Ripasudil for Fuchs' Dystrophy

Overseen By Michael D Straiko, M.D.

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Michael D. Straiko, MD

Must be taking: Rho kinase inhibitors

Disqualifiers: Uncontrolled glaucoma, Secondary corneal pathology, others

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

Approved in 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 3

Duration: 2-4 weeks

72 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine if Ripasudil eye drops can accelerate corneal healing after DMEK surgery, a procedure for treating Fuchs' Dystrophy, which affects the eye's clear outer layer. Ripasudil, already used in Japan for glaucoma, may speed recovery and reduce complications post-surgery. Participants will receive either Ripasudil or a placebo to compare outcomes. Individuals diagnosed with Fuchs' Dystrophy and experiencing vision issues may be suitable for this study. As a Phase 2 trial, this research focuses on evaluating the treatment's effectiveness in an initial, smaller group, offering participants a chance to contribute to potential advancements in eye care.

Do I have to stop taking my current medications for the trial?

The trial protocol does not specify whether you need to stop taking your current medications. However, if you have uncontrolled glaucoma (IOP >25 mmHg) or have had certain types of glaucoma surgery, you may not be eligible to participate.

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

Research has shown that Ripasudil, a medication used in Japan since 2014, is safe for treating glaucoma. This long-term use indicates it is well-tolerated. In other studies, Ripasudil was used after certain eye surgeries and produced good results without major safety issues. For example, one study found that individuals using Ripasudil experienced less corneal damage compared to those who did not. Another trial combined Ripasudil with a procedure called Descemet Stripping Only, and both local and overall body safety were carefully monitored, supporting its role as a safe treatment. Overall, these findings suggest that Ripasudil is generally safe for use in eye conditions. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for Fuchs' Dystrophy?

Most treatments for Fuchs' Dystrophy, like corneal transplants, focus on replacing damaged tissue. But Ripasudil eye drops work differently, targeting the cellular level by inhibiting a protein called Rho kinase. This approach aims to improve the health of corneal cells and reduce the need for invasive surgery. Researchers are excited because Ripasudil might offer a non-surgical alternative that could be quicker and more convenient for patients, with the potential to stabilize or even improve vision in just weeks.

What evidence suggests that Ripasudil might be an effective treatment for Fuchs' Dystrophy?

Research has shown that ripasudil, a type of medication, may help treat Fuchs' dystrophy by protecting and healing the cornea. In this trial, participants will receive either ripasudil (Glanatec) or a placebo control. Studies have found that eyes treated with ripasudil experienced significantly less cell loss. In one study, the number of healthy cells in the cornea increased after treatment. Ripasudil is believed to aid healing by improving cell health in the eye. It has also proven effective in other eye conditions, particularly in reducing cell damage. This suggests ripasudil might be promising for Fuchs' dystrophy patients after surgery. ^{1 2 3 5 6}

Who Is on the Research Team?

Michael Straiko, MD

Principal Investigator

Devers Eye Institute

Are You a Good Fit for This Trial?

This trial is for people with Fuchs' Dystrophy, specifically grades 2-5 on the Krachmer scale. Participants must have decreased vision primarily due to central guttae or stromal edema and a visual acuity of 20/40 or worse. They can be phakic or pseudophakic with certain types of lens implants.

Inclusion Criteria

The peripheral cornea to the central 6mm is devoid of guttata changes

My vision loss is mainly due to corneal swelling.

Phakic or pseudophakic with posterior capsule supported, suture-fixated, or sulcus-supported posterior chamber intraocular lens

Exclusion Criteria

I have an eye infection or an autoimmune condition affecting my cornea.

I have had a cornea transplant before.

History of herpes simplex virus or cytomegalovirus keratitis

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either Glanatec eye drops or Optive artificial tears 6 times per day for 2-4 weeks following DMEK surgery

2-4 weeks

Regular visits for monitoring during treatment

Follow-up

Participants are monitored for safety and effectiveness after treatment, including endothelial cell density, post-surgery complications, and visual acuity

6 months

Specular imaging and visual acuity tests at 3 and 6 months

What Are the Treatments Tested in This Trial?

Interventions

• Ripasudil

Trial Overview The study tests Ripasudil (Glanatec ophthalmic solution) used after Descemet Membrane Endothelial Keratoplasty (DMEK) surgery in Fuchs' Dystrophy patients. The aim is to see if it speeds up corneal clearing and reduces post-op complications compared to standard treatment.

How Is the Trial Designed?

Group I: Glanatec Experimental Treatment 2 Interventions

Glanatec eye drops will be administered 6x per day for 2-4 weeks

Group II: Placebo Control Placebo Group 2 Interventions

Optive artificial tears will be administered 6x per day for 2-4 weeks

Who Is Running the Clinical Trial?

Michael D. Straiko, MD

Lead Sponsor

Trials

1

Recruited

70+

Eye Bank Association of America

Collaborator

Trials

2

Recruited

1,200+

Lions VisionGift Research

Collaborator

Trials

2

Recruited

120+

Published Research Related to This Trial

In a study involving mdx mice, a model for Duchenne muscular dystrophy (DMD), treatment with racemic halofuginone improved motor coordination and reduced muscle fibrosis, with the (+)-halofuginone enantiomer showing even greater benefits.

The treatment led to significant reductions in collagen content and muscle degeneration, as well as increased muscle fiber size, highlighting the potential of (+)-halofuginone as an effective antifibrotic therapy for DMD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Differential Effects of Halofuginone Enantiomers on Muscle Fibrosis and Histopathology in Duchenne Muscular Dystrophy. Mordechay, S., Smullen, S., Evans, P., et al.[2021]

Halofuginone significantly reduced fibrosis-related parameters in mdx mice, indicating its potential as an effective treatment for fibrosis in Duchenne muscular dystrophy (DMD).

The study found that the hydroxy group in halofuginone is crucial for its anti-fibrotic effects, suggesting that modifications to its structure could lead to the development of more effective and safer therapies for DMD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hydroxy group requirement for halofuginone-dependent inhibition of muscle fibrosis and improvement of histopathology in the mdx mouse model for Duchenne muscular dystrophy. Wellner, G., Mordechay, S., Evans, P., et al.[2019]

Cthrc1 is identified as a significant marker in the progression of muscular dystrophies, showing high levels in both mouse models and human patients with Duchenne muscular dystrophy (DMD), indicating its potential role in disease severity.

The study suggests that targeting Cthrc1 could be a therapeutic strategy, as reducing its levels with halofuginone in mouse models led to decreased collagen levels and may influence muscle fibrosis associated with dystrophies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The involvement of collagen triple helix repeat containing 1 in muscular dystrophies. Spector, I., Zilberstein, Y., Lavy, A., et al.[2013]

Fluorine substituents on ibutilide analogues improved metabolic stability and maintained their ability to enhance cardiac tissue refractoriness, which is important for antiarrhythmic activity.

The S-enantiomers of these compounds showed lower proarrhythmic potential compared to their racemic counterparts, with one compound, trecetilide fumarate, demonstrating excellent antiarrhythmic efficacy and safety in a rabbit model, making it a candidate for further development.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Progress toward the development of a safe and effective agent for treating reentrant cardiac arrhythmias: synthesis and evaluation of ibutilide analogues with enhanced metabolic stability and diminished proarrhythmic potential. Hester, JB., Gibson, JK., Buchanan, LV., et al.[2019]

In a study of 13 patients on long-term flecainide therapy, the R-(-)-enantiomer was found to have significantly higher plasma levels than the S-(+)-enantiomer, indicating enantioselective disposition of the drug.

Both enantiomers of flecainide produced similar effects on cardiac action potentials, suggesting that using a single enantiomer instead of the racemic mixture would not provide any therapeutic advantage.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Flecainide enantiomers: disposition in human subjects and electrophysiologic actions in vitro. Kroemer, HK., Turgeon, J., Parker, RA., et al.[2019]

In a study of 46 fetuses with tachyarrhythmia, flecainide was found to be highly effective, converting 81.2% of treated fetuses to sinus rhythm within a median time of 3 days, regardless of whether they had hydrops or not.

Flecainide should be considered as a first-line therapy for fetal supraventricular tachycardia, as it demonstrated similar efficacy in both hydropic (72% conversion) and nonhydropic (90% conversion) fetuses, with no significant differences in outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

High-dose flecainide is the most effective treatment of fetal supraventricular tachycardia. Strizek, B., Berg, C., Gottschalk, I., et al.[2022]

Pilsicainide hydrochloride demonstrated a greater efficacy in suppressing ventricular arrhythmias compared to disopyramide, with effective doses being lower for pilsicainide (2.5 and 5 mg/kg) than for disopyramide (5 mg/kg).

Pilsicainide caused less QTc prolongation at effective plasma concentrations compared to disopyramide, suggesting it may have a safer profile regarding the risk of lethal arrhythmias like torsades de pointes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Antiarrhythmic effects of pilsicainide hydrochloride and effects on cardiac function and ECG in dogs: comparison with disopyramide]. Hidaka, T., Inoue, T., Komoriya, K., et al.[2019]

Pip6a-PMO, a cell-penetrating peptide-mediated delivery system for PMOs, shows high efficiency in delivering therapeutic agents for exon-skipping in Duchenne Muscular Dystrophy (DMD), with a low nanomolar effective concentration (EC50).

The study reveals that Pip6a-PMO uptake occurs through different endocytosis pathways in skeletal muscle cells and cardiomyocytes, which may explain the varying effectiveness of exon-skipping therapy in these tissues.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cellular trafficking determines the exon skipping activity of Pip6a-PMO in mdx skeletal and cardiac muscle cells. Lehto, T., Castillo Alvarez, A., Gauck, S., et al.[2022]

In a safety evaluation of tocainide involving 369 patients with life-threatening ventricular arrhythmias, the drug was found to have a favorable risk-benefit ratio, with adverse effects primarily being transient neurological and gastrointestinal issues.

Despite some patients experiencing side effects leading to discontinuation (16%), there was no evidence of permanent organ injury, and routine lab tests showed no significant abnormalities, indicating tocainide's overall safety in emergency use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety evaluation of tocainide in the American Emergency Use Program. Horn, HR., Hadidian, Z., Johnson, JL., et al.[2019]

In a study involving eight conscious beagle dogs, ibutilide and its R- and S-enantiomers were found to similarly prolong the QTc interval, a key indicator of antiarrhythmic activity, without causing significant changes in mean arterial pressure or heart rate.

All forms of ibutilide were well tolerated, showing no adverse effects like enhanced ventricular ectopy, which supports the safety profile of racemic ibutilide as a promising candidate for treating arrhythmias.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cardiovascular effects of the R- and S-enantiomers of ibutilide in conscious beagle dogs. Humphrey, SJ., Smith, MP., Hsu, CY., et al.[2019]

In a study of 10 chronic hemodialysis patients, a 25 mg dose of pilsicainide hydrochloride effectively reduced supraventricular premature contractions (SVPC) by over 90% while maintaining plasma concentrations within the therapeutic range during a 6-month follow-up.

Despite some patients experiencing elevated plasma concentrations leading to dosage adjustments, no adverse effects were observed in electrocardiography, echocardiography, or biochemistry, indicating the treatment's safety in this population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Appropriate dosing of pilsicainide hydrochloride in patients on hemodialysis. Matsumoto, M., Fujii, Z., Kawata, Y., et al.[2017]

A young, healthy individual experienced life-threatening polymorphous ventricular tachycardia after ingesting a dangerously high dose of 3800 mg of flecainide acetate, which is significantly above the therapeutic range.

The patient's sinus rhythm was restored using a combination of a beta-sympathomimetic agent and sodium load, highlighting the importance of monitoring drug levels and the effectiveness of specific interventions in managing flecainide toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Life-threatening flecainide toxicity. A pharmacodynamic approach. Winkelmann, BR., Leinberger, H.[2019]

In a study involving older mdx dystrophic mice treated with halofuginone (Halo) for up to 12 weeks, the treatment significantly reduced fibrosis and collagen expression in muscle tissues, indicating its potential to improve muscle health.

Halo treatment also led to marked improvements in cardiac and respiratory function, suggesting it could be an effective therapeutic option to reduce complications associated with Duchenne muscular dystrophy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Functional resolution of fibrosis in mdx mouse dystrophic heart and skeletal muscle by halofuginone. Huebner, KD., Jassal, DS., Halevy, O., et al.[2020]

An 88-year-old man developed ventricular tachycardia due to pilsicainide toxicity, highlighting the risks of this medication in elderly patients with cardiac and renal dysfunction.

Treatment with fluid infusion and continuous hemodiafiltration effectively reduced the serum pilsicainide level, leading to improvements in both electrocardiographic findings and the patient's condition, suggesting that monitoring serum levels and ECG changes is crucial in managing toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A case of the toxicity of pilsicainide hydrochloride with comparison of the serial serum pilsicainide levels and electrocardiographic findings. Horita, Y., Kanaya, H., Uno, Y., et al.[2019]

In a study of 12 patients with frequent ventricular premature complexes (VPCs), recainam hydrochloride showed significant antiarrhythmic efficacy, particularly at a dose of 1,500 mg/day, which resulted in a 79% reduction in VPCs and substantial suppression of repetitive beats.

The treatment was generally safe, with minimal noncardiac adverse reactions reported, and responders to the medication had higher plasma concentrations of recainam compared to nonresponders, indicating a potential dose-response relationship.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of recainam, a new antiarrhythmic drug, for control of ventricular arrhythmias. Anderson, JL., Anastasiou-Nana, MI., Heath, BM., et al.[2019]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/39946654/

Efficacy of the Rho-Kinase Inhibitor for Corneal Endothelial ... Results: There was significantly less cell loss among those eyes treated with ripasudil. C-ECD significantly increased from a baseline of 2361 ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT03813056

Study Details | NCT03813056 | Ripasudil for Enhanced ... The goal of this study is to test the potential benefits of Ripasudil therapy administered after Descemet Membrane Endothelial Keratoplasty (DMEK) surgery. We ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8423139/

A Close Look at the Clinical Efficacy of Rho-Associated ... ROCK-inhibitor eye drops may eventually be deemed a cutting-edge therapy for Fuchs endothelial corneal dystrophy patients with acute corneal endothelial defect.

4. sciencedirect.com sciencedirect.com/science/article/pii/S2451993623000476

Twelve-year outcome of Rho-associated protein kinase ... The purpose of this case report is to present the long-term outcome of the treatment by ROCK inhibitor eye drops and trans-corneal freezing of damaged CECs.

5. aao.org aao.org/education/editors-choice/rock-inhibitor-may-help-protect-cornea-post-phaco-

A ROCK Inhibitor May Help Protect the Cornea Post-Phaco ... Three-month paracentral ECD loss was also lower in the ripasudil group (0.4%) than in the control group (7.3%), though this difference did not ...

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/32740006/

Descemet Stripping Only Supplemented With Topical ... This trial of DSO supplemented with ripasudil included local and systemic safety analysis. We judge that this treatment option is emerging ...