PHMB + Topical Corticosteroids for Acanthamoeba Keratitis

(PUTT Trial)

Recruiting at 17 trial locations

Overseen By Krisi Aromin

Age: Any Age

Sex: Any

Trial Phase: Phase 3

Sponsor: Jeremy Keenan, MD, MPH

Must not be taking: Systemic corticosteroids

Disqualifiers: Interstitial keratitis, Herpetic keratitis, Fungal keratitis, others

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

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

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 4 weeks

232 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine if adding a specific type of eye medication, topical corticosteroids, can improve vision for people with acanthamoeba keratitis (AK), an eye infection causing severe pain and vision problems. Participants will be divided into two groups: one will receive the corticosteroid treatment, and the other will receive a placebo, a harmless substance with no treatment effect. Ideal candidates are those diagnosed with AK who still experience eye inflammation after a month of anti-amoebic treatment. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants a chance to contribute to potentially groundbreaking treatment advancements.

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 currently on systemic corticosteroids.

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

Research has shown that using certain steroid creams or ointments for some eye infections, such as herpetic keratitis, is usually safe when combined with the appropriate treatment. For acanthamoeba keratitis, one study found that starting steroid treatment after anti-amoebic medication did not worsen the condition, suggesting general safety. However, another study identified issues when steroids were used for infections unresponsive to antibiotics. While evidence indicates these treatments can be safe in specific cases, careful and correct use is crucial. ^{1 2 3 4 5}

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

Researchers are excited about using PHMB (polyhexamethylene biguanide) combined with topical corticosteroids for treating Acanthamoeba keratitis because this approach may enhance anti-amoebic therapy effectiveness. Unlike the standard treatment options, which often rely solely on anti-amoebic agents like biguanides or diamidines, the addition of corticosteroids aims to reduce inflammation and potentially accelerate recovery. This combination could offer a more comprehensive treatment by not only targeting the infection but also controlling the inflammation, which is a significant challenge in managing this eye condition.

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

This trial will compare topical steroids with a topical placebo alongside anti-amoebic therapy for treating acanthamoeba keratitis (AK), a serious eye infection. Research has shown that using steroid creams or drops with anti-amoebic treatment may aid recovery from AK. In one study, 73.7% of patients using steroid drops were cured after receiving anti-amoebic treatment. Another study found that outcomes improved by 1.59 times for those who included steroids in their treatment. However, using steroids before an AK diagnosis can worsen vision because AK is often mistaken for other eye conditions early on. Overall, when used correctly and at the right time, steroids appear to help in treating AK. ^{3 6 7 8 9}

Who Is on the Research Team?

Jeremy Keenan, MD, MPH

Principal Investigator

Proctor Foundation, UCSF

Gerami Seitzman, MD

Principal Investigator

Proctor Foundation, UCSF

Are You a Good Fit for This Trial?

This trial is for patients with a parasitic eye infection called Acanthamoeba Keratitis, who still have inflammation after 4 weeks of initial treatment. They must not have other types of keratitis, corneal perforation, previous eye surgery for this condition, severe vision loss in the affected eye, steroid allergies or reactions, or be on systemic steroids.

Inclusion Criteria

I have eye inflammation after a month of treatment for an amoeba infection.

AK on at least one of the following: culture, smear, PCR, shotgun sequencing, biopsy, or confocal microscopy

Exclusion Criteria

I am currently taking corticosteroids.

My eye's cornea is at risk of or has a hole.

I have a brain infection caused by amoebas.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive anti-amoebic therapy and are randomized to receive either topical corticosteroids or placebo

4 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment, including assessments of visual acuity and ocular health

6 months

Extended Follow-up

Participants are monitored for long-term outcomes such as clinical resolution and absence of inflammation

12 months

What Are the Treatments Tested in This Trial?

Interventions

• Topical corticosteroid

Trial Overview The PUTT aims to see if adding topical corticosteroids to the usual treatment improves vision in those with Acanthamoeba Keratitis and persistent inflammation. Participants will be randomly assigned to either receive a corticosteroid or a placebo eyedrop.

How Is the Trial Designed?

Group I: Topical steroids Experimental Treatment 2 Interventions

Participants in this arm will receive anti-amoebic therapy plus topical steroids.

Group II: Topical placebo Placebo Group 2 Interventions

Participants in this arm will receive anti-amoebic therapy plus topical placebo.

Topical corticosteroid is already approved in European Union, United States, Canada for the following indications:

Approved in European Union as Topical corticosteroids for:

• eczema
• contact dermatitis
• psoriasis
• atopic eczema
• seborrheic dermatitis
• stasis dermatitis
• intertrigo
• perianal inflammation

Approved in United States as Topical corticosteroids for:

• eczema
• contact dermatitis
• psoriasis
• atopic eczema
• seborrheic dermatitis
• stasis dermatitis
• intertrigo
• perianal inflammation

Approved in Canada as Topical corticosteroids for:

• eczema
• contact dermatitis
• psoriasis
• atopic eczema
• seborrheic dermatitis
• stasis dermatitis
• intertrigo
• perianal inflammation

Who Is Running the Clinical Trial?

Jeremy Keenan, MD, MPH

Lead Sponsor

Trials

1

Recruited

230+

Johns Hopkins University

Collaborator

Trials

2,366

Recruited

15,160,000+

University of Miami

Collaborator

Trials

976

Recruited

423,000+

Oregon Health and Science University

Collaborator

Trials

1,024

Recruited

7,420,000+

National Eye Institute (NEI)

Collaborator

Trials

572

Recruited

1,320,000+

University of Illinois at Chicago

Collaborator

Trials

653

Recruited

1,574,000+

University of California, Los Angeles

Collaborator

Trials

1,594

Recruited

10,430,000+

University of Pennsylvania

Collaborator

Trials

2,118

Recruited

45,270,000+

Columbia University

Collaborator

Trials

1,529

Recruited

2,832,000+

University of Iowa

Collaborator

Trials

486

Recruited

934,000+

Published Research Related to This Trial

Topical corticosteroids, specifically betamethasone sodium phosphate (BSP), can worsen Acanthamoeba keratitis (AK) in rabbits when the cornea is infected with a significant number of bacteria, indicating a potential risk factor for this condition.

Using corticosteroids after Acanthamoeba infection has begun, especially in the presence of low bacterial counts, can lead to severe keratitis, suggesting that timing and bacterial load are critical factors in the management of AK.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Corticosteroid eye drop instillation aggravates the development of Acanthamoeba keratitis in rabbit corneas inoculated with Acanthamoeba and bacteria. Nakagawa, H., Koike, N., Ehara, T., et al.[2021]

In a study comparing various topical corticosteroids, fluocortin butylester (FCB) demonstrated significantly fewer dermal and systemic side effects compared to clobetasone and hydrocortisone formulations.

The study utilized a specialized apparatus to ensure that the drugs were absorbed only through the skin, confirming that side effects were not due to oral ingestion of the medications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Dermal and systemic side effects of fluocortin butylester. Comparative skin tearing experiments with active principles from commercial preparations]. Kapp, JF., Gliwitzki, B., Josefiuk, P., et al.[2013]

Prolonged use of very potent topical corticosteroids, like Clobetasol, can lead to serious systemic side effects such as Cushing's syndrome and HPA axis suppression, particularly in children, with 43 reported cases over 35 years.

In a specific case, an 8-month-old infant developed Cushing's syndrome from inappropriate use of Clobetasol for diaper dermatitis, highlighting the risks of unsupervised steroid use; recovery from HPA axis suppression took about 3.5 months after treatment with hydrocortisone.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Exogenous Cushing's syndrome due to topical corticosteroid application: case report and review literature. Tempark, T., Phatarakijnirund, V., Chatproedprai, S., et al.[2021]

In a study of 196 patients with Acanthamoeba keratitis, the use of topical corticosteroids after starting antiamoebic therapy did not lead to worse outcomes, suggesting they can be safely used to manage inflammation without negatively impacting recovery.

However, prior use of corticosteroids before starting antiamoebic therapy was linked to worse outcomes, highlighting the importance of timing in corticosteroid use during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Impact of Topical Corticosteroids Used in Conjunction with Antiamoebic Therapy on the Outcome of Acanthamoeba Keratitis. Carnt, N., Robaei, D., Watson, SL., et al.[2022]

A study identified 10 cases of contact dermatitis caused by topical corticosteroids through patch testing, revealing that individual sensitivity plays a crucial role in reactions to these medications.

Further testing showed that most patients had sensitivities to multiple corticosteroids, suggesting that a comprehensive corticosteroid series should be conducted for anyone with known sensitivity to help prevent adverse reactions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Contact allergies to topical corticosteroids: 10 cases of contact dermatitis. Dunkel, FG., Elsner, P., Burg, G.[2019]

In a study involving six patients with Acanthamoeba keratitis who did not respond to conventional treatments, PHMB 0.02% was used and resulted in complete resolution of inflammation in 5 out of 6 cases, indicating its efficacy as a new treatment option.

PHMB was found to be cysticidal at low concentrations against Acanthamoeba, and it showed no toxicity to the ocular surface, making it a safer alternative compared to other treatments like propamidine and neomycin.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of Acanthamoeba keratitis with polyhexamethylene biguanide. Larkin, DF., Kilvington, S., Dart, JK.[2022]

Mometasone furoate is a highly potent topical corticosteroid that demonstrates greater anti-inflammatory activity and a longer duration of action compared to betamethasone, making it effective for various indications in both adults and children.

It has a low risk of local and systemic adverse effects due to its low systemic availability and rapid metabolism, which means it does not significantly impact the hypothalamic-pituitary-adrenal axis, making it a safer option for long-term use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparative safety and efficacy of topical mometasone furoate with other topical corticosteroids. Spada, F., Barnes, TM., Greive, KA.[2018]

In a study of 38 patients with Acanthamoeba keratitis, those diagnosed within one month of symptom onset had a higher chance of being cured with medical therapy alone, highlighting the importance of early diagnosis (p = 0.02).

Topical corticosteroids did not increase the failure rate of medical treatment for Acanthamoeba keratitis; in fact, they can be safely used in patients with severe symptoms, as long as they are selected carefully.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The role of topical corticosteroids in the management of Acanthamoeba keratitis. Park, DH., Palay, DA., Daya, SM., et al.[2022]

A 44-year-old woman with Acanthamoeba keratitis achieved successful treatment and improved vision (6/9) through medical management.

The case suggests that tapering off topical corticosteroids too quickly during treatment may lead to flare-ups of inflammatory keratitis, indicating the need for a very gradual withdrawal to prevent immune reactions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Steroid sensitive Acanthamoeba keratitis. Horsburgh, B., Hirst, LW., Carey, T., et al.[2019]

Three cases of Acanthamoeba keratitis with fungal infection were successfully treated using a combination of polyhexamethylene biguanide (PHMB), fluconazole, and anegyn eye drops, demonstrating the efficacy of this aggressive treatment approach.

All patients underwent therapeutic penetrating keratoplasty after infection control, resulting in good visual outcomes for two patients, highlighting the importance of early diagnosis and prompt treatment in preventing severe complications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of Acanthamoeba keratitis combined with fungal infection with polyhexamethylene biguanide. Tien, SH., Sheu, MM.[2016]

Newer topical corticosteroids, such as budesonide and mometasone furoate, show higher anti-inflammatory effects and better patient compliance due to their once-daily application, while minimizing the risk of adverse effects compared to older agents.

Fifth-generation corticosteroids like betamethasone dipropionate and clobetasol propionate are effective but carry a higher risk of both topical and systemic side effects, highlighting the need for ongoing development of safer alternatives.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New and established topical corticosteroids in dermatology: clinical pharmacology and therapeutic use. Brazzini, B., Pimpinelli, N.[2018]

Topical corticosteroid use before the diagnosis of Acanthamoeba keratitis (AK) significantly increases the risk of suboptimal visual outcomes, with an odds ratio of 3.90, indicating a strong association with poorer vision after treatment.

Factors such as older age (60+ years) and advanced disease stage at presentation also predict worse visual outcomes, highlighting the importance of accurate diagnosis and caution in using corticosteroids for keratitis in contact lens users.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The impact of topical corticosteroid use before diagnosis on the outcome of Acanthamoeba keratitis. Robaei, D., Carnt, N., Minassian, DC., et al.[2016]

In a study of seven patients with Acanthamoeba keratitis, six were successfully cured using a prolonged and intensive triple antiamoebic therapy, highlighting the efficacy of this treatment approach.

The use of triple therapy, which included neomycin-polymyxin B-gramicidin, propamidine isethionate, and miconazole nitrate, proved effective even in advanced cases, suggesting it may be a promising option for managing this serious eye infection.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Successful medical management of Acanthamoeba keratitis. Berger, ST., Mondino, BJ., Hoft, RH., et al.[2022]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/9143798/

The role of topical corticosteroids in the management ... Fourteen (73.7%) of 19 patients treated with topical corticosteroids at any time were cured after antiamoebal therapy alone, whereas five (26.3%) patients ...

2. sciencedirect.com sciencedirect.com/science/article/pii/S1542012425000527

Acanthamoeba keratitis treatment outcomes compared for ... The unadjusted outcomes for both centres combined showed significantly improved outcomes for per-protocol treatment with a 1.59-fold improvement in MCR_12 (95 % ...

3. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/24630688/

The impact of topical corticosteroid use before diagnosis ... Corticosteroid use before diagnosis of AK is highly predictive of a poorer visual outcome. This is largely due to the initial misdiagnosis of AK as herpetic ...

4. aaojournal.org aaojournal.org/article/s0161-6420(14)00093-1/fulltext

The Impact of Topical Corticosteroid Use before Diagnosis ... The outcomes of patients treated with topical corticosteroids before diagnosis of AK were compared with those not treated with topical ...

5. sciencedirect.com sciencedirect.com/science/article/pii/S2950253524000959

Clinical and management factors linked to good visual ... Patients who used corticosteroids before the diagnosis of AK were approximately 82 % less likely to achieve a final CDVA of 20/25 or better than ...

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/38112645/

Steroids in the Management of Infectious Keratitis - PubMed Randomized trials have found that corticosteroids are safe and effective for herpetic keratitis when used with appropriate antiviral therapy, ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11989993/

Acanthamoeba Keratitis Management and Prognostic Factors All were given PHMB 0.02% eye drops, gradually tapered according to the response to treatment, presenting a cure rate of 63.6% (7 out of 11 eyes) ...

8. sciencedirect.com sciencedirect.com/science/article/abs/pii/S1367048423003673

Clinical outcomes and prognostic factors in Acanthamoeba ... Carnt et al. reported that medical treatment with topical corticosteroids is not associated with worse outcomes when initiated after starting antiamoebic ...

9. tandfonline.com tandfonline.com/doi/full/10.2147/OPTH.S297202

Topical Corticosteroids for Infectious Keratitis Before ... Our findings show that it is harmful to apply topical corticosteroids for keratitis that does not respond to empirical antibiotic therapy, ...