First-line Antimetabolites as Steroid-sparing Treatment Uveitis Pilot Trial (FAST)

This study has been completed.
Sponsor:
Collaborator:
Aravind Eye Hospitals, India
Information provided by (Responsible Party):
University of California, San Francisco
ClinicalTrials.gov Identifier:
NCT01232920
First received: November 1, 2010
Last updated: March 13, 2013
Last verified: March 2013
  Purpose

The proposed study is a masked trial, with stratified block randomization by site, designed to determine which treatment, methotrexate or mycophenolate mofetil, is more effective as first-line steroid-sparing treatment for patients with non-infectious uveitis requiring corticosteroid-sparing therapy.

One hundred non-infectious uveitis patients in need of corticosteroid-sparing therapy will be randomized to receive either oral methotrexate or oral mycophenolate mofetil at Aravind Eye Hospitals (Madurai and Coimbatore, South India). They will be followed monthly for 6 months after enrollment or until treatment failure. The investigators hypothesize that the proportion achieving corticosteroid-sparing success at 6 months for patients taking mycophenolate mofetil will be improved in comparison with patients taking methotrexate.


Condition Intervention Phase
Uveitis
Drug: Methotrexate
Drug: Mycophenolate mofetil
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: First-line Antimetabolites as Steroid-sparing Treatment Uveitis Pilot Trial

Resource links provided by NLM:


Further study details as provided by University of California, San Francisco:

Primary Outcome Measures:
  • Proportion achieving overall treatment success at 6 months. [ Time Frame: 6 months ] [ Designated as safety issue: No ]

    TREATMENT SUCCESS is defined as controlled ocular inflammation in both eyes with less than or equal to 10 mg/day of prednisone and/or 2 topical steroid drops/day sustained for 2 visits separated by at least 28 days (control of inflammation and prednisone dose must be achieved by 5-month visit and sustained until 6-month visit).

    Discontinuation of study medication at any time due to efficacy, tolerability, or safety may result in a declaration of TREATMENT FAILURE. Note that all patients will be classified as either a treatment success or failure.



Secondary Outcome Measures:
  • Time to control of inflammation [ Time Frame: 6 months ] [ Designated as safety issue: No ]
  • Proportion achieving treatment success and complete discontinuation of corticosteroids [ Time Frame: 6 months ] [ Designated as safety issue: No ]
  • Change in best spectacle-corrected visual acuity (BSCVA) [ Time Frame: 6 months ] [ Designated as safety issue: No ]
  • Rate of discontinuation due to intolerability [ Time Frame: 6 months ] [ Designated as safety issue: No ]
  • Rate of adverse events [ Time Frame: 6 months ] [ Designated as safety issue: Yes ]
  • Change in health- and vision-related quality of life, as measured by SF-36 and IND-VFQ-33 respectively [ Time Frame: 6 months ] [ Designated as safety issue: No ]
  • Change in cystoid macular edema (CME) [ Time Frame: 6 months ] [ Designated as safety issue: No ]

Enrollment: 80
Study Start Date: October 2010
Study Completion Date: June 2012
Primary Completion Date: June 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Methotrexate Drug: Methotrexate
All methotrexate doses will be taken orally once per week in a divided dose (half in the morning, half in the evening), and should be taken with food. For the first two weeks, a loading dose of 15 mg/week orally will be administered to assess tolerability. After two weeks, the dose will be ramped up to 25 mg/week until the end of follow-up or until treatment failure due to intolerability, adverse events, or of lack of efficacy. If the study ophthalmologist decides to reduce the study treatment dose due to intolerability, the dose will be reduced to 20 mg per week while maintaining masking. If side effects persist and the study ophthalmologist wishes to reduce the dose a second time, the dose will be reduced to 15 mg per week.
Active Comparator: Mycophenolate mofetil Drug: Mycophenolate mofetil
Mycophenolate mofetil will be taken twice daily on an empty stomach. For the first two weeks, a loading dose of 500 mg/BID orally will be administered to assess tolerability. After two weeks, the dose will be ramped up to 1 g/BID until the end of follow-up or until treatment failure due to intolerability, adverse events, or lack of efficacy. If the study ophthalmologist decides to reduce the study treatment dose due to intolerability, the dose will be reduced to 750 mg/BID while maintaining masking. If side effects persist and the study ophthalmologist wishes to reduce the dose a second time, the dose will be reduced to 500 mg/BID.
Other Name: Cellcept

Detailed Description:

Uveitis, a set of conditions defined by intraocular inflammation, is a significant cause of vision loss and morbidity in the United States and the world. The incidence was recently estimated to be more than 50 cases per 100,000 person-years, with a prevalence of approximately 115 per 100,000 persons. Additionally, uveitis is believed to be the cause of up to 10% of cases of legal blindness in the United States, or approximately 30,000 new cases of blindness per year. In contrast to common age-related eye disorders, uveitis may have a stronger socio-economic impact because it disproportionately affects younger working-age patients. Although the etiology of uveitis is varied, most cases are presumed to be immune-mediated and lack a known infectious cause. Even in developing countries such as India that have a larger burden of infection, the vast majority of cases are non-infectious.

The current mainstay of treatment for noninfectious uveitis is corticosteroids (topical, systemic, locally injected, or corticosteroid-eluting implants). Due to the well documented local and systemic side effects associated with corticosteroid therapy, other immunosuppressive therapies are frequently used as corticosteroid-sparing agents in patients who need long-term therapy. These include antimetabolites, calcineurin inhibitors, alkylating agents, and biologic drugs. Cost and morbidity associated with uncontrolled inflammation make the selection of an effective initial steroid-sparing agent extremely important.

It is common practice for patients requiring a steroid-sparing agent to be treated first with the less expensive methotrexate and then switched to mycophenolate mofetil in the event of treatment failure. However, results from non-comparative retrospective case series indicate that uveitis patients may be much more likely to achieve controlled inflammation and tolerate treatment with mycophenolate mofetil. Furthermore, approximately half of the patients who fail treatment with methotrexate go on to successful treatment with mycophenolate mofetil. There have been no prospective randomized, controlled trials to systematically determine which antimetabolite is more clinically efficacious as initial corticosteroid-sparing therapy, making it difficult for clinicians to make informed, evidence-based decisions about first-line immunosuppressive treatment.

Our contribution is expected to be a definitive understanding of the comparative efficacy, tolerability, and quality of life of these two antimetabolites as initial steroid-sparing therapy for uveitis patients requiring chronic therapy. This contribution is significant because it will enable clinicians to make evidence-based decisions when prescribing first-line immunosuppressive therapy for their uveitis patients. The use of optimal first-line therapy will improve quality of life by reducing the risk of vision loss and complications associated with uncontrolled ocular inflammation and long-term corticosteroid use.

  Eligibility

Ages Eligible for Study:   16 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Non-infectious anterior, intermediate, posterior or panuveitis
  • Active uveitis within the last 60 days (defined by the presence of any of the following according to SUN criteria: ≥ 1+ anterior chamber cells, anterior vitreous cells, vitreous haze, active retinal or choroidal lesions)
  • Prednisone dose ≥ 15 mg/day
  • History of corticosteroid taper failure (inability to taper to prednisone 10 mg or less) or obvious chronic disease necessitating corticosteroid-sparing immunosuppressive treatment

Exclusion Criteria:

  • Any infectious cause of uveitis
  • Tuberculosis: Evidence of active TB (PPD and CXR required - latent TB patients are still eligible)
  • Positive for Hepatitis: HBsAg and/or Hep C antibody
  • Positive for Syphilis: RPR/VDRL and/or FTA-ABS
  • Abnormal CBC (<2500 WBC or <75,000 Plts or <10 Hgb)
  • Abnormal liver and/or kidney tests (ALT/AST >2x normal or CR>1.5)
  • Pregnancy or breast-feeding (blood or urine pregnancy test for all females, excluding those who are post-menopausal)
  • Chronic hypotony (IOP < 5 mm Hg for > 3 months)
  • Prior use of any immunosuppressive drug for the treatment of uveitis in the past 6 months
  • Prior failed treatment with methotrexate or mycophenolate mofetil
  • Periocular or intravitreal corticosteroid injection in the past 3 months
  • Fluocinolone acetonide implant surgery in either eye in < 3 years
  • Intraocular surgery in < 30 days, or any ocular surgery scheduled during the 6-month study period
  • VA of hand motions or worse in better eye
  • < 16 years of age at enrollment
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT01232920

Locations
India
Aravind Eye Hospital
Coimbatore, Tamil Nadu, India
Aravind Eye Hospital
Madurai, Tamil Nadu, India
Sponsors and Collaborators
University of California, San Francisco
Aravind Eye Hospitals, India
Investigators
Principal Investigator: S R Rathinam, MD Aravind Eye Hospital
Principal Investigator: M B Babu, MD Aravind Eye Hospital
Principal Investigator: Nisha Acharya, MD MS Proctor Foundation, UCSF
  More Information

No publications provided

Responsible Party: University of California, San Francisco
ClinicalTrials.gov Identifier: NCT01232920     History of Changes
Other Study ID Numbers: 10-00235
Study First Received: November 1, 2010
Last Updated: March 13, 2013
Health Authority: United States: Institutional Review Board
India: Institutional Review Board

Keywords provided by University of California, San Francisco:
uveitis
antimetabolite
immunosuppressive
clinical trial

Additional relevant MeSH terms:
Uveitis
Chorioretinitis
Uveal Diseases
Eye Diseases
Retinitis
Retinal Diseases
Choroiditis
Choroid Diseases
Uveitis, Posterior
Panuveitis
Antimetabolites
Methotrexate
Mycophenolic Acid
Mycophenolate mofetil
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Abortifacient Agents, Nonsteroidal
Abortifacient Agents
Reproductive Control Agents
Physiological Effects of Drugs
Therapeutic Uses
Antimetabolites, Antineoplastic
Antineoplastic Agents
Dermatologic Agents
Enzyme Inhibitors
Folic Acid Antagonists
Immunosuppressive Agents
Immunologic Factors
Antirheumatic Agents
Nucleic Acid Synthesis Inhibitors

ClinicalTrials.gov processed this record on April 15, 2014