Clinical trial NCT06090227: AMPK-activation by Metformin in FSGS: AMP-FSGS
Official title: AMPK-activation by Metformin in FSGS: AMP-FSGS
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
PHASE2
Conditions: Focal Segmental Glomerulosclerosis
Lead sponsor: Yale University
Sponsor class: OTHER
Collaborators: name: United States Department of Defense
First posted: 2023-10-19
Enrollment: 30
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: Inclusion Criteria:

1. Provision of signed and dated informed consent form
2. Stated willingness to comply with all study procedures and availability for the duration of the study
3. Male or female, aged greater than or equal to 18 years, but \</= 80 years age at the time of signing the informed consent
4. 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).
5. Therapeutic plan by treating physician for immunomodulatory treatment using Glucocorticoids.
6. Ability to take oral medication and be willing to adhere to the MF or Placebo regimen
7. 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:

1. Liver disease: confirmed cirrhosis liver (any stage), acute hepatitis (\> 2 fold increase in liver enzymes, any coagulopathy, hyperbilirubinemia, ascites or encephalopathy)
2. estimated GFR \< 32 ml/min
3. Diabetes Mellitus diagnosis at the time of biopsy or need for oral hypoglycemic agents/Insulin, or taking Metformin for other indications
4. Treatment with another investigational drug or other intervention within 3 months
5. Current pregnancy or desire to become pregnant during the study period
6. Unwilling to use two forms of birth control (for women of childbearing age)
7. Under hospice care
8. Confirmed Dementia diagnoses in EMR problem list
9. Incarceration
10. Homelessness
11. Inability to consent
12. Currently enrolled in (or completed within the past 30 days) a study of an investigational drug or device.
13. Life expectancy of less than 6 months as determined by the clinical judgement of the patient's primary physician
14. Allergy or sensitivity to Metformin
15. Platelet count \< 100,000/µL; INR \> 1.5; Bleeding diathesis or blood thinner use contraindicating biopsy.
16. Simultaneous use of Carbonic anhydrase inhibitor agents
17. Use of systemic immunosuppressive medication for non-renal indications.

Primary outcomes:
measure: Slope of urinary NPHS2:Creatinine ratio
timeFrame: 6 months following randomization
Secondary outcomes:
measure: estimated Glomerular Filtration Rate (eGFR)
timeFrame: 6 months post-randomization
measure: Slope of eGFR
timeFrame: 6 months post-randomization
measure: Urine protein:creatinine ratio
timeFrame: 6 months post-randomization
measure: Slope of urine protein:creatinine ratio
timeFrame: 6 months post-randomization
measure: Complete remission
timeFrame: 6 months post-randomization
measure: Complete or partial remission
timeFrame: 6 months post-randomization
measure: Discontinuation of study drug
timeFrame: Within 6 months post-randomization
measure: Modified Kidney Disease Quality of Life (KDQOL) score
timeFrame: 1 month post-randomization
measure: Modified Kidney Disease Quality of Life (KDQOL) score
timeFrame: 6 months post-randomization
measure: Hypoglycemia symptom scores
timeFrame: 6 months post-randomization
measure: Gastrointenstinal symptom scores
timeFrame: 1 month post-randomization
measure: Gastrointenstinal symptom scores
timeFrame: 6 months post-randomization
measure: Kidney biopsy fibrosis scores
timeFrame: 6 months post-randomization
measure: Number of patients with Lactate levels>2.5
timeFrame: Within 6 months post-randomization
measure: Number of patients with Lactate levels>5
timeFrame: Within 6 months post-randomization
measure: Number of patients with Vitamin B12 levels <lower limit of Normal
timeFrame: Within 6 months post-randomization
measure: Number of patients with serum glutamic-oxaloacetic transaminase (SGOT) >2 fold increase
timeFrame: Within 6 months post-randomization
measure: Number of patients with Serum Glutamic Pyruvic Transaminase (SGPT) >2 fold increase
timeFrame: Within 6 months post-randomization
measure: Number of patients with Serum amyloid P component (SAP) >2 fold increase
timeFrame: Within 6 months post-randomization
measure: Number of patients with Bililirubin-Total >2
timeFrame: Within 6 months post-randomization
measure: Number of patients with Bilirubin indirect >1
timeFrame: Within 6 months post-randomization
measure: Number of patients with hemoglobin (Hb) <9
timeFrame: Within 6 months post-randomization
measure: Number of patients with hematocrit (Hct) <27
timeFrame: Within 6 months post-randomization
measure: Number of patients with mean corpuscular volume (MCV) >100
timeFrame: Within 6 months post-randomization
measure: Number of patients with Total White Blood Cells (WBC) <1500
timeFrame: Within 6 months post-randomization
measure: Slope of Urine Nphs2
timeFrame: 6 months post-randomization
measure: Slope of Urine Aqp2
timeFrame: 6 months post-randomization
measure: Slope of Urine Tgfb1
timeFrame: 6 months post-randomization
Other outcomes:
measure: Body Mass Index (BMI)
timeFrame: 3 months post-randomization
measure: Body Mass Index (BMI)
timeFrame: 6 months post-randomization
Locations:
city: New Haven
country: United States
facility: Yale New Haven Hospital
state: Connecticut
city: New York
country: United States
facility: Mount Sinai Hospital
state: New York
Study officials:
affiliation: Yale University
name: Madhav Menon, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Icahn School of Medicine at Mount Sinai
name: Cijiang He
role: PRINCIPAL_INVESTIGATOR
References: