Ignite Creation Date:
2024-05-06 @ 7:40 PM
Last Modification Date:
2024-10-26 @ 3:11 PM
Study NCT ID:
NCT06090227
Status:
RECRUITING
Last Update Posted:
2024-06-13
First Post:
2023-10-13
Brief Title:
AMPK-activation by Metformin in FSGS AMP-FSGS
Sponsor:
Yale University
Organization:
Yale University
Study Overview
Official Title:
AMPK-activation by Metformin in FSGS AMP-FSGS
Status:
RECRUITING
Status Verified Date:
2024-06
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
AMP-FSGS
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 andor 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 injuryFPE 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 injurydepletion 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 23 randomized trial which will evaluate the efficacy of MF treatment versus placebo in attenuating proteinuria and kidney function decline in FSGS
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 injuryFPE 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 injurydepletion 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 23 randomized trial which will evaluate the efficacy of MF treatment versus placebo in attenuating proteinuria and kidney function decline in FSGS
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
True
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
False
Is an FDA AA801 Violation?:
None
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| HT9425-23-1-0454 | OTHER_GRANT | Department of the Army | None |