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The Pediatric Lupus Nephritis Mycophenolate Mofetil (PLUMM) Study (PLUMM)

Primary Purpose

Lupus Nephritis

Status
Not yet recruiting
Phase
Phase 2
Locations
Study Type
Interventional
Intervention
Mycophenolate Mofetil
Mycophenolate Mofetil
Sponsored by
Children's Hospital Medical Center, Cincinnati
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Lupus Nephritis

Eligibility Criteria

8 Years - 18 Years (Child, Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  1. Male or female aged 8 to < 18 years;
  2. Must meet Classification Criteria for SLE as per the criteria of the American College of Rheumatology (ACR)/ European League Against Rheumatism 1-3 (Appendix 0);
  3. Newly diagnosed with proliferative LN as per the International Society of Nephrology/Renal Pathology Society based on kidney biopsy done within 60 days prior to enrollment into the study; Subjects may have been previously diagnosed with other Classes of LN. For study inclusion, the kidney biopsy must be newly interpreted as one of the following classes: Class 3, Class 3/5, Class 4, or Class 4/5.
  4. SLEDAI renal domain score > 0;
  5. Treatment of LN with twice daily MMF as per the decision of the treating physician. During the screening period the subject will take MMF as prescribed by their treating physician for a minimum of 4 days (or 8 doses).
  6. Subject tolerates MMF as per the treating physician's opinion;
  7. Able to swallow MMF tablets and capsules;
  8. Subjects may be treated with hydroxychloroquine. The allowable dose of hydroxychloroquine cannot exceed 5 mg/kg/day and the medication must have been started at least 1 week prior to Baseline visit;
  9. Subjects who are treated with belimumab must be on a stable dose 3 months prior to the Baseline visit;
  10. Subjects who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures;
  11. Evidence of a personally signed and dated Informed Consent document and Assent document (as appropriate) indicating that the subject and a legally acceptable representative/ parent(s)/legal guardian has been informed of all pertinent aspects of the study.
  12. Parent or legal guardian must have a smart phone available and able to support the PLUMM smart phone application.
  13. Must be able to complete study questionnaires in English or Spanish

Exclusion Criteria:

  1. Perceived or stated inability to adhere to the study protocol;
  2. Hypersensitivity to MMF or any component of the drug product;
  3. Presence of features (from SLE or other chronic disease) that a-priori suggest that the subject benefits from other therapies than that suggested or allowable by the study protocol; These disease features include but are not limited to severe, progressive, or uncontrolled hepatic, hematologic, gastrointestinal, metabolic, endocrine, pulmonary, cardiac or neurologic disease.
  4. History of other kidney disease besides LN or prior to the diagnosis of SLE;
  5. Need for renal replacement therapy within 2 weeks from Baseline. Subjects can have required short-term renal replacement therapy prior to Baseline, for example due to preceding acute kidney injury.
  6. Infections:

    1. Untreated latent or active tuberculosis (TB);
    2. Chronic infections requiring treatment;
    3. A subject known to be infected with Human Immunodeficiency Virus (HIV), Hepatitis B, or Hepatitis C;
    4. Any infection requiring hospitalization, parenteral antimicrobial therapy or judged to be opportunistic by the investigator within 4 weeks prior of Baseline visit;
    5. Any treated infections within 2 weeks of Baseline visit;
    6. History of infected joint prosthesis with prosthesis still in situ;
  7. Blood dyscrasias, including:

    1. Hemoglobin <8.5 g/dL or Hematocrit <22%;
    2. White Blood Cell count <2.6 x 109/L;
    3. Neutrophil count <1.2 x 109/L;
    4. Platelet count <100 x 109/L;
    5. Lymphocyte count <0.5 x 109/L.
  8. Estimated glomerular filtration rate [GFR] <40 mL/min/1.73 m2 calculated using the modified Schwartz equation5 (see Appendix 4);
  9. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >1.5 times the upper limit of normal;
  10. Vaccinated or exposed to a live or attenuated vaccine within the 4 weeks prior to Baseline visit;
  11. History or current symptoms suggestive of lymphoproliferative disorders (e.g. Epstein Barr Virus [EBV] related lymphoproliferative disorder, lymphoma, leukemia, myeloproliferative disorders, or multiple myeloma);
  12. Current malignancy or history of any malignancy with the exception of adequate treated or excised basal cell or squamous cell or cervical cancer in situ;
  13. Recent (within 4 weeks prior to Baseline visit) significant trauma or major surgery;
  14. Herbal supplements with pharmaceutical properties must be discontinued at least 4 weeks prior to Baseline visit, unless there are sufficient data available regarding the duration of an herbal medication's pharmacokinetic and pharmacodynamic effects to allow a shorter or longer washout to be specified (e.g. 5 half-lives).
  15. Oral or intravenous cyclophosphamide must be discontinued 12 weeks prior to Baseline visit
  16. Rituximab or other selective B lymphocyte depleting agents: Must be discontinued for 6 months prior to Baseline visit or CD19/20+ counts must be normal by FACS analysis;
  17. Use of prohibited prescription medication as listed in Appendix 3 within the specified time frame prior to Baseline visit
  18. Participation in other studies involving investigational drug(s) within 4 weeks or 5 half-lives (whichever is longer) prior to Baseline visit and/or during study participation; Exposure to investigational biologics should be discussed with the Sponsor.
  19. Pregnant female subjects; breastfeeding female subjects; male subjects with partners currently pregnant; male subjects able to father children and female subjects of childbearing potential who are unwilling or unable to use two highly effective methods of contraception or are abstinent (see Section 4.4.) for the duration of the study;
  20. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the subject inappropriate for entry into this study.

Sites / Locations

    Arms of the Study

    Arm 1

    Arm 2

    Arm Type

    Active Comparator

    Experimental

    Arm Label

    MMFBSA

    MMFPK

    Arm Description

    MMF dosed as per body-surface area

    MMF dosed as per pharmacokinetically-guided precision-dosing

    Outcomes

    Primary Outcome Measures

    To compare the efficacy of MMFPK therapy to the efficacy of MMFBSA therapy
    the percentage of subjects achieving at least partial remission of LN (PRR) as per the adapted ACR/EULAR Criteria at Week 26

    Secondary Outcome Measures

    Full Information

    First Posted
    September 9, 2022
    Last Updated
    August 28, 2023
    Sponsor
    Children's Hospital Medical Center, Cincinnati
    Collaborators
    National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), Genentech, Inc.
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    1. Study Identification

    Unique Protocol Identification Number
    NCT05538208
    Brief Title
    The Pediatric Lupus Nephritis Mycophenolate Mofetil (PLUMM) Study
    Acronym
    PLUMM
    Official Title
    Efficacy & Safety of Pharmacokinetically-Driven Dosing of Mycophenolate Mofetil for the Treatment of Pediatric Proliferative Lupus Nephritis- A Double-Blind Placebo Controlled Clinical Trial
    Study Type
    Interventional

    2. Study Status

    Record Verification Date
    August 2023
    Overall Recruitment Status
    Not yet recruiting
    Study Start Date
    August 2023 (Anticipated)
    Primary Completion Date
    July 2025 (Anticipated)
    Study Completion Date
    March 2026 (Anticipated)

    3. Sponsor/Collaborators

    Responsible Party, by Official Title
    Principal Investigator
    Name of the Sponsor
    Children's Hospital Medical Center, Cincinnati
    Collaborators
    National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), Genentech, Inc.

    4. Oversight

    Studies a U.S. FDA-regulated Drug Product
    Yes
    Studies a U.S. FDA-regulated Device Product
    No
    Product Manufactured in and Exported from the U.S.
    Yes
    Data Monitoring Committee
    Yes

    5. Study Description

    Brief Summary
    The study is a 1-year 2-part double-blinded placebo controlled 2-arm clinical trial. Treatment arms are (1) MMF dosed as per body-surface area (MMFBSA; 600mg/m2 body surface area per dose about every 12 hours) and (2) pharmacokinetically-guided precision-dosing of MMF (MMFPK; MMF dosed twice daily to achieve an area under the concentration-time curve (AUC0-12h) of MPA >60-70 mg*h/L. The study goal is to determine the safety and efficacy of MMFPK compared to MMFBSA for the treatment of proliferative LN in subjects 8 to <18 years.
    Detailed Description
    Subjects will be randomized 1:1 to receive blinded treatment with MMFPK or MMFBSA for up to 53 weeks. The primary endpoint, clinical remission of LN, is measured at the end of Part 1 at week 26. Subjects in the MMFBSA arm who have only partial renal response (PRR) at the end of Part 1 will newly receive MMFPK upon entering Part 2 of the study (week 26 - 53). Subjects with complete renal responses (CRR) at the end of Part 1 will continue the same dosing regimen of MMF (MMFBSA or MMFPK) in Part 2 as was given in Part 1 of the study. Subjects in the MMFPK arm with PRR at the end of Part 1 will enter Part 2 and continue in the MMFPK arm. Subjects who are LN non-responders by the end of Part 1 at week 26 will be considered treatment failures and discontinued from the study intervention. All subjects who are discontinued from the study intervention for reasons of efficacy or safety will receive LN treatment and monitoring as per the treating physician's decision. However, these subjects will be asked to participate in study visits at weeks 26 and 53/End of Study.

    6. Conditions and Keywords

    Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
    Lupus Nephritis

    7. Study Design

    Primary Purpose
    Treatment
    Study Phase
    Phase 2
    Interventional Study Model
    Parallel Assignment
    Model Description
    Eligible patients enrolled in the study will be randomized (1:1) at baseline to the 53-week double-blind, active comparator 2-part study to receive either MMFPK or MMFBSA. Subjects who are partial renal responders (PRR) to MMFBSA at week 26, will cross over to the MMFPK arm. Complete renal responders (CRR) at week 26 in MMFBSA arm will continue to be treated with MMFBSA. Subjects with at least a PRR (or even CRR) in the MMFPK arm at week 26 will remain in the MMFPK arm and continue to receive MMF dosage targeting MPA-AUC0-12 > 60-70 mg*h/l. Subjects whose LN fails to respond to therapy by week 26 will be discontinued from the study interventions to receive LN treatment as per their local physician's decision. Subjects who experience a single episode of a LN flare during Part 1 of the study or fulfill other criteria for discontinuation from the study intervention, will also receive LN treatment as per their local physician's decision.
    Masking
    ParticipantCare ProviderInvestigatorOutcomes Assessor
    Masking Description
    During this double-blinded study, the Sponsor, subject, and investigator site staff will all be blinded to the subject's treatment assignment.
    Allocation
    Randomized
    Enrollment
    105 (Anticipated)

    8. Arms, Groups, and Interventions

    Arm Title
    MMFBSA
    Arm Type
    Active Comparator
    Arm Description
    MMF dosed as per body-surface area
    Arm Title
    MMFPK
    Arm Type
    Experimental
    Arm Description
    MMF dosed as per pharmacokinetically-guided precision-dosing
    Intervention Type
    Drug
    Intervention Name(s)
    Mycophenolate Mofetil
    Other Intervention Name(s)
    MMF dosed per body surface area
    Intervention Description
    MMF dosed 600mg/m2 body surface area per dose about every 12 hours
    Intervention Type
    Drug
    Intervention Name(s)
    Mycophenolate Mofetil
    Other Intervention Name(s)
    MMF dosed phrmacokinetically
    Intervention Description
    MMF dosed twice daily to achieve an area under the concentration-time curve (AUC 0-12h) of MPA >=60-70 mg*h/L
    Primary Outcome Measure Information:
    Title
    To compare the efficacy of MMFPK therapy to the efficacy of MMFBSA therapy
    Description
    the percentage of subjects achieving at least partial remission of LN (PRR) as per the adapted ACR/EULAR Criteria at Week 26
    Time Frame
    26 week

    10. Eligibility

    Sex
    All
    Minimum Age & Unit of Time
    8 Years
    Maximum Age & Unit of Time
    18 Years
    Accepts Healthy Volunteers
    No
    Eligibility Criteria
    Inclusion Male or female aged 8 to < 18 years; Must meet Classification Criteria for SLE as per the criteria of the American College of Rheumatology (ACR)/ European League Against Rheumatism 1-3 (Appendix 0); Newly diagnosed with proliferative LN as per the International Society of Nephrology/Renal Pathology Society4 based on kidney biopsy done within 60 days prior to enrollment into the study; Subjects may have been previously diagnosed with other Classes of LN. For study inclusion, the kidney biopsy must be newly interpreted as one of the following classes: Class 3, Class 3/5, Class 4, or Class 4/5. SLEDAI renal domain score > 0; Treatment of LN with twice daily MMF as per the decision of the treating physician. The subject will have taken MMF as prescribed by their treating physician for a minimum of 4 days (or 8 doses). Subject tolerates MMF as per the treating physician's opinion; Able to swallow MMF tablets and capsules; If subject is treated with belimumab, must be IV or SQ; Subjects who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures; Evidence of a personally signed and dated Informed Consent document and Assent document (as appropriate) indicating that the subject and a legally acceptable representative/ parent(s)/legal guardian has been informed of all pertinent aspects of the study. Parent or legal guardian must have a smart phone available and able to support the PLUMM smart phone application. Must be able to complete study questionnaires in English or Spanish. Exclusion Criteria: Perceived or stated inability to adhere to the study protocol; Hypersensitivity to MMF or any component of the drug product; Presence of features (from SLE or other chronic disease) that a-priori suggest that the subject benefits from other therapies than that suggested or allowable by the study protocol; These disease features include but are not limited to severe, progressive, or uncontrolled hepatic, hematologic, gastrointestinal, metabolic, endocrine, pulmonary, cardiac or neurologic disease. History of other kidney disease besides LN or prior to the diagnosis of SLE; Need for renal replacement therapy within 2 weeks from Baseline Subjects can have required short-term renal replacement therapy prior to Baseline, for example due to preceding acute kidney injury. Infections: Untreated latent or active tuberculosis (TB); Chronic infections requiring treatment; A subject known to be infected with Human Immunodeficiency Virus (HIV), Hepatitis B; Any infection requiring hospitalization, parenteral antimicrobial therapy or judged to be opportunistic by the investigator within 4 weeks prior of Baseline visit; Any treated infections within 2 weeks of Baseline visit; History of infected joint prosthesis with prosthesis still in situ; Blood dyscrasias, including: Hemoglobin <8.5 g/dL or Hematocrit <22%; White Blood Cell count <2.6 x 109/L; Neutrophil count <1.2 x 109/L; Platelet count <100 x 109/L; Lymphocyte count <0.5 x 109/L. Estimated glomerular filtration rate [GFR] <40 mL/min/1.73 m2 calculated using the modified Schwartz equation5 (see Appendix 4); Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >1.5 times the upper limit of normal; Vaccinated or exposed to a live or attenuated vaccine within the 4 weeks prior to Baseline visit; History or current symptoms suggestive of lymphoproliferative disorders (e.g., Epstein Barr Virus [EBV] related lymphoproliferative disorder, lymphoma, leukemia, myeloproliferative disorders, or multiple myeloma); Current malignancy or history of any malignancy with the exception of adequate treated or excised basal cell or squamous cell or cervical cancer in situ; Recent (within 4 weeks prior to Baseline visit) significant trauma or major surgery; Herbal supplements with pharmaceutical properties must be discontinued at least 1week prior to Baseline visit, unless there are sufficient data available regarding the duration of an herbal medication's pharmacokinetic and pharmacodynamic effects to allow a shorter or longer washout to be specified (e.g., 5 half-lives). Hydroxychloroquine exceeding 5mg/kg/day or started within 1 week prior to Baseline visit; Oral or intravenous cyclophosphamide must be discontinued 12 weeks prior to Baseline visit Rituximab or other selective B lymphocyte depleting agents: Must be discontinued for 6 months prior to Baseline visit or CD19/20+ counts must be normal by FACS analysis; Use of prohibited prescription medication as listed in Appendix 3 within the specified time frame prior to Baseline visit Participation in other studies involving investigational drug(s) within 4 weeks or 5 half-lives (whichever is longer) prior to Baseline visit and/or during study participation; Exposure to investigational biologics should be discussed with the Sponsor. Pregnant female subjects; breastfeeding female subjects; male subjects with partners currently pregnant; male subjects able to father children and female subjects of childbearing potential who are unwilling or unable to use two highly effective methods of contraception or are abstinent (see Section 4.4.) for the duration of the study; Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the subject inappropriate for entry into this study.
    Central Contact Person:
    First Name & Middle Initial & Last Name or Official Title & Degree
    Angela Sr CRC
    Phone
    513-803-2118
    Email
    plumm@cchmc.org
    Overall Study Officials:
    First Name & Middle Initial & Last Name & Degree
    Hermine I Brunner, MD
    Organizational Affiliation
    Children's Hospital Medical Center, Cincinnati
    Official's Role
    Principal Investigator

    12. IPD Sharing Statement

    Plan to Share IPD
    Yes
    IPD Sharing Plan Description
    The Sponsor fulfills its commitment to publicly disclose clinical trial results through posting the results of studies on ClinicalTrials.gov, or EudraCT, and/or www.cincinnatichildrens.com, and other public registries in accordance with applicable local laws/regulations. In all cases, study results are reported by the Sponsor regardless of the outcome of the study. Every effort will be made to report the basic results within 1 year of the end of the trial. Results will be posted at www.clinicaltrials.gov/. For all publications relating to the study, the institution and investigators will comply with recognized ethical standards concerning publications and authorship, including Section II - "Ethical Considerations in the Conduct and Reporting of Research" of the Uniform Requirements for Manuscripts Submitted to Biomedical Journals, http://www.icmje.org/index.html#authorship. A Publication Committee will be established to oversee publication of the results.
    IPD Sharing Time Frame
    within one year for
    IPD Sharing Access Criteria
    results are available to the public
    IPD Sharing URL
    http://www.clinicaltrials.gov

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    The Pediatric Lupus Nephritis Mycophenolate Mofetil (PLUMM) Study

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