Study to Assess the Efficacy and Safety of LX201 for Prevention of Corneal Allograft Rejection Episodes and Graft Failure in Subjects at Increased Immunological Risk

This was a pivotal trial to determine whether LX201 reduces the likelihood of a graft rejection episode following corneal transplantation in patients at high immunological risk for rejection.

LX201 was a novel sustained-release silicone implant containing 30% cyclosporine A by weight. LX201 was intended for surgical episcleral placement in the eye.

The study was a Phase 2/3, multi-center, placebo-controlled, randomized, parallel-group, dose-ranging study of LX201 for prevention of corneal allograft rejection or graft failure following penetrating keratoplasty with LX201 implantation. Subjects were to be followed in an outpatient setting for safety and efficacy at 4-6 week intervals for 52 weeks following transplantation surgery.

After Visit 12 (Week 52), subjects in the USA and India with the implant in the study eye were to be followed for safety at least once per year for a 2-year period or until time of implant removal. For subjects in the USA and India, if the implant was removed at any time prior to the 3 year safety follow-up, the subject was to have a final safety follow up visit at 3 months post removal. In Germany, the implant was to be removed at Week 52 with a 3-month safety follow-up period after removal.

Eligibility Criteria:
Inclusion Criteria:

* Subjects are candidates for a corneal transplant and are at increased immunological risk for graft failure, as evidenced by one or more of the following:

  * ≥ 1 quadrant deep corneal vascularization
  * verifiable history of graft failure due to rejection
  * position of graft is \< 1 mm from the limbus

Exclusion Criteria:

* Any condition that would greatly increase the risk of non-rejection graft failure such as Stevens-Johnson syndrome, xerophthalmia or severe exposure keratitis.
* Schirmer's test ≤ 5 mm in 1 minute
* Clinical evidence of limbal stem cell deficiency
* History of or active herpes simplex virus keratitis or other acute corneal infection
* Subjects who have had \> 3 failed grafts in the study eye
* Uncontrolled glaucoma as evidenced by an intraocular pressure of \>21 mmHg while on maximal medical therapy
* Clinically suspected or confirmed ocular lymphoma
* Treatment with a systemic immunosuppressive regimen within the previous 30 days; systemic prednisone (or its equivalent) of ≤ 10 mg daily is, however, permitted.
* Any implantable corticosteroid-eluting device (e.g., Retisert™, Posurdex®, Medidur™, I-vation™ TA intravitreal implant)
* Subjects who periodically require high-dose systemic steroid treatment (e.g., for exacerbation of chronic obstructive pulmonary disease).
* Subjects who have received treatment with a monoclonal antibody or any other biologic therapy within the previous 90 days or alemtuzumab within the previous 12 months
* History of herpes zoster or varicella infection within 6 weeks prior to enrollment, or chicken pox exposure within 21 days before enrollment
* Seropositivity for human immunodeficiency virus (HIV)
* Previous exposure or known contraindication to administration of cyclosporine
* Recipients of a solid organ transplant
* Currently pregnant or lactating
* Active, extraocular and/or systemic infection requiring the prolonged or chronic use of antimicrobial agents or the presence of active hepatitis A, B or C
* Severe anemia (hemoglobin \< 6 g/dL), leukopenia (white blood cell count \[WBC\] \< 2500 mm3), thrombocytopenia (platelet count \< 80,000 mm3), polycythemia (hematocrit \[Hct\] \> 54% \[male\] or Hct \> 49% \[female\]) or clinically significant coagulopathy
* Current malignancy or a history of malignancy (within the previous 5 years) except non-metastatic basal or squamous cell carcinoma of the skin or carcinoma-in-situ of the cervix that has been treated successfully
* Active peptic ulcer disease
* Co-morbid conditions that require immunosuppression