12 from baseline.
arm group label: Control arm: No repeat kidney biopsy
arm group type: No Intervention
description: Patients will not undergo repeat kidney biopsy at month 12 from baseline.
intervention type: Procedure
intervention name: Repeat kidney biopsy
description: Intensification of immunosuppression if NIH AI > 3
arm group label: Intervention arm: Repeat kidney biopsy at M12
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Ioannis Parodis, MD PhD
role: Study Chair
affiliation: Karolinska Institutet
last name: Farah Tamirou, MD PhD
role: Study Chair
affiliation: Université Catholique de Louvain
last name: Julia Weinmann-Menke, MD PhD
role: Study Chair
affiliation: Johannes Gutenberg University Mainz
last name: Hans-Joachim Anders, Professor
role: Study Chair
affiliation: Ludwig-Maximilians - University of Munich
last name: Brad H Rovin, Professor
role: Study Chair
affiliation: Ohio State University
last name: Frédéric A Houssiau, Professor
role: Study Chair
affiliation: Université Catholique de Louvain
last name: Ioannis Parodis, MD PhD | Associate Professor
phone: +46722321322
email: ioannis.parodis@ki.se
last name: Farah Tamirou, MD PhD
phone: +32487586016
email: farah.tamirou@uclouvain.be
facility: 
status: Recruiting
contact: 
country: Sweden
citation: Tamirou F, Lauwerys BR, Dall'Era M, Mackay M, Rovin B, Cervera R, Houssiau FA; MAINTAIN Nephritis Trial Investigators. A proteinuria cut-off level of 0.7 g/day after 12 months of treatment best predicts long-term renal outcome in lupus nephritis: data from the MAINTAIN Nephritis Trial. Lupus Sci Med. 2015 Nov 12;2(1):e000123. doi: 10.1136/lupus-2015-000123. eCollection 2015.
PMID: 26629352
citation: Ugolini-Lopes MR, Seguro LPC, Castro MXF, Daffre D, Lopes AC, Borba EF, Bonfa E. Early proteinuria response: a valid real-life situation predictor of long-term lupus renal outcome in an ethnically diverse group with severe biopsy-proven nephritis? Lupus Sci Med. 2017 Jun 12;4(1):e000213. doi: 10.1136/lupus-2017-000213. eCollection 2017.
PMID: 29238603
citation: Pineiro GJ, Arrizabalaga P, Sole M, Abellana RM, Espinosa G, Cervera R. Repeated Renal Biopsy - A Predictive Tool to Assess the Probability of Renal Flare in Lupus Nephritis. Am J Nephrol. 2016;44(6):439-446. doi: 10.1159/000452229. Epub 2016 Oct 28.
PMID: 27788504
citation: Parodis I, Adamichou C, Aydin S, Gomez A, Demoulin N, Weinmann-Menke J, Houssiau FA, Tamirou F. Per-protocol repeat kidney biopsy portends relapse and long-term outcome in incident cases of proliferative lupus nephritis. Rheumatology (Oxford). 2020 Nov 1;59(11):3424-3434. doi: 10.1093/rheumatology/keaa129.
PMID: 32353879
responsible party type: Principal Investigator
investigator affiliation: Karolinska Institutet
investigator full name: Ioannis Parodis
investigator title: Principle Investigator
mesh term: Nephritis
mesh term: Lupus Nephritis
sharing ipd: Yes
ipd description: Datasets needed for addressing research questions that have not been addressed in the original publications.
ipd info type: Study Protocol
ipd info type: Informed Consent Form (ICF)
ipd time frame: Starting ten years after the baseline visit of the last study participant recruited.
ipd access criteria: The REBIOLUP steering committee will review all proposals and provide IPD to investigators upon reasonable request, however highly depending on the research questions to be addressed.
ipd url: http://rebiolup.com