PHMB + Topical Corticosteroids for Acanthamoeba Keratitis

(PUTT Trial)

Recruiting at 14 trial locations

Overseen By Gerami Seitzman, MD

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

Trial Summary

What is the purpose of this trial?

The Parasitic Ulcer Treatment Trial (PUTT) is a multi-center, parallel-group, randomized clinical trial. The purpose of this study is to determine whether including topical corticosteroids in a regimen for acanthamoeba keratitis (AK) will improve vision. Patients presenting to all enrollment centers with evidence of acanthamoeba keratitis will be eligible for the trial if there is evidence of ocular inflammation after 4 weeks of anti-amoebic therapy. Those who agree to participate will be randomized to one of two treatment groups: * Group 1: Topical corticosteroid * Group 2: Topical placebo

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.

What data supports the effectiveness of the drug PHMB + Topical Corticosteroids for Acanthamoeba Keratitis?

The research suggests that while topical corticosteroids can be part of a treatment plan for Acanthamoeba keratitis, they may worsen the condition if used improperly, especially when the infection is already established. However, in some cases, when used alongside antiamoebic therapy, they have been part of successful treatment outcomes. ^{1 2 3 4 5}

Is the combination of PHMB and topical corticosteroids safe for treating Acanthamoeba Keratitis?

Topical corticosteroids, like mometasone furoate, are generally safe with low risk of side effects when used properly, but they can cause skin reactions in some people and, if misused, may lead to serious conditions like Cushing's syndrome. It's important to use them under medical supervision to minimize risks. ^{6 7 8 9 10}

How does the drug PHMB + Topical Corticosteroids differ from other treatments for Acanthamoeba Keratitis?

The combination of PHMB (a disinfectant effective against Acanthamoeba cysts) and topical corticosteroids (which can reduce inflammation) is unique because PHMB is specifically effective at low concentrations against the cyst form of Acanthamoeba, while corticosteroids need careful management to avoid worsening the condition, especially if bacterial infection is present. ^{4 5 11 12 13}

Research Team

Jeremy Keenan, MD, MPH

Principal Investigator

Proctor Foundation, UCSF

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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 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 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]

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]

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]

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]

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]

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]

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]

References

1. United States pubmed.ncbi.nlm.nih.gov

The Impact of Topical Corticosteroids Used in Conjunction with Antiamoebic Therapy on the Outcome of Acanthamoeba Keratitis. [2022]

2. United States pubmed.ncbi.nlm.nih.gov

The impact of topical corticosteroid use before diagnosis on the outcome of Acanthamoeba keratitis. [2016]

3. United States pubmed.ncbi.nlm.nih.gov

Successful medical management of Acanthamoeba keratitis. [2022]

4. England pubmed.ncbi.nlm.nih.gov

Corticosteroid eye drop instillation aggravates the development of Acanthamoeba keratitis in rabbit corneas inoculated with Acanthamoeba and bacteria. [2021]

5. United States pubmed.ncbi.nlm.nih.gov

The role of topical corticosteroids in the management of Acanthamoeba keratitis. [2022]

6. England pubmed.ncbi.nlm.nih.gov

Contact allergies to topical corticosteroids: 10 cases of contact dermatitis. [2019]

7. Australia pubmed.ncbi.nlm.nih.gov

Comparative safety and efficacy of topical mometasone furoate with other topical corticosteroids. [2018]

8. New Zealand pubmed.ncbi.nlm.nih.gov

New and established topical corticosteroids in dermatology: clinical pharmacology and therapeutic use. [2018]

9. Germany pubmed.ncbi.nlm.nih.gov

[Dermal and systemic side effects of fluocortin butylester. Comparative skin tearing experiments with active principles from commercial preparations]. [2013]

10. United States pubmed.ncbi.nlm.nih.gov

Exogenous Cushing's syndrome due to topical corticosteroid application: case report and review literature. [2021]

11. Australia pubmed.ncbi.nlm.nih.gov

Steroid sensitive Acanthamoeba keratitis. [2019]

12. United States pubmed.ncbi.nlm.nih.gov

Treatment of Acanthamoeba keratitis with polyhexamethylene biguanide. [2022]

13. China (Republic : 1949- ) pubmed.ncbi.nlm.nih.gov

Treatment of Acanthamoeba keratitis combined with fungal infection with polyhexamethylene biguanide. [2016]