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

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ClinicalTrials.gov Identifier: NCT03586284
Recruitment Status : Not yet recruiting
First Posted : July 13, 2018
Last Update Posted : April 11, 2019
Sponsor:
Collaborators:
Huang Pacific Foundation
Khon Kaen University
King Chulalongkorn Memorial Hospital
National Taiwan University
Francis I. Proctor Foundation
Information provided by (Responsible Party):
University of California, San Francisco

Brief Summary:

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.


Condition or disease Intervention/treatment Phase
Cytomegalovirus Anterior Uveitis Drug: Valganciclovir Hydrochloride Drug: Ganciclovir Sodium Drug: Placebo Oral Tablet Drug: Topical placebo Phase 2 Phase 3

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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 99 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Multicenter, double-masked, randomized, placebo-controlled clinical trial
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Systemic and Topical Antivirals for Control of Cytomegalovirus Anterior Uveitis: Treatment
Estimated Study Start Date : October 2019
Estimated Primary Completion Date : October 2019
Estimated Study Completion Date : June 2020


Arm Intervention/treatment
Active Comparator: Oral Valganciclovir
Oral Valganciclovir 900mg PO BID Topical placebo solution, 1 drop applied 6 times daily
Drug: Valganciclovir Hydrochloride
28 days of oral valganciclovir treatment

Drug: Topical placebo
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
28 days of topical ganciclovir solution treatment

Drug: Placebo Oral Tablet
28 days of placebo pill treatment

Placebo Comparator: Placebo
Topical placebo solution, 1 drop applied 6 times daily Placebo pills PO BID
Drug: Placebo Oral Tablet
28 days of placebo pill treatment

Drug: Topical placebo
28 days of topical placebo treatment




Primary Outcome Measures :
  1. Change in viral load [ Time Frame: Day 0 (pre-treatment viral load) to Day 35 (post-treatment viral load) ]
    (pre-treatment viral load minus post-treatment viral load)/pre-treatment viral load


Secondary Outcome Measures :
  1. Percent that achieved clinical quiescence [ Time Frame: Day 0 to Day 35 (final visit) ]
    Comparison between arms of percent that achieved clinical quiescence by final visit

  2. Effect of topical corticosteroid [ Time Frame: Day 0 (pre-treatment viral load) ]
    What effect did topical corticosteroid use prior to enrollment have on pre-treatment viral load (Day 0)



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

pharmacologics, 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03586284


Contacts
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Contact: John A Gonzales, MD 415.502.2664 john.gonzales@ucsf.edu

Sponsors and Collaborators
University of California, San Francisco
Huang Pacific Foundation
Khon Kaen University
King Chulalongkorn Memorial Hospital
National Taiwan University
Francis I. Proctor Foundation
Investigators
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Principal Investigator: John A Gonzales, MD UCSF Proctor Foundation

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Responsible Party: University of California, San Francisco
ClinicalTrials.gov Identifier: NCT03586284     History of Changes
Other Study ID Numbers: 18-24396
First Posted: July 13, 2018    Key Record Dates
Last Update Posted: April 11, 2019
Last Verified: April 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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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

Keywords provided by University of California, San Francisco:
Cytomegalovirus uveitis
Cytomegalovirus endotheliitis
Cytomegalovirus keratouveitis
Cytomegalovirus iridocyclitis

Additional relevant MeSH terms:
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Uveitis
Uveitis, Anterior
Iridocyclitis
Uveal Diseases
Eye Diseases
Panuveitis
Iris Diseases
Antiviral Agents
Ganciclovir
Valganciclovir
Ganciclovir triphosphate
Anti-Infective Agents
Nucleic Acid Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action