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AMPK-activation by Metformin in FSGS: AMP-FSGS (AMP-FSGS)

Primary Purpose

Focal Segmental Glomerulosclerosis

Status
Not yet recruiting
Phase
Phase 1
Locations
Study Type
Interventional
Intervention
Metformin + Standard of Care
Placebo + Standard of Care
Sponsored by
Yale University
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Focal Segmental Glomerulosclerosis

Eligibility Criteria

18 Years - 80 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria: Provision of signed and dated informed consent form Stated willingness to comply with all study procedures and availability for the duration of the study Male or female, aged greater than or equal to 18 years, but </= 80 years age at the time of signing the informed consent Biopsy-confirmed primary FSGS as defined by expert renal pathology at either institutions. For homogeneity of diagnoses, demonstrable segmental or global sclerosis lesions (>/=1 glomerulus) with diffuse podocyte foot process effacement by electron microscopy (>/+ 50% of examined glomerular tufts). Therapeutic plan by treating physician for immunomodulatory treatment using Glucocorticoids. Ability to take oral medication and be willing to adhere to the MF or Placebo regimen For females of reproductive potential: use of highly effective contraception for at least 1 month prior to screening and agreement to use such a method during study participation and for an additional 12 weeks after the end of VPA administration. For males of reproductive potential: use of condoms or other methods to ensure effective contraception with partner. Exclusion Criteria: Liver disease: confirmed cirrhosis liver (any stage), acute hepatitis (> 2 fold increase in liver enzymes, any coagulopathy, hyperbilirubinemia, ascites or encephalopathy) estimated GFR < 32 ml/min Diabetes Mellitus diagnosis at the time of biopsy or need for oral hypoglycemic agents/Insulin, or taking Metformin for other indications Treatment with another investigational drug or other intervention within 3 months Current pregnancy or desire to become pregnant during the study period Unwilling to use two forms of birth control (for women of childbearing age) Under hospice care Confirmed Dementia diagnoses in EMR problem list Incarceration Homelessness Inability to consent Currently enrolled in (or completed within the past 30 days) a study of an investigational drug or device. Life expectancy of less than 6 months as determined by the clinical judgement of the patient's primary physician Allergy or sensitivity to Metformin Platelet count < 100,000/µL; INR > 1.5; Bleeding diathesis or blood thinner use contraindicating biopsy. Simultaneous use of Carbonic anhydrase inhibitor agents Use of systemic immunosuppressive medication for non-renal indications.

Sites / Locations

    Arms of the Study

    Arm 1

    Arm 2

    Arm Type

    Experimental

    Placebo Comparator

    Arm Label

    Metformin + Standard of Care

    Placebo + Standard of Care

    Arm Description

    Administration of daily oral extended-release Metformin 500 mg tablets with standard of care for 6 months.

    Administration of daily placebo tablets with standard of care for 6 months.

    Outcomes

    Primary Outcome Measures

    Slope of urinary NPHS2:Creatinine ratio
    Measure of podocinuria via evaluation of urine podocin mRNA(nphs2) (measured as number of molecules detected by qPCR in the collected urine pellet) over the creatinine concentration. Intended for evaluation of efficacy of metformin versus placebo.

    Secondary Outcome Measures

    estimated Glomerular Filtration Rate (eGFR)
    Calculated from serum creatinine (mg/dl) using the CKD-EPI formula. Intended for evaluation of efficacy of metformin versus placebo.
    Slope of eGFR
    Change in eGFR from randomization to 6 months by incorporating eGFR at all timepoints in study between baseline and 6 months post-randomization. eGFR calculated from serum creatinine (mg/dl) using the CKD-EPI formula. Intended for evaluation of efficacy of metformin versus placebo.
    Urine protein:creatinine ratio
    Calculated ratio of urine protein and creatinine, each collected from the electronic medical record. Intended for evaluation of clinical efficacy of metformin versus placebo.
    Slope of urine protein:creatinine ratio
    Change in urine protein:creatinine ratio from randomization to 6 months by incorporating urine protein:creatinine ratio at all timepoints in study between baseline and 6 months post-randomization. Intended for evaluation of clinical efficacy of metformin versus placebo.
    Complete remission
    Calculated as the number of patients in complete remission, defined as <0.5 gm urine protein excretion over 24 hours, or urine protein creatinine ratio < 0.5 at 6 months post-randomization. Intended for evaluation of clinical efficacy of metformin versus placebo.
    Complete or partial remission
    Calculated as the number of patients with complete remission (defined as <0.5 gm urine protein excretion over 24 hours, or urine protein creatinine ratio < 0.5) or partial remission (>50% reduction in proteinuria from pre-randomization). Intended for evaluation of clinical efficacy of metformin versus placebo.
    Discontinuation of study drug
    Number of patients who discontinued study drug for any reason within 6 months of randomization. Intended for evaluation of patient compliance of metformin use.
    Modified Kidney Disease Quality of Life (KDQOL) score
    Calculated as the mean (standard deviation) of all total scores. Total scores are calculated by combining scores of 8 subsections of the KDQOL, and range from 0 - 163, with higher scores representing better quality of life. Intended for evaluation of adverse effects of metformin versus placebo.
    Modified Kidney Disease Quality of Life (KDQOL) score
    Calculated as the mean (standard deviation) of all total scores. Total scores are calculated by combining scores of 8 subsections of the KDQOL, and range from 0 - 163, with higher scores representing better quality of life. Intended for evaluation of adverse effects of metformin versus placebo.
    Hypoglycemia symptom scores
    Calculated as the mean (standard deviation) of all total scores. Total scores are calculated by combining scores of 6 subsections of the questionnaire, and range from 0 - 18, with higher scores representing greater symptoms. Intended for evaluation of adverse effects of metformin versus placebo.
    Gastrointenstinal symptom scores
    Calculated as the mean (standard deviation) of all total scores. Total scores are calculated by combining scores of 15 subsections of the questionnaire, and range from 0 - 105, with higher scores representing greater symptoms. Intended for evaluation of adverse effects of metformin versus placebo.
    Gastrointenstinal symptom scores
    Calculated as the mean (standard deviation) of all total scores. Total scores are calculated by combining scores of 15 subsections of the questionnaire, and range from 0 - 105, with higher scores representing greater symptoms. Intended for evaluation of adverse effects of metformin versus placebo.
    Kidney biopsy fibrosis scores
    Evaluation of kidney fibrosis as measured by quantification of Masson's Trichrome staining under microscopy of biopsy at 6 months post-randomization. Scores will be grouped by the following: <10%, 10-25%, 25-50%, > 50%. Intended for evaluation of clinical efficacy of metformin versus placebo.
    Number of patients with Lactate levels>2.5
    As determined from the electronic medical record. Intended for evaluation of adverse effects of metformin versus placebo.
    Number of patients with Lactate levels>5
    As determined from the electronic medical record. Intended for evaluation of adverse effects of metformin versus placebo.
    Number of patients with Vitamin B12 levels <lower limit of Normal
    As determined from the electronic medical record. Intended for evaluation of adverse effects of metformin versus placebo.
    Number of patients with serum glutamic-oxaloacetic transaminase (SGOT) >2 fold increase
    As determined from the electronic medical record. Intended for evaluation of adverse effects of metformin versus placebo.
    Number of patients with Serum Glutamic Pyruvic Transaminase (SGPT) >2 fold increase
    As determined from the electronic medical record. Intended for evaluation of adverse effects of metformin versus placebo.
    Number of patients with Serum amyloid P component (SAP) >2 fold increase
    As determined from the electronic medical record. Intended for evaluation of adverse effects of metformin versus placebo.
    Number of patients with Bililirubin-Total >2
    As determined from the electronic medical record. Intended for evaluation of adverse effects of metformin versus placebo.
    Number of patients with Bilirubin indirect >1
    As determined from the electronic medical record. Intended for evaluation of adverse effects of metformin versus placebo.
    Number of patients with hemoglobin (Hb) <9
    As determined from the electronic medical record. Intended for evaluation of disease progression and adverse effects of metformin versus placebo.
    Number of patients with hematocrit (Hct) <27
    As determined from the electronic medical record. Intended for evaluation of disease progression and adverse effects of metformin versus placebo.
    Number of patients with mean corpuscular volume (MCV) >100
    As determined from the electronic medical record. Intended for evaluation of disease progression and adverse effects of metformin versus placebo.
    Number of patients with Total White Blood Cells (WBC) <1500
    As determined from the electronic medical record. Intended for evaluation of disease progression and adverse effects of metformin versus placebo.
    Slope of Urine Nphs2
    Change in urine podocin mRNA(Nphs2), measured as number of molecules detected by qPCR in the collected urine pellet over the creatinine concentration. Slope measured by incorporating nphs2 measurements at all timepoints in study between baseline and 6 months post-randomization. Intended for evaluation of efficacy of metformin versus placebo.
    Slope of Urine Aqp2
    Change in urine Aquaporin-2 mRNA(Aqp2), measured as number of molecules detected by qPCR in the collected urine pellet over the creatinine concentration. Slope measured by incorporating Aqp2 measurements at all timepoints in study between baseline and 6 months post-randomization. Intended for evaluation of efficacy of metformin versus placebo.
    Slope of Urine Tgfb1
    Change in urine transforming growth factor-beta1 mRNA (Tgfb1), measured as number of molecules detected by qPCR in the collected urine pellet over the creatinine concentration. Slope measured by incorporating Tgfb1 measurements at all timepoints in study between baseline and 6 months post-randomization. Intended for evaluation of efficacy of metformin versus placebo.

    Full Information

    First Posted
    October 13, 2023
    Last Updated
    October 13, 2023
    Sponsor
    Yale University
    Collaborators
    United States Department of Defense
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    1. Study Identification

    Unique Protocol Identification Number
    NCT06090227
    Brief Title
    AMPK-activation by Metformin in FSGS: AMP-FSGS
    Acronym
    AMP-FSGS
    Official Title
    AMPK-activation by Metformin in FSGS: AMP-FSGS
    Study Type
    Interventional

    2. Study Status

    Record Verification Date
    October 2023
    Overall Recruitment Status
    Not yet recruiting
    Study Start Date
    November 2023 (Anticipated)
    Primary Completion Date
    November 2027 (Anticipated)
    Study Completion Date
    November 2027 (Anticipated)

    3. Sponsor/Collaborators

    Responsible Party, by Official Title
    Sponsor
    Name of the Sponsor
    Yale University
    Collaborators
    United States Department of Defense

    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.
    No
    Data Monitoring Committee
    Yes

    5. Study Description

    Brief Summary
    The primary objective of this study is to determine whether extended-release MF (in addition to standard of care (S-o-C)) is superior to placebo in reducing podocyte injury and promoting podocyte survival by 6-months in Focal Segmental Glomerulosclerosis (FSGS).
    Detailed Description
    Focal Segmental glomerulosclerosis (FSGS) is currently the most common primary glomerular disease that progresses to ESKD in the US. FSGS is typified by significant proteinuria, and by disorganization of the actin cytoskeleton of highly specialized epithelial cells which support the glomerular capillary loop called podocytes. Podocytes are characterized by foot processes, whose disorganization with injury is visualized on electron microscopy as foot process effacement (FPE). Podocytes are also incapable of self-renewal, and podocyte loss over ~40% per glomerulus leads to proteinuria, the nephrotic syndrome (NS) and FSGS. Such critical podocyte loss alone is sufficient for progressive CKD and ESKD. Currently, the reported rate of complete and/or partial response is 40-70% in various series with a rate of progression to ESKD 30-53% in 5-10 years. Distinct from FSGS, Minimal Change Disease (MCD), which despite showing similar diffuse FPE and NS, has preserved podocyte numbers and rare progression to ESKD (5-20% in 20 years). MCD can be morphologically indistinguishable from early FSGS, and some MCD cases reportedly transition to FSGS. Hence, identifying and targeting mechanisms in MCD that specifically promote survival of injured podocytes with FPE, could help switch an FSGS phenotype to an "MCD-like" phenotype, and prevent or retard progression of FSGS. Currently, therapeutics in FSGS focus on immune modulation, or on hemodynamic interventions used in generically all cases of NS. Specific strategies to directly promote podocyte survival and limit podocytopenia to within the critical threshold during injury, have not been pursued clinically. Hence, many FSGS cases will progress to ESKD or encounter dose limiting side-effects of immune therapies (corticosteroids, or other agents), representing a significant therapeutic gap in the field. In this context, MF is an Ampk-activator that is widely used, demonstrably safe, and inexpensive with reported renal benefit in diabetic and non-diabetic CKD. Its specific utility to promote cell survival of injured podocytes in FSGS has never been tested. Our preclinical data shows that an "MCD-like" pathology with podocyte injury/FPE transitioned to podocytopenia and FSGS by AMPK inhibition, while AMPK activation with MF mitigated podocytopenia in FSGS models. The purpose of this study is to test whether Metformin use in individuals with FSGS as an adjunct to standard -of-care (corticosteroids, anti RAAS measures, BP control) is safe and will activate kidney cell AMPK and reduce podocyte injury. The primary objective is to determine whether extended-release MF (in addition to standard of care (S-o-C)) is superior to placebo in reducing podocyte injury and promoting podocyte survival by 6-months in Focal Segmental Glomerulosclerosis (FSGS). Specifically, for this purpose, this study will primarily evaluate sequential urinary podocyte mRNA excretion to identify individual urinary mRNA trajectories representing podocyte injury/depletion and potential prognostic signals in the MF study limb vs control. A secondary objective of this study is to use multiple blood, urine and biopsy assays to test whether the addition of Metformin ( to S-o-C) mitigates kidney disease progression parameters superior to placebo. These assays will include large scale urine and serum protein profiling, protein and RNA tests performed in kidney biopsies. Another secondary objective of this study is to test whether the addition of Metformin ( to S-o-C) is safe in patients with proteinuria and FSGS. This will be accomplished by specific questionnaires and blood tests geared towards MF-associated adverse effects. Results of this study will inform a larger, phase 2/3 randomized trial which will evaluate the efficacy of MF treatment versus placebo in attenuating proteinuria and kidney function decline in FSGS.

    6. Conditions and Keywords

    Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
    Focal Segmental Glomerulosclerosis

    7. Study Design

    Primary Purpose
    Treatment
    Study Phase
    Phase 1, Phase 2
    Interventional Study Model
    Parallel Assignment
    Masking
    ParticipantCare ProviderInvestigator
    Allocation
    Randomized
    Enrollment
    30 (Anticipated)

    8. Arms, Groups, and Interventions

    Arm Title
    Metformin + Standard of Care
    Arm Type
    Experimental
    Arm Description
    Administration of daily oral extended-release Metformin 500 mg tablets with standard of care for 6 months.
    Arm Title
    Placebo + Standard of Care
    Arm Type
    Placebo Comparator
    Arm Description
    Administration of daily placebo tablets with standard of care for 6 months.
    Intervention Type
    Drug
    Intervention Name(s)
    Metformin + Standard of Care
    Intervention Description
    Administration of daily oral extended-release Metformin 500 mg tablets with standard of care for 6 months.
    Intervention Type
    Other
    Intervention Name(s)
    Placebo + Standard of Care
    Intervention Description
    Administration of daily placebo tablets with standard of care for 6 months.
    Primary Outcome Measure Information:
    Title
    Slope of urinary NPHS2:Creatinine ratio
    Description
    Measure of podocinuria via evaluation of urine podocin mRNA(nphs2) (measured as number of molecules detected by qPCR in the collected urine pellet) over the creatinine concentration. Intended for evaluation of efficacy of metformin versus placebo.
    Time Frame
    6 months following randomization
    Secondary Outcome Measure Information:
    Title
    estimated Glomerular Filtration Rate (eGFR)
    Description
    Calculated from serum creatinine (mg/dl) using the CKD-EPI formula. Intended for evaluation of efficacy of metformin versus placebo.
    Time Frame
    6 months post-randomization
    Title
    Slope of eGFR
    Description
    Change in eGFR from randomization to 6 months by incorporating eGFR at all timepoints in study between baseline and 6 months post-randomization. eGFR calculated from serum creatinine (mg/dl) using the CKD-EPI formula. Intended for evaluation of efficacy of metformin versus placebo.
    Time Frame
    6 months post-randomization
    Title
    Urine protein:creatinine ratio
    Description
    Calculated ratio of urine protein and creatinine, each collected from the electronic medical record. Intended for evaluation of clinical efficacy of metformin versus placebo.
    Time Frame
    6 months post-randomization
    Title
    Slope of urine protein:creatinine ratio
    Description
    Change in urine protein:creatinine ratio from randomization to 6 months by incorporating urine protein:creatinine ratio at all timepoints in study between baseline and 6 months post-randomization. Intended for evaluation of clinical efficacy of metformin versus placebo.
    Time Frame
    6 months post-randomization
    Title
    Complete remission
    Description
    Calculated as the number of patients in complete remission, defined as <0.5 gm urine protein excretion over 24 hours, or urine protein creatinine ratio < 0.5 at 6 months post-randomization. Intended for evaluation of clinical efficacy of metformin versus placebo.
    Time Frame
    6 months post-randomization
    Title
    Complete or partial remission
    Description
    Calculated as the number of patients with complete remission (defined as <0.5 gm urine protein excretion over 24 hours, or urine protein creatinine ratio < 0.5) or partial remission (>50% reduction in proteinuria from pre-randomization). Intended for evaluation of clinical efficacy of metformin versus placebo.
    Time Frame
    6 months post-randomization
    Title
    Discontinuation of study drug
    Description
    Number of patients who discontinued study drug for any reason within 6 months of randomization. Intended for evaluation of patient compliance of metformin use.
    Time Frame
    Within 6 months post-randomization
    Title
    Modified Kidney Disease Quality of Life (KDQOL) score
    Description
    Calculated as the mean (standard deviation) of all total scores. Total scores are calculated by combining scores of 8 subsections of the KDQOL, and range from 0 - 163, with higher scores representing better quality of life. Intended for evaluation of adverse effects of metformin versus placebo.
    Time Frame
    1 month post-randomization
    Title
    Modified Kidney Disease Quality of Life (KDQOL) score
    Description
    Calculated as the mean (standard deviation) of all total scores. Total scores are calculated by combining scores of 8 subsections of the KDQOL, and range from 0 - 163, with higher scores representing better quality of life. Intended for evaluation of adverse effects of metformin versus placebo.
    Time Frame
    6 months post-randomization
    Title
    Hypoglycemia symptom scores
    Description
    Calculated as the mean (standard deviation) of all total scores. Total scores are calculated by combining scores of 6 subsections of the questionnaire, and range from 0 - 18, with higher scores representing greater symptoms. Intended for evaluation of adverse effects of metformin versus placebo.
    Time Frame
    6 months post-randomization
    Title
    Gastrointenstinal symptom scores
    Description
    Calculated as the mean (standard deviation) of all total scores. Total scores are calculated by combining scores of 15 subsections of the questionnaire, and range from 0 - 105, with higher scores representing greater symptoms. Intended for evaluation of adverse effects of metformin versus placebo.
    Time Frame
    1 month post-randomization
    Title
    Gastrointenstinal symptom scores
    Description
    Calculated as the mean (standard deviation) of all total scores. Total scores are calculated by combining scores of 15 subsections of the questionnaire, and range from 0 - 105, with higher scores representing greater symptoms. Intended for evaluation of adverse effects of metformin versus placebo.
    Time Frame
    6 months post-randomization
    Title
    Kidney biopsy fibrosis scores
    Description
    Evaluation of kidney fibrosis as measured by quantification of Masson's Trichrome staining under microscopy of biopsy at 6 months post-randomization. Scores will be grouped by the following: <10%, 10-25%, 25-50%, > 50%. Intended for evaluation of clinical efficacy of metformin versus placebo.
    Time Frame
    6 months post-randomization
    Title
    Number of patients with Lactate levels>2.5
    Description
    As determined from the electronic medical record. Intended for evaluation of adverse effects of metformin versus placebo.
    Time Frame
    Within 6 months post-randomization
    Title
    Number of patients with Lactate levels>5
    Description
    As determined from the electronic medical record. Intended for evaluation of adverse effects of metformin versus placebo.
    Time Frame
    Within 6 months post-randomization
    Title
    Number of patients with Vitamin B12 levels <lower limit of Normal
    Description
    As determined from the electronic medical record. Intended for evaluation of adverse effects of metformin versus placebo.
    Time Frame
    Within 6 months post-randomization
    Title
    Number of patients with serum glutamic-oxaloacetic transaminase (SGOT) >2 fold increase
    Description
    As determined from the electronic medical record. Intended for evaluation of adverse effects of metformin versus placebo.
    Time Frame
    Within 6 months post-randomization
    Title
    Number of patients with Serum Glutamic Pyruvic Transaminase (SGPT) >2 fold increase
    Description
    As determined from the electronic medical record. Intended for evaluation of adverse effects of metformin versus placebo.
    Time Frame
    Within 6 months post-randomization
    Title
    Number of patients with Serum amyloid P component (SAP) >2 fold increase
    Description
    As determined from the electronic medical record. Intended for evaluation of adverse effects of metformin versus placebo.
    Time Frame
    Within 6 months post-randomization
    Title
    Number of patients with Bililirubin-Total >2
    Description
    As determined from the electronic medical record. Intended for evaluation of adverse effects of metformin versus placebo.
    Time Frame
    Within 6 months post-randomization
    Title
    Number of patients with Bilirubin indirect >1
    Description
    As determined from the electronic medical record. Intended for evaluation of adverse effects of metformin versus placebo.
    Time Frame
    Within 6 months post-randomization
    Title
    Number of patients with hemoglobin (Hb) <9
    Description
    As determined from the electronic medical record. Intended for evaluation of disease progression and adverse effects of metformin versus placebo.
    Time Frame
    Within 6 months post-randomization
    Title
    Number of patients with hematocrit (Hct) <27
    Description
    As determined from the electronic medical record. Intended for evaluation of disease progression and adverse effects of metformin versus placebo.
    Time Frame
    Within 6 months post-randomization
    Title
    Number of patients with mean corpuscular volume (MCV) >100
    Description
    As determined from the electronic medical record. Intended for evaluation of disease progression and adverse effects of metformin versus placebo.
    Time Frame
    Within 6 months post-randomization
    Title
    Number of patients with Total White Blood Cells (WBC) <1500
    Description
    As determined from the electronic medical record. Intended for evaluation of disease progression and adverse effects of metformin versus placebo.
    Time Frame
    Within 6 months post-randomization
    Title
    Slope of Urine Nphs2
    Description
    Change in urine podocin mRNA(Nphs2), measured as number of molecules detected by qPCR in the collected urine pellet over the creatinine concentration. Slope measured by incorporating nphs2 measurements at all timepoints in study between baseline and 6 months post-randomization. Intended for evaluation of efficacy of metformin versus placebo.
    Time Frame
    6 months post-randomization
    Title
    Slope of Urine Aqp2
    Description
    Change in urine Aquaporin-2 mRNA(Aqp2), measured as number of molecules detected by qPCR in the collected urine pellet over the creatinine concentration. Slope measured by incorporating Aqp2 measurements at all timepoints in study between baseline and 6 months post-randomization. Intended for evaluation of efficacy of metformin versus placebo.
    Time Frame
    6 months post-randomization
    Title
    Slope of Urine Tgfb1
    Description
    Change in urine transforming growth factor-beta1 mRNA (Tgfb1), measured as number of molecules detected by qPCR in the collected urine pellet over the creatinine concentration. Slope measured by incorporating Tgfb1 measurements at all timepoints in study between baseline and 6 months post-randomization. Intended for evaluation of efficacy of metformin versus placebo.
    Time Frame
    6 months post-randomization
    Other Pre-specified Outcome Measures:
    Title
    Body Mass Index (BMI)
    Description
    Measured in kg/m2. Exploratory outcome intended for evaluation of adverse effects of metformin versus placebo.
    Time Frame
    3 months post-randomization
    Title
    Body Mass Index (BMI)
    Description
    Measured in kg/m2. Exploratory outcome intended for evaluation of adverse effects of metformin versus placebo.
    Time Frame
    6 months post-randomization

    10. Eligibility

    Sex
    All
    Minimum Age & Unit of Time
    18 Years
    Maximum Age & Unit of Time
    80 Years
    Accepts Healthy Volunteers
    No
    Eligibility Criteria
    Inclusion Criteria: Provision of signed and dated informed consent form Stated willingness to comply with all study procedures and availability for the duration of the study Male or female, aged greater than or equal to 18 years, but </= 80 years age at the time of signing the informed consent Biopsy-confirmed primary FSGS as defined by expert renal pathology at either institutions. For homogeneity of diagnoses, demonstrable segmental or global sclerosis lesions (>/=1 glomerulus) with diffuse podocyte foot process effacement by electron microscopy (>/+ 50% of examined glomerular tufts). Therapeutic plan by treating physician for immunomodulatory treatment using Glucocorticoids. Ability to take oral medication and be willing to adhere to the MF or Placebo regimen For females of reproductive potential: use of highly effective contraception for at least 1 month prior to screening and agreement to use such a method during study participation and for an additional 12 weeks after the end of VPA administration. For males of reproductive potential: use of condoms or other methods to ensure effective contraception with partner. Exclusion Criteria: Liver disease: confirmed cirrhosis liver (any stage), acute hepatitis (> 2 fold increase in liver enzymes, any coagulopathy, hyperbilirubinemia, ascites or encephalopathy) estimated GFR < 32 ml/min Diabetes Mellitus diagnosis at the time of biopsy or need for oral hypoglycemic agents/Insulin, or taking Metformin for other indications Treatment with another investigational drug or other intervention within 3 months Current pregnancy or desire to become pregnant during the study period Unwilling to use two forms of birth control (for women of childbearing age) Under hospice care Confirmed Dementia diagnoses in EMR problem list Incarceration Homelessness Inability to consent Currently enrolled in (or completed within the past 30 days) a study of an investigational drug or device. Life expectancy of less than 6 months as determined by the clinical judgement of the patient's primary physician Allergy or sensitivity to Metformin Platelet count < 100,000/µL; INR > 1.5; Bleeding diathesis or blood thinner use contraindicating biopsy. Simultaneous use of Carbonic anhydrase inhibitor agents Use of systemic immunosuppressive medication for non-renal indications.
    Central Contact Person:
    First Name & Middle Initial & Last Name or Official Title & Degree
    Madhav C Menon, MD
    Phone
    20373734507
    Email
    madhav.menon@yale.edu
    Overall Study Officials:
    First Name & Middle Initial & Last Name & Degree
    Madhav Menon, MD
    Organizational Affiliation
    Yale University
    Official's Role
    Principal Investigator

    12. IPD Sharing Statement

    Plan to Share IPD
    Undecided

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