K-877-ER + CSG452 for NASH

Not currently recruiting at 178 trial locations

Overseen By Director, Clinical Operations

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Kowa Research Institute, Inc.

Disqualifiers: Other liver diseases, Alcohol use, others

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

Duration: 48 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a combination of two treatments, CSG452 (also known as Tofogliflozin, a type of medication) and K-877-ER, to determine their effectiveness for Nonalcoholic steatohepatitis (NASH), a liver disease. Researchers aim to discover if these treatments together can improve liver health and reduce NASH symptoms. Participants will receive either one of the treatments, both, or a placebo (a substance with no therapeutic effect). This trial suits adults diagnosed with NASH who have specific characteristics in their liver biopsies. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

Do I need to stop my current medications for this trial?

The trial information does not specify whether you need to stop taking your current medications. Please consult with the study team for guidance.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Studies have shown that CSG452, an SGLT2 inhibitor, can improve liver health in people with non-alcoholic fatty liver disease (NAFLD). This medication is promising because it aids the liver without causing many side effects. Research indicates that these drugs do not lead to more negative side effects than usual.

For K-877-ER, specific safety information is limited, but it is being studied alongside CSG452 for potential benefits in treating liver diseases like nonalcoholic steatohepatitis (NASH). This study is in an early phase, and while initial tests suggest safety, further research is necessary.

Overall, both treatments are still under investigation, but early findings about their safety are encouraging. However, joining a trial always involves some risk, so discussing any concerns with the trial team is important. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments, CSG452 and K-877-ER, for NASH (Non-Alcoholic Steatohepatitis) because they have a unique approach compared to the standard options like lifestyle changes, vitamin E, or pioglitazone. CSG452 and K-877-ER may work by targeting specific pathways involved in fat metabolism and inflammation, which are key factors in NASH progression. This targeted action could potentially slow down or even reverse liver damage more effectively than existing treatments. Additionally, K-877-ER may offer a novel mechanism by enhancing the removal of liver fat, which is a critical component in managing NASH. These innovative approaches provide hope for more effective management of this challenging condition.

What evidence suggests that this trial's treatments could be effective for NASH?

Studies have shown that CSG452, an SGLT2 inhibitor, can reduce liver fat and improve liver function. This is crucial for individuals with conditions like NASH, a liver disease characterized by fat accumulation. Research on similar drugs suggests they may help prevent liver damage. In this trial, some participants will receive CSG452 alone, while others will receive K-877-ER, another drug under investigation for its potential to improve liver health in people with NASH. Additionally, some participants will receive a combination of both CSG452 and K-877-ER, as early findings suggest that using these two drugs together might be even more effective in treating NASH. ^{1 6 7 8 9}

Who Is on the Research Team?

Shona Pendse, MD, MMSc

Principal Investigator

Kowa Research Institute, Inc.

Are You a Good Fit for This Trial?

Adults with Nonalcoholic Steatohepatitis (NASH) and liver fibrosis can join this trial. They must have a minimum score on a liver health test, not be in another study recently, and not drink significant alcohol. Other chronic liver diseases or conditions outlined in the protocol also disqualify them.

Inclusion Criteria

My liver biopsy shows a NAS of 4 or more with some steatosis, inflammation, and ballooning.

My liver fibrosis stage is between 1 and below 4.

Meet all inclusion criteria outlined in clinical study protocol

Exclusion Criteria

I have a long-term liver condition.

Does not meet any other exclusion criteria outlined in clinical study protocol

Participation in another clinical trial involving an investigational agent within 30 days prior to signing the Informed Consent Form (ICF) for this study

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive combination therapy with K-877-ER and CSG452 for the treatment of NASH

48 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• CSG452
• K-877-ER
• Placebo

Trial Overview The trial is testing two experimental drugs, K-877-ER and CSG452, against a placebo to see if they're effective for treating NASH with liver fibrosis. Participants will randomly receive either the drugs or placebo.

How Is the Trial Designed?

Group I: K-877-ER Experimental Treatment 2 Interventions

K-877-ER and CSG452 Placebo QD

Group II: K-001 Experimental Treatment 2 Interventions

K-877-ER and CSG452 Once daily (QD)

Group III: CSG452 Experimental Treatment 2 Interventions

CSG452 and K-877-ER Placebo QD

Group IV: Placebo Placebo Group 1 Intervention

Who Is Running the Clinical Trial?

Kowa Research Institute, Inc.

Lead Sponsor

Trials

46

Recruited

16,400+

Published Research Related to This Trial

In a 24-month study involving 6,897 patients with type 2 diabetes, tofogliflozin was found to be safe and well-tolerated, with low incidence rates of adverse drug reactions (11.25%) and serious adverse reactions (1.21%).

Tofogliflozin significantly reduced glycated hemoglobin A1c by -0.70% and body weight by -2.95 kg, indicating its effectiveness in managing diabetes and promoting weight loss over the observation period.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and effectiveness of tofogliflozin in Japanese patients with type 2 diabetes mellitus: Results of 24-month interim analysis of a long-term post-marketing study (J-STEP/LT). Utsunomiya, K., Kakiuchi, S., Senda, M., et al.[2022]

Tofogliflozin, a medication for type 2 diabetes, showed no clinically significant changes in its pharmacokinetics across patients with normal to severe renal impairment, suggesting it is safe for use in these populations.

While renal impairment did lead to decreased urinary glucose excretion, which may affect glycemic control, the overall safety profile remained positive, indicating no need for dose adjustments in patients with renal issues.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of Renal Impairment on the Pharmacokinetics and Pharmacodynamics of Tofogliflozin (A SELECTIVE SGLT2 Inhibitor) in Patients with Type 2 Diabetes Mellitus. Ikeda, S., Takano, Y., Schwab, D., et al.[2019]

Tofogliflozin, an oral medication for type 2 diabetes, was found to be rapidly absorbed and eliminated, with a dose-proportional increase in exposure up to 320 mg, indicating its effective pharmacokinetics in both Japanese and Caucasian subjects.

The drug was generally well tolerated with no serious adverse events or hypoglycemia reported, and it effectively increased urinary glucose excretion in a dose-dependent manner, suggesting its efficacy in managing blood sugar levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetics and Pharmacodynamics of Tofogliflozin (a Selective SGLT2 Inhibitor) in Healthy Male Subjects. Kasahara-Ito, N., Fukase, H., Ogama, Y., et al.[2022]

In a case study of a 67-year-old woman with type 2 diabetes and NASH, the SGLT2 inhibitor ipragliflozin led to significant clinical and histological improvements in liver function after four months of treatment.

Key markers of liver health, including serum ALT and fibrotic markers, returned to normal levels, and imaging studies showed a reduction in liver fat deposits, suggesting ipragliflozin could be a promising treatment for NASH.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Improvement of the Hepatic Histological Findings in a Patient with Non-alcoholic Steatohepatitis with Type 2 Diabetes after the Administration of the Sodium-glucose Cotransporter 2 Inhibitor Ipragliflozin. Takeda, A., Irahara, A., Nakano, A., et al.[2022]

In the EFFECT-II study involving 84 participants with type 2 diabetes and non-alcoholic fatty liver disease (NAFLD), the combination of dapagliflozin and omega-3 carboxylic acids significantly reduced liver fat content by 21% compared to placebo, indicating a strong therapeutic effect.

Dapagliflozin alone also demonstrated a disease-modifying effect by reducing biomarkers of hepatocyte injury, suggesting it may help improve liver health in patients with NAFLD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of dapagliflozin and n-3 carboxylic acids on non-alcoholic fatty liver disease in people with type 2 diabetes: a double-blind randomised placebo-controlled study. Eriksson, JW., Lundkvist, P., Jansson, PA., et al.[2021]

SGLT-2 inhibitors, tested in 12 randomized controlled trials involving 850 overweight or obese individuals with NAFLD, significantly reduced liver enzyme levels and liver fat content over a median treatment period of 24 weeks.

Specifically, treatment with SGLT-2 inhibitors led to a decrease in serum alanine aminotransferase by 10.0 IU/L and gamma-glutamyltransferase by 14.49 IU/L, indicating their potential efficacy in managing nonalcoholic fatty liver disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sodium-Glucose Cotransporter-2 Inhibitors for Treatment of Nonalcoholic Fatty Liver Disease: A Meta-Analysis of Randomized Controlled Trials. Mantovani, A., Petracca, G., Csermely, A., et al.[2021]

In a rodent model of non-alcoholic steatohepatitis (NASH), the SGLT2 inhibitor luseogliflozin significantly improved glucose levels and reduced liver damage caused by a high-fat diet, indicating its potential efficacy in treating NASH.

Luseogliflozin not only decreased liver weight gain and lipid accumulation but also normalized fibrotic changes and inflammatory responses in the liver, suggesting it could be a promising treatment for NASH associated with diabetes in humans.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment with the SGLT2 inhibitor luseogliflozin improves nonalcoholic steatohepatitis in a rodent model with diabetes mellitus. Qiang, S., Nakatsu, Y., Seno, Y., et al.[2022]

In a study of 107 patients with nonalcoholic steatohepatitis (NASH), the 150 mg dose of licogliflozin resulted in a significant 32% reduction in serum alanine aminotransferase levels after 12 weeks, indicating its potential efficacy in treating NASH.

While licogliflozin was generally well-tolerated, diarrhea was reported in a majority of patients, particularly at the higher dose, suggesting that while the drug shows promise, its side effects need to be monitored in future studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Licogliflozin for nonalcoholic steatohepatitis: a randomized, double-blind, placebo-controlled, phase 2a study. Harrison, SA., Manghi, FP., Smith, WB., et al.[2023]

A 60-year-old woman with type 2 diabetes and diagnosed non-alcoholic steatohepatitis (NASH) showed significant improvement in liver function and glycemic control after 15 months of treatment with luseogliflozin, an SGLT2 inhibitor.

The treatment led to better liver enzyme levels and histological improvements in liver biopsies, suggesting that luseogliflozin could be a promising long-term therapy for patients with diabetes-related liver diseases like NAFLD/NASH.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term luseogliflozin therapy improves histological activity of non-alcoholic steatohepatitis accompanied by type 2 diabetes mellitus. Fujimori, N., Tanaka, N., Kimura, T., et al.[2022]

Dapagliflozin, a sodium-glucose cotransporter-2 inhibitor, significantly improved nonalcoholic steatohepatitis (NASH) in db/db mice over a 12-week treatment period, as indicated by decreased liver enzymes and NAFLD activity scores.

The drug works by reducing lipid accumulation, inflammation, and fibrosis in the liver, suggesting it could be a potential treatment option for NASH in humans.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dapagliflozin protects against nonalcoholic steatohepatitis in db/db mice. Qiao, P., Jia, Y., Ma, A., et al.[2022]

Sodium-glucose cotransporter 2 inhibitors (SGLT2-i) have shown efficacy in improving liver conditions like non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) in patients with type 2 diabetes mellitus (T2DM), based on a systematic review of 21 randomized controlled trials.

These medications, including dapagliflozin, empagliflozin, and canagliflozin, work by enhancing insulin sensitivity, promoting weight loss, and reducing glucotoxicity and lipotoxicity, leading to significant improvements in liver health markers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Effects of Sodium-Glucose Cotransporter 2-Inhibitors on Steatosis and Fibrosis in Patients with Non-Alcoholic Fatty Liver Disease or Steatohepatitis and Type 2 Diabetes: A Systematic Review of Randomized Controlled Trials. Bica, IC., Stoica, RA., Salmen, T., et al.[2023]

In a study involving obese and diabetic mice, the sodium glucose cotransporter 2 inhibitor tofogliflozin significantly reduced the development of liver tumors and improved liver health by decreasing hepatic steatosis and inflammation.

Tofogliflozin showed potential as a chemopreventive agent against obesity-related liver cancer by lowering pro-inflammatory markers and serum glucose levels, although it did not inhibit the growth of liver cancer cells directly.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preventive effects of the sodium glucose cotransporter 2 inhibitor tofogliflozin on diethylnitrosamine-induced liver tumorigenesis in obese and diabetic mice. Obara, K., Shirakami, Y., Maruta, A., et al.[2018]

Tofogliflozin, an oral medication for type 2 diabetes, works by promoting glucose excretion in urine without being affected by other common anti-diabetes drugs, indicating its unique mechanism of action.

In a study involving 108 healthy male volunteers, tofogliflozin did not alter the effectiveness or safety of other diabetes medications, suggesting it can be safely combined with them without adverse interactions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Pharmacokinetic/Pharmacodynamic Drug-Drug Interaction Study of Tofogliflozin (a New SGLT2 Inhibitor) and Selected Anti-Type 2 Diabetes Mellitus Drugs. Kasahara, N., Fukase, H., Ohba, Y., et al.[2018]

Canagliflozin is effective in improving glycemic control in adults with type 2 diabetes, specifically by inhibiting SGLT2 to increase urinary glucose excretion, with a focus on patients having a baseline eGFR of 45 mL/min/1.73 m² or higher.

The safety analyses conducted during the clinical development of canagliflozin provided a comprehensive understanding of its impact on renal function, allowing for informed dosing recommendations in patients with renal impairment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Canagliflozin use in patients with renal impairment-Utility of quantitative clinical pharmacology analyses in dose optimization. Khurana, M., Vaidyanathan, J., Marathe, A., et al.[2022]

Citations

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Preventive effects of the sodium glucose cotransporter 2 ... In this study, we investigated the effects of the sodium glucose cotransporter 2 inhibitor tofogliflozin on the development of non-alcoholic fatty liver disease ...

2. sciencedirect.com sciencedirect.com/science/article/pii/S0753332221005205

The sodium-glucose cotransporter-2 inhibitor Tofogliflozin ... This study provides a unique animal model of NASH-associated liver tumors, which is applicable for assessing drug efficacy to prevent or treat NASH-associated ...

3. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/34029949/

The sodium-glucose cotransporter-2 inhibitor Tofogliflozin ... This study provides a unique animal model of NASH-associated liver tumors, which is applicable for assessing drug efficacy to prevent or treat ...

4. researchgate.net researchgate.net/publication/351853660_The_sodium-glucose_cotransporter-2_inhibitor_Tofogliflozin_prevents_the_progression_of_nonalcoholic_steatohepatitis-associated_liver_tumors_in_a_novel_murine_model

The sodium-glucose cotransporter-2 inhibitor Tofogliflozin ... This study provides a unique animal model of NASH-associated liver tumors, which is applicable for assessing drug efficacy to prevent or treat ...

5. asploro.com asploro.com/hepatoprotective-effect-of-sglt2-inhibitor-on-nonalcoholic-fatty-liver-disease/

Hepatoprotective Effect of SGLT2 Inhibitor on Nonalcoholic ... NAFLD patients with type 2 diabetes can be indicated for SGLT2 inhibitor, because they are obese, have insulin resistance, and at high risk of cardiovascular ...

6. sciencedirect.com sciencedirect.com/science/article/pii/S1590865821007337

Meta-Analysis The safety and efficacy evaluation of sodium ... SGLT2is seem to be a promising treatment for patients with NAFLD to improve metabolic and fibrosis indexes without increasing the incidence of adverse events.

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8953901/

SGLT-2 Inhibitors in NAFLD: Expanding Their Role beyond ... In this review, we summarize the current understanding of the NAFLD pathophysiology, and specifically focus on the potential impact of SGLT-2i in NAFLD ...

8. trialx.com trialx.com/clinical-trials/listings/243296/efficacy-and-safety-of-dapagliflozin-in-patients-with-non-alcoholic-steatohepatitis/

Efficacy and Safety of Dapagliflozin in Patients With Non- ... Patients with non-alcoholic fatty liver disease (NAFLD) are at increased risk of more aggressive liver disease; non-alcoholic steatohepatitis ( ...

9. mdpi.com mdpi.com/1648-9144/59/6/1136

The Effects of Sodium-Glucose Cotransporter 2-Inhibitors ... This systematic review offers encouraging results that place the SGLT2-i class at the top of the therapeutic arsenal for patients diagnosed with T2DM and NAFLD ...