Prospective Randomized Controlled Treatment Trial for Chronic Central Serous Chorioretinopathy

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Brief Title

Prospective Randomized Controlled Treatment Trial for Chronic Central Serous Chorioretinopathy

Official Title

A Prospective Randomized Controlled Multicentre Trial Comparing Half-dose Photodynamic Therapy (PDT) With High-density Subthreshold Micropulse Laser Treatment in Patients With Chronic Central Serous Chorioretinopathy (CSC)

Brief Summary

      Chronic central serous chorioretinopathy (CSC) is a relatively frequent eye disease that
      often occurs in patients in the professionally active age range. In this disease, there is
      pooling of fluid under the central retina (the macula). This specific form of macular
      degeneration can cause permanent vision loss, image distortion, loss of color and contrast
      vision due to this fluid under the retina. An early diagnosis and treatment may improve the
      visual outcome and quality of life. To date there is no international consensus on the
      optimal treatment of chronic CSC. Many retrospective studies suggest that treatment with
      photodynamic therapy (PDT) is effective in chronic CSC. Micropulse laser (ML) therapy may
      also be effective in this disease.

      The proposed study is the first prospective randomized controlled trial in chronic CSC. In
      this study, participants with chronic CSC will be randomized into two treatment groups, PDT
      or ML treatment. The trial is a superiority study, because retrospective studies suggest that
      PDT treatment may be more effective than ML treatment. Therefore, PDT treatment is challenged
      against ML treatment.

      The null hypothesis of the study is that PDT treatment is more effective than ML treatment in
      patients with active chronic CSC. The alternative hypothesis is that PDT treatment is not
      more effective than ML treatment in these patients.

      Treatment success will not only be based on anatomical improvement, but also on functional
      endpoints, which are most important from a patient's perspective.

      The study will take place in five large tertiary referral university hospitals in Europe that
      have extensive experience with conducting clinical trials (in Nijmegen, the Netherlands;
      Cologne, Germany; Leiden, the Netherlands; Oxford, United Kingdom; and Paris, France). Each
      of these centers has confirmed sufficient funding to conduct the research. The study will
      last max. 8 months per participant. Each participant will come for 5 (in the case of 1
      treatment) or 7 visits (in the case of 2 treatments). Study evaluations will be mostly part
      of regular clinical care. The whole study will last for max. 24 months.
    

Detailed Description

      PURPOSE AND DESIGN There is no international consensus on the optimal treatment protocol of
      chronic CSC. Nevertheless, photodynamic therapy (PDT) has emerged as the treatment of choice
      in many centres worldwide. PDT uses a photosensitive drug, verteporfin (Visudyne®), that is
      administered once intravenously before treatment with a specific type of laser. PDT treatment
      has been developed originally as treatment for another form of macular degeneration,
      age-related macular degeneration, on which there are extensive data available. There are
      several other retinal diseases for which PDT with verteporfin is successfully used as an
      off-label treatment. The use of PDT treatment in chronic CSC is based on the high rate of
      anatomic success, the increase of visual acuity, the improvement in retinal sensitivity, and
      an excellent safety profile reported in many retrospective studies. The PDT strategies that
      are generally used are either with half the dose of verteporfin (Visudyne®) and full fluence
      (energy) of laser treatment, half the fluence level and the full dose of verteporfin, or half
      the treatment time using the full dose of verteporfin and full fluence, as compared to the
      original protocol that was used for neovascular age-related macular degeneration. These PDT
      strategies that use either half-dose of half-fluence treatment have been developed because a
      combination of the dosage and fluence that was originally used for the treatment of
      neovascular age-related macular degeneration showed a higher risk of developing choroidal
      ischemia and retinal atrophic changes. The half-dose and half-fluence PDT strategies,
      however, have been shown to be safe and effective in relatively large retrospective studies
      and one non-controlled non-randomized prospective study by Chan et al. in chronic CSC
      patients with sufficient follow-up periods.

      Therefore, tailoring the therapy to obtain the maximal treatment effect with minimal toxicity
      is essential in treating patients with CSC. By reducing the dose of verteporfin, studies have
      demonstrated that the potential retinal damage caused by PDT can be minimized while the
      photodynamic effects in inducing choroidal vasculature changes required for treating CSC
      remain sufficient. We have chosen for half-dose because this "safety-enhanced" protocol
      appeared to be one of the safest and effective treatment options in patients with active
      chronic CSC.

      PDT will be compared with micropulse laser (ML) treatment as a control arm, and not with sham
      or conventional laser treatment, for a number of reasons. First, sham (no treatment) was
      studied by Chan et al. who showed a large difference in anatomic outcome (complete resolution
      of subretinal fluid) and functional outcome (visual acuity) between the half-dose PDT and
      placebo group in the acute form of CSC, which often resolves spontaneously after a few weeks
      in contrast to chronic CSC. As it is well-established that prolonged leakage of subretinal
      fluid under the macula due to chronic CSC may lead to permanent visual loss, it is not
      desirable to compare half-dose PDT treatment with sham. Apart from these ethical
      considerations to refrain from comparing with sham, adding a third sham study arm would
      require an extra amount of study patients that would complicate the recruitment process. The
      treatment of CSC with ML treatment has been shown to be effective and safe in retrospective
      studies in 41-58% of patients. The safety and efficacy of ML treatment has also been shown in
      various other retinal diseases. In contrast, it has been shown that conventional laser
      treatment of focal leakage point on fluorescein angiography in CSC does not result in a
      better visual outcome. Also, conventional laser treatment has a higher risk of complications
      then ML and PDT, including visual loss, scotoma, decreased color vision, decreased contrast
      sensitivity, and choroidal neovascularization.

      The proposed study is a superiority study, as retrospective studies suggest that the rate of
      anatomical and functional success of half-dose PDT treatment might be higher than ML
      treatment. However, none of these previous studies on half-dose PDT and ML treatment were
      prospective, randomized, as well as controlled. Therefore, we have chosen to challenge the
      half-dose PDT treatment arm against a treatment arm of ML treatment.

      The number of visits and examinations have been reduced to a minimum, and conform to standard
      clinical care as much as possible. Extra examinations include a more extensive visual acuity
      measurement, microperimetry, and a questionnaire. These extra examinations are required to
      evaluate the functional vision-related endpoints of the study. Care will be taken to plan all
      examinations on the same day as much as possible.

      RECRUITMENT AND CONSENT Patients will be informed about the treatment options for their eye
      disease that are currently available. Study investigators will obtain consent for
      participation in the study, but consent for currently available treatments outside the study
      will be obtained by medical and nursing staff as would be done routinely. Written and verbal
      versions of the participant information and informed consent will be presented to the
      participants, detailing the exact nature of the study, the implications and constraints of
      the protocol, the known side effects, and any risks involved in taking part. It will be
      clearly stated that the participant is free to withdraw from the study at any time for any
      reason without prejudice to future care, and with no obligation to give the reason for
      withdrawal. Care will be taken to avoid coercion and undue influence of the "recruiter" on
      the potential participant.

      The potential participant will be allowed as much time as wished to consider the information,
      and the opportunity to question the Investigator, their General Practitioner or other
      independent parties to decide whether they will participate in the study.

      CONFIDENTIALITY The source documents and participants' Case Report Form (CRF) data will
      always remain in the study centre in which the patient is treated (either Oxford, Cologne,
      Paris, or Nijmegen). No person-identifiable information will be used unless it is absolutely
      necessary. The trial staff will ensure that the participants' anonymity is maintained. The
      participants will be identified only by initials and a participants identification number on
      the CRF and the electronic database. All documents will be stored securely and only
      accessible by trial staff and authorised personnel. The study will comply with the Data
      Protection Act which requires data to be anonymized as soon as it is practical to do so.
      Anonymized data will be entered into a purpose-built digital database that is maintained by a
      contract research organisation, the Clinical Research Centre Nijmegen (www.crcn.nl), which is
      affiliated with the coordinating academic centre, the Institute of Ophthalmology of the
      Radboud University Nijmegen Medical Centre in Nijmegen the Netherlands.
    

Study Phase

Phase 4

Study Type

Interventional


Primary Outcome

Absence of subretinal fluid on OCT scan

Secondary Outcome

 Best-corrected visual acuity

Condition

Chronic Central Serous Chorioretinopathy

Intervention

Half-dose photodynamic therapy (PDT)

Study Arms / Comparison Groups

 Half-dose photodynamic therapy (PDT)
Description:  In the PDT treatment arm, all patients will receive an intravenous drip through which half-dose (3 mg/m2) verteporfin (Visudyne ®) is administered, with an infusion time of 10 minutes. At 15 minutes after the start of the infusion, PDT laser treatment is performed with standard 50 J/cm2 fluency, a wavelength of 689 nm, and a treatment duration of 83 seconds.
If there still is subretinal fluid on OCT scan at Evaluation Visit 1 (6-8 weeks after Treatment Visit 1 / the first treatment with half-dose PDT), a second treatment with half-dose PDT will be performed (Treatment Visit 2).

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Procedure

Estimated Enrollment

140

Start Date

December 2013

Completion Date

May 2017

Primary Completion Date

May 2017

Eligibility Criteria

        INCLUSION CRITERIA:

          -  male and female patients ≥ 18 years of age who are able to give written informed
             consent

          -  active chronic central serous chorioretinopathy

          -  subjective visual loss > 6 weeks, interpreted as onset of active disease

          -  subretinal fluid that includes the fovea on OCT scanning at Baseline Examination.

        Please NOTE: Subretinal fluid does not have to include fovea on OCT to be eligible for
        treatment at Control Visit 1, as long as there is persistent subretinal fluid in the
        macula, which is interpreted as persistently active disease (see 5.7 "Retreatment criteria
        and considerations").

          -  hyperfluorescent areas on ICG angiography

          -  ≥1 ill-defined hyperfluorescent leakage areas on fluorescein angiography with retinal
             pigment epithelial window defect(s) that are compatible with chronic CSC

        EXCLUSION CRITERIA:

        The participant may not enter the study if ANY of the following apply:

          -  any previous treatments for active CSC in the study eye

          -  current treatment with corticosteroids (topical or systemic), or anticipated start of
             corticosteroid treatment within the first 7-8 months from the start of the trial
             period

          -  evidence of other diagnosis that can explain serous subretinal fluid or visual loss

          -  BCVA < 20/200 (Snellen equivalent)

          -  profound chorioretinal atrophy in central macular area on ophthalmoscopy and OCT

          -  myopia > 6 dioptres

          -  visual loss and/or serous detachment on OCT < 6 weeks

          -  continuous and/or progressive visual loss > 18 months or serous detachment on OCT > 18
             months

          -  no hyperfluorescence on ICG angiography

          -  intraretinal edema on OCT

          -  (relative) contraindications for PDT treatment (pregnancy, porphyria, severely
             disturbed liver function). Pregnancy will not be routinely tested in female patients,
             but the possibility of pregnancy will be discussed during eligibility screening

          -  (relative) contraindications for fluorescein angiography or ICG angiography (known
             allergies especially against shellfish, previous reactions)

          -  Soft drusen in treated eye or fellow eye, signs of choroidal neovascularization on
             ophthalmoscopy and/or fluorescein angiography/indocyanine green angiography
      

Gender

All

Ages

18 Years - N/A

Accepts Healthy Volunteers

No

Contacts

Camiel JF Boon, MD PhD FEBO, , 

Location Countries

France

Location Countries

France

Administrative Informations


NCT ID

NCT01797861

Organization ID

PLACE


Responsible Party

Sponsor

Study Sponsor

Radboud University Medical Center

Collaborators

 University of Cologne

Study Sponsor

Camiel JF Boon, MD PhD FEBO, Study Chair, Leiden University Medical Center & Radboud University Nijmegen Medical Center


Verification Date

April 2016