Systemic and Topical Antivirals for Control of Cytomegalovirus Anterior Uveitis: Treatment Outcomes (STACCATO)

Systemic and Topical Antivirals for Control of Cytomegalovirus Anterior Uveitis: Treatment

Cytomegalovirus (CMV) is generally a latent and asymptomatic infection in healthy, immunocompetent individuals. In immunocompromised patients CMV is well known to cause a retinitis that can lead to blindness. In immunocompetent patients, however, CMV can cause recurrent inflammation in the front of the eye (anterior uveitis). CMV anterior uveitis produces complications including pain, glaucoma, corneal failure, and vision loss. CMV anterior uveitis is commonly misdiagnosed as a non-infectious anterior uveitis and treated as such, which can beget further complications. Diagnosis requires directed polymerase chain reaction (PCR) testing. While antiviral therapy exists for CMV, identifying the appropriate therapy has been challenging because no randomized trials comparing routes of therapy (particularly oral or topical) have been performed. Oral antiviral therapy of CMV carries blood and kidney side effects that requires laboratory monitoring. Topical therapy has been reported to be effective, but no consensus as to the appropriate drug concentration exists.

Here we propose a double-masked randomized controlled clinical trial comparing the efficacy of oral valganciclovir, topical ganciclovir 2%, and placebo for the treatment of PCR-proven CMV anterior uveitis. This pilot study will provide valuable information concerning the treatment of CMV anterior uveitis with oral and topical medications, including effective concentrations and side-effect profile. The information obtained from this study will help inform future larger clinical trials in CMV anterior uveitis.

Study Overview

• Status: Recruiting
• Conditions: Cytomegalovirus Anterior Uveitis
• Intervention / Treatment: Drug: Valganciclovir Hydrochloride; Drug: Topical placebo; Drug: Ganciclovir Sodium; Drug: Placebo Oral Tablet

Detailed Description

Recurrent anterior uveitis in immunocompetent individuals can be caused by multiple members of the herpes virus group, including cytomegalovirus (CMV). Repeated bouts of CMV intraocular inflammation can be associated with ocular hypertension, glaucoma, pain, vision reduction or blindness. CMV anterior uveitis is commonly misdiagnosed as a non-infectious anterior uveitis and treated as such, which can beget further complications. Diagnosis requires directed polymerase chain reaction (PCR) testing. While antiviral therapy exists for CMV, identifying the appropriate therapy has been challenging because no randomized trials comparing routes of therapy (particularly oral or topical) have been performed. Currently, CMV anterior uveitis is typically treated with oral valganciclovir in the United States but carries the risk of serious systemic side effects that necessitate laboratory monitoring. There is evidence that suggests topical ganciclovir can be used to treat and prevent recurrences of CMV anterior uveitis, though the appropriate concentration is not well defined. Topical ganciclovir is attractive because it does not require laboratory monitoring, though a unique side effect profile that includes corneal epitheliopathy and conjunctivitis may preclude long-term use. While anterior chamber paracentesis with polymerase chain reaction (PCR) testing demonstrates CMV during an initial flare of inflammation, it is unknown whether repeated recurrences of inflammation are mediated by viral re-infection and replication in the anterior chamber or if a sterile immune response is at play. Consequently, patients may be submitted to many years of oral or topical antiviral therapy. This strategy poses challenges without proper evaluation of the multiple treatment and long-term management approaches. Further studies are needed to elucidate the most appropriate antiviral therapies that balance efficacy and toxicity while treating CMV anterior uveitis.

There are no studies comparing antivirals for the treatment of CMV anterior uveitis. However, multiple studies have utilized PCR to obtain an initial viral load before treating CMV anterior uveitis. The collective initial CMV viral load from these prior studies (39 patients in total) was approximately 600,000 IU/ml. There was minimal variation within studies in terms of initial viral load, but large variation between studies. To control for variability that can arise from different assays used or assays performed at different centers, we will perform all quantitative PCR at the same United States location. Even fewer studies have documented post-treatment viral loads. Many of the post-treatment PCR values showed undetectable viral loads, making it difficult to estimate viral load reduction trends between treatment groups. Of note, the limited data demonstrated that both intravenous ganciclovir and topical ganciclovir 2% groups showed significant and rapid reductions in viral load, almost always resulting in undetectable levels by 12 weeks, and occasionally as rapidly as 2-3 weeks. We identified three patients from the literature with CMV anterior uveitis that had detectable PCR values during the course of treatment. These patients had a 95% average reduction in viral load 14 days after treatment.

We are proposing a double-masked randomized controlled clinical trial comparing the efficacy of oral valganciclovir, topical ganciclovir 2%, and placebo for the treatment of PCR-proven CMV anterior uveitis. The primary outcome will be percent reduction in viral load. We hypothesize that the oral valganciclovir arm will experience the greatest reduction in viral load. Secondary outcomes will include time to clinical quiescence and the effect of pre-enrollment topical corticosteroid use on initial viral load.

This pilot study will provide valuable information concerning the treatment of CMV anterior uveitis with oral and topical medications, including effective concentrations and side-effect profile. The information obtained from this study will help inform future larger clinical trials in CMV anterior uveitis.

• Study Type: Interventional
• Enrollment (Estimated): 99
• Phase: Phase 2; Phase 3

Contacts and Locations

• Study Contact: Name: John A Gonzales, MD; Phone Number: 415.502.2664; Email: john.gonzales@ucsf.edu

Study Locations

• United States
  • California
    • San Francisco, California, United States, 94158
      • Recruiting
      • Proctor Foundation, UCSF
      • Contact: John A Gonzales, MD; Phone Number: 415-476-1442

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Clinical impression consistent with CMV anterior uveitis
• Directed PCR positive for CMV OR previous PCR-proven CMV anterior uveitis
• Willingness to use an acceptable method of contraception during the study period (i.e.

pharmacologic, devices, barrier methods) or abstinence.

Exclusion Criteria:

• Patients <18 years of age
• Intermediate or posterior inflammation (involvement of vitreous, choroid, or retina)
• Received antiviral therapy <14 days prior to enrollment
• Received periocular or intraocular corticosteroid injection < 8 weeks prior to enrollment
• Currently taking oral corticosteroids
• Immunocompromised (primary or secondary immunosuppressive disorders)
• Prior immunosuppressive therapy in the past 6 months
• Directed PCR negative for CMV
• Directed PCR positive for herpes simplex virus (HSV) or varicella zoster virus (VZV)
• Planning to conceive during the study period, pregnant or breast-feeding (blood or urine pregnancy test for all females of child-bearing age is mandatory within 4 weeks prior to enrollment)
• Complete blood count with white blood cell, absolute neutrophil, or platelet count lower than the lower limit of reference laboratory normal
• BUN or Cr above the upper limit of reference laboratory normal
• Recent ocular surgery within the past 30 days, or planned surgery within the next 45 days
• Systemic autoimmune disease or ocular condition (besides anterior uveitis) anticipated to dictate or alter treatment course

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Oral Valganciclovir; Oral Valganciclovir 900mg PO BID Topical placebo solution, 1 drop applied 6 times daily	Drug: Valganciclovir Hydrochloride; 21 to 28 days of oral valganciclovir treatment; Drug: Topical placebo; 21 to 28 days of topical placebo treatment
Active Comparator: Topical Ganciclovir 2%; Topical Ganciclovir 2% solution, 1 drop applied 6 times daily Placebo pills PO BID	Drug: Ganciclovir Sodium; 21 to 28 days of topical ganciclovir solution treatment; Drug: Placebo Oral Tablet; 21 to 28 days of placebo pill treatment
Placebo Comparator: Placebo; Topical placebo solution, 1 drop applied 6 times daily Placebo pills PO BID	Drug: Topical placebo; 21 to 28 days of topical placebo treatment; Drug: Placebo Oral Tablet; 21 to 28 days of placebo pill treatment

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in viral load	(pre-treatment viral load minus post-treatment viral load)/pre-treatment viral load	Day 0 (pre-treatment viral load) to Day 28 (post-treatment viral load)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percent that achieved clinical quiescence	Comparison between arms of percent that achieved clinical quiescence by final visit	Day 0 to Day 28 (final visit)
Effect of topical corticosteroid	What effect did topical corticosteroid use prior to enrollment have on pre-treatment viral load (Day 0)	Day 0 (pre-treatment viral load)

Collaborators and Investigators

• Sponsor: University of California, San Francisco
• Collaborators: Khon Kaen University; King Chulalongkorn Memorial Hospital; Huang Pacific Foundation
• Investigators: Principal Investigator: John A Gonzales, MD, UCSF Proctor Foundation

Publications and helpful links

General Publications

• Takhar JS, Joye AS, Somkijrungroj T, Laovirojjanakul W, Lin CP, Lietman TM, Porco TC, Keenan JD, Gebreegziabher EA, Seitzman GD, Rose-Nussbaumer J, Doan TA, Acharya NR, Gonzales JA. A double masked randomised 4-week, placebo-controlled study in the USA, Thailand and Taiwan to compare the efficacy of oral valganciclovir and topical 2% ganciclovir in the treatment of cytomegalovirus anterior uveitis: study protocol. BMJ Open. 2019 Dec 19;9(12):e033175. doi: 10.1136/bmjopen-2019-033175.

Study record dates

Study Major Dates

• Study Start (Actual): March 15, 2020
• Primary Completion (Estimated): March 1, 2025
• Study Completion (Estimated): December 1, 2025

Study Registration Dates

• First Submitted: July 2, 2018
• First Submitted That Met QC Criteria: July 2, 2018
• First Posted (Actual): July 13, 2018

Study Record Updates

• Last Update Posted (Actual): November 29, 2023
• Last Update Submitted That Met QC Criteria: November 27, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Keywords: Cytomegalovirus uveitis; Cytomegalovirus endotheliitis; Cytomegalovirus keratouveitis; Cytomegalovirus iridocyclitis
• Additional Relevant MeSH Terms: Eye Diseases; Panuveitis; Uveal Diseases; Iris Diseases; Uveitis; Uveitis, Anterior; Iridocyclitis; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Valganciclovir; Ganciclovir; Ganciclovir triphosphate
• Other Study ID Numbers: 18-24396

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes