Metformin for FSGS

(AMP-FSGS Trial)

Recruiting at 1 trial location

Overseen By Madhav C Menon, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Yale University

Must be taking: Glucocorticoids

Must not be taking: Metformin, Carbonic anhydrase inhibitors

Disqualifiers: Liver disease, Diabetes, Dementia, others

Approved in 6 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 6 months

30 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

The trial aims to determine if adding metformin, a medication commonly used for type 2 diabetes, to the usual treatment can protect kidney cells in individuals with Focal Segmental Glomerulosclerosis (FSGS), a disease that causes kidney scarring. Participants will receive either metformin alongside their usual care or a placebo, which resembles the medicine but lacks active ingredients. This study is suitable for individuals with an FSGS diagnosis confirmed through a kidney biopsy and who are not diabetic. As a Phase 1, Phase 2 trial, the research focuses on understanding how metformin works in people and measuring its effectiveness in an initial, smaller group.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot participate if you are using certain medications like Metformin for other reasons, carbonic anhydrase inhibitors, or systemic immunosuppressive medication for non-kidney issues.

Is there any evidence suggesting that this treatment is likely to be safe for humans?

Research shows that metformin, a medication often used for diabetes, is generally safe and well-tolerated. It is widely used and has a strong safety record. Studies have found that metformin can help protect the kidneys by reducing damage to certain kidney cells, suggesting it might be a good option for people with Focal Segmental Glomerulosclerosis (FSGS), a type of kidney disease.

Other research has shown that metformin can improve kidney function in both people with and without diabetes. While this ongoing study specifically examines metformin's use for FSGS, its proven safety in other areas suggests potential safety for this condition as well. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for FSGS?

Unlike the standard treatments for FSGS, which typically involve immunosuppressants and corticosteroids, metformin is being explored for its unique mechanism. Metformin, a drug commonly used for diabetes, is thought to offer kidney-protective effects by reducing inflammation and improving cellular energy processes, which is different from how current FSGS treatments work. Researchers are excited because metformin could provide a novel, non-immunosuppressive approach to managing FSGS, potentially reducing side effects and offering a new way to preserve kidney function.

What evidence suggests that Metformin might be an effective treatment for FSGS?

This trial will evaluate Metformin's effectiveness in treating Focal Segmental Glomerulosclerosis (FSGS). Research has shown that Metformin, a drug commonly used for diabetes, might help treat FSGS. Earlier studies found that Metformin activates a protein called AMPK, which protects kidney cells known as podocytes. This action reduced podocyte loss and improved kidney function in people with FSGS. Observational studies also suggest that Metformin can lower protein levels in urine, benefiting kidney health. While these findings are promising, more research is needed to confirm Metformin's effectiveness for FSGS. Participants in this trial will receive either Metformin with standard care or a placebo with standard care to further investigate these effects. ^{1 2 4 6 7}

Who Is on the Research Team?

Madhav Menon, MD

Principal Investigator

Yale University

Cijiang He

Principal Investigator

Icahn School of Medicine at Mount Sinai

Are You a Good Fit for This Trial?

This trial is for adults aged 18-80 with biopsy-confirmed primary FSGS who can take oral medication and follow the study procedures. Participants must use effective contraception, have a plan for immunomodulatory treatment, and not have liver disease, severe kidney impairment, diabetes requiring medication, or be pregnant. They shouldn't be on other investigational drugs or treatments.

Inclusion Criteria

Provision of signed and dated informed consent form

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.

I am willing and able to follow all study rules and attend all appointments.

Exclusion Criteria

Currently enrolled in (or completed within the past 30 days) a study of an investigational drug or device.

My medical records confirm a dementia diagnosis.

You are in prison.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive daily oral extended-release Metformin 500 mg tablets or placebo with standard of care for 6 months

6 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Metformin

Trial Overview The AMP-FSGS trial is testing if extended-release Metformin plus standard care is better than placebo at reducing podocyte injury in FSGS patients over six months. The goal is to see if Metformin helps podocytes survive better than usual treatments alone.

How Is the Trial Designed?

Group I: Metformin + Standard of Care Experimental Treatment 1 Intervention

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

Group II: Placebo + Standard of Care Placebo Group 1 Intervention

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

Metformin is already approved in European Union, United States, Canada, Japan, China, Switzerland for the following indications:

Approved in European Union as Glucophage for:

• Type 2 diabetes

Approved in United States as Glucophage for:

• Type 2 diabetes

Approved in Canada as Glucophage for:

• Type 2 diabetes

Approved in Japan as Glucophage for:

• Type 2 diabetes

Approved in China as Glucophage for:

• Type 2 diabetes

Approved in Switzerland as Glucophage for:

• Type 2 diabetes

Who Is Running the Clinical Trial?

Yale University

Lead Sponsor

Trials

1,963

Recruited

3,046,000+

United States Department of Defense

Collaborator

Trials

940

Recruited

339,000+

Published Research Related to This Trial

In a study of 107 patients, 19 were diagnosed with metformin-associated lactic acidosis (MALA), primarily occurring in those with acute kidney injury (AKI) due to dehydration and sepsis, highlighting the importance of monitoring kidney function in patients taking metformin.

The overall mortality rate for MALA was 36.8%, with aggressive treatment including renal replacement therapy improving outcomes; however, 46.7% of AKI patients died, emphasizing the need for heightened awareness and education regarding the risks of metformin use in at-risk populations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Metformin-associated lactic acidosis (MALA): Is it an underestimated entity? A retrospective, single-center case series. Kim, S., Sarwal, A., Yee, XT., et al.[2023]

In a study of 20,070 patients with type 2 diabetes, adding a Thiazolidinedione (TZD) to metformin resulted in the most durable glycaemic control, while adding a Dipeptidyl-peptidase-4 (DPP-4) inhibitor led to an increased risk of treatment failure compared to Sulphonylureas (SU).

The study found that after 2 years, the failure rates for dual therapy were 26% for SU, 38% for DPP-4 inhibitors, and only 12% for TZDs, indicating that TZDs provide a more stable long-term treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Important differences in the durability of glycaemic response among second-line treatment options when added to metformin in type 2 diabetes: a retrospective cohort study. Mamza, J., Mehta, R., Donnelly, R., et al.[2017]

Oral semaglutide, the first oral GLP-1 receptor agonist, significantly reduced HbA1c levels by 1.1-1.5% and body weight by up to 5 kg in clinical trials, outperforming other diabetes medications like empagliflozin and liraglutide.

The most common side effects were mild-to-moderate gastrointestinal issues, primarily transient nausea, indicating a generally safe profile for patients with type 2 diabetes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Will oral semaglutide be a game-changer in the management of type 2 diabetes in primary care? Seidu, S., Mellbin, L., Kaiser, M., et al.[2021]

A study comparing gut microbiota in overweight and pre-diabetic participants showed that treatment with metformin (MET) and metformin plus liraglutide (MET+LRG) significantly altered gut bacteria profiles compared to those who progressed to type-2 diabetes (T2DM).

The addition of liraglutide to metformin therapy resulted in different gut microbiota changes, indicating that liraglutide may have an additive effect on gut bacteria composition, which could influence diabetes management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The effect of metformin combined with liraglutide on gut microbiota of Chinese patients with type 2 diabetes. Niu, X., Lu, P., Huang, L., et al.[2023]

Dapagliflozin, a selective SGLT2 inhibitor, has been shown to improve glycaemic control in adults with type 1 diabetes (T1D) and a BMI of ≥27 kg/m2, allowing for reduced insulin doses and weight loss over 24 weeks, with effects maintained up to 52 weeks.

The drug has a favorable safety profile, with a lower incidence of diabetic ketoacidosis in patients with higher BMI compared to the overall population, making it a promising adjunct treatment for those not achieving adequate control with insulin alone.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dapagliflozin: A Review in Type 1 Diabetes. Paik, J., Blair, HA.[2021]

A study of 405 patients with type 2 diabetes showed that both sodium-glucose cotransporter-2 inhibitors (SGLT2i) and glucagon-like peptide 1 receptor agonists (GLP-1 RAs) are safe to use alongside other glucose-lowering medications over a 12-month period.

The safety evaluation indicated no significant adverse effects on kidney function or liver enzymes, suggesting that these medications can be effectively integrated into standard diabetes treatment regimens without compromising safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Safety Profile of Sodium-Glucose Cotransporter-2 Inhibitors and Glucagon-like Peptide 1 Receptor Agonists in the Standard of Care Treatment of Type 2 Diabetes Mellitus. Salmen, T., Bobirca, FT., Bica, IC., et al.[2023]

Subcutaneous semaglutide (Ozempic®), a GLP-1 receptor agonist, has shown significant efficacy in improving glycemic control and reducing HbA1c, albuminuria, and blood pressure in patients with advanced diabetic kidney disease (DKD) during a 6-month follow-up study involving patients on maintenance hemodialysis.

The treatment not only aids in weight loss and appetite suppression but also helps preserve residual kidney function, potentially improving patient outcomes and facilitating their inclusion on kidney transplant waiting lists.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and Safety of Semaglutide, a Glucagon-Like Peptide-1 Receptor Agonist in Real-Life: A Case Series of Patients in Maintenance Incremental Hemodialysis. De la Flor, JC., Lorenzo, JD., Marschall, A., et al.[2022]

SGLT2 inhibitors significantly reduce the risk of acute kidney injury (RR 0.75) and show a trend towards lower severe hypoglycemia risk (RR 0.86), indicating a safety benefit in patients with chronic diseases.

However, SGLT2 inhibitors are associated with increased risks of diabetic ketoacidosis (RR 2.57), genital infections (RR 3.75), and volume depletion (RR 1.14), suggesting that these specific adverse events should be closely monitored in clinical practice.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety of four SGLT2 inhibitors in three chronic diseases: A meta-analysis of large randomized trials of SGLT2 inhibitors. Qiu, M., Ding, LL., Zhang, M., et al.[2022]

SGLT2 inhibitors, when added to metformin and sulfonylurea, significantly reduced glycated hemoglobin (HbA1c) by 0.79%, fasting plasma glucose by 1.73 mmol/L, and body weight by 1.85 kg over 52-78 weeks in a study involving 5,143 patients.

While SGLT2 inhibitors were effective in managing blood sugar and weight, they were associated with a higher incidence of hypoglycemia and genital tract infections, indicating the need for careful monitoring of side effects during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of sodium-glucose cotransporter 2 inhibitors as add-on to metformin and sulfonylurea treatment for the management of type 2 diabetes: a meta-analysis. Li, J., Shao, YH., Wang, XG., et al.[2018]

In a study of 126 overweight and obese patients with type 2 diabetes, dulaglutide (DU) showed a significant and sustained reduction in HbA1c levels over 18 months, with a mean decrease of -0.85% at 6 months, indicating its effectiveness as an add-on therapy to metformin.

Dulaglutide was associated with a higher percentage of patients achieving glycemic targets (HbA1c ≤ 7.0%) compared to liraglutide (LIRA) at 18 months, with 64.8% of DU patients reaching this target versus 42.6% for LIRA, highlighting its potential as a more effective treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical Effectiveness and Safety of Once-Weekly GLP-1 Receptor Agonist Dulaglutide as Add-On to Metformin or Metformin Plus Insulin Secretagogues in Obesity and Type 2 Diabetes. Mirabelli, M., Chiefari, E., Tocci, V., et al.[2021]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11068976/

Rationale and Design of a Phase 2, Double-blind, Placebo ... Conversely, in FSGS, AMPK-activation using metformin (MF) mitigated podocytopenia and azotemia. Observational studies also support beneficial effects of MF on ...

2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/38707807/

Rationale and Design of a Phase 2, Double-blind, Placebo ... Our phase 2 trial will provide insight into the potential efficacy and safety of MF as adjunctive therapy in FSGS-a crucial step to ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT06090227

NCT06090227 | AMPK-activation by Metformin in FSGS: ... 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 ...

4. researchgate.net researchgate.net/publication/378199940_Rationale_and_Design_of_a_of_a_Phase_2_Double-blind_Placebo-controlled_Randomized_Trial_Evaluating_AMPK-activation_by_Metformin_in_Focal_Segmental_Glomerulosclerosis

Rationale and Design of a of a Phase 2, Double-blind ... Observational studies also support beneficial effects of MF on proteinuria and chronic kidney disease (CKD) outcomes in diabetes. A randomized ...

5. tandfonline.com tandfonline.com/doi/full/10.2147/DDDT.S498457?src=

Advances in Focal Segmental Glomerulosclerosis ... FSGS patients treated with dapagliflozin exhibited a reduced rate of chronic eGFR decline, implying that this treatment may confer long-term benefits to the ...

6. sciencedirect.com sciencedirect.com/science/article/pii/S0753332221002390

Mechanism and application of metformin in kidney diseases In conclusion, metformin can alleviate AKI in various models via a series of cell events. However, the relationship between metformin and the AKI outcome ...

7. dovepress.com dovepress.com/advances-in-focal-segmental-glomerulosclerosis-treatment-from-the-pers-peer-reviewed-fulltext-article-DDDT

Advances in FSGS Treatment from the Perspective of ... Metformin (MF), an AMPK activator and mTORC1 inhibitor, is currently the subject of a Phase II clinical trial to assess its efficacy and safety ...