Prevention of ProliFerative Vitreoretinopathy With Intravitreal MethotreXate in Primary Retinal DEtachment Repair (FIXER) Trial

I. Title Prevention of ProliFerative Vitreoretinopathy with Intravitreal MethotreXate in Primary Retinal DEtachment Repair (FIXER) Trial

IV. General Study Information ing on the surgeon and technique, successful retinal reattachment rates range from 70-80% for PR, and even higher with SB and/or PPV.10 Proliferative vitreoretinopathy (PVR), the formation of proliferative fibrocellular membranous tissue overlying the retina, can cause contracture and subsequent recurrent tractional retinal detachment. PVR is the leading cause of failure following RRD repair, complicating 10% of routine RRD procedures and a higher fraction of RRD in the setting of higher risk scenarios and occurs approximately 4,000 times per year in the US.11,12 Risk factors for PVR formation, including duration of RRD, uveitis, myopia (>-5.00), lens status, number of retinal breaks, size of breaks, duration of photopsias/floaters/shadows, presence of macula detachment, giant retinal tears, vitreous hemorrhage, and history of trauma. These risk factors will all be collected. Intraoperative data collected will include vitrectomy gauge, use of a drainage retinotomy, use of scleral buckle, type of retinal tamponade (air, SF6, C3F8, or silicone oil), fellow surgeon involvement, duration of surgery, development of choroidal detachment, amount of laser spots, amount of laser energy, number of retinal breaks, total clock hours of retinal breaks, and surgical complications. Surgically removing PVR to reattach the retina can be exceedingly challenging, resulting in poor visual outcomes, with reattachment rates ranging from 60-80%.11 Furthermore, even with successful anatomic reattachment, only 40-80% of patients recover ambulatory vision or better.11 The most commonly cited classification system to grade PVR is the updated Retina Society Classification in 2016. This system describes PVR into grades A-C with increasing severity. Grade A PVR is described as haziness in the vitreous haze or clumps of pigment, representing the migration of RPE cells into the vitreous. Grade B is described wrinkling of the retinal surface, rolled edges of a retinal tear, or retinal stiffness. Grade C-Posterior is described as a full-thickness retinal folds or subretinal strands posterior to equator. Grade C-Anterior is described as full-thickness retinal folds or subretinal strands anterior to equator, anterior displacement, and condensed vitreous strands.13 As of this writing, there are no prospective human studies demonstrating that a prophylactic medication can successfully prevent PVR. PVR prevention represents a significant unmet medical need. Methotrexate's proven antiproliferative and anti-inflammatory properties make it a promising candidate for prevention of PVR. Methotrexate exerts several anti-inflammatory and antiproliferative biochemical mechanisms, including competitive antagonism of dihydrofolate reductase, inhibition of purine and pyrimidine synthesis, transmethylation reactions, and nitric oxide production.14 Moreover, methotrexate has long been used to treat intraocular lymphoma and refractory uveitis, with an established intraocular dosing regimen and excellent intraocular safety profiles as described above.

Based on these long established - now standard of care - protocols in the ocular oncology and uveitis literature, a rational dosing strategy for our study of methotrexate for PBVR prevention was established as follows. The standard intravitreal dose of methotrexate for primary intraocular lymphoma and refractory posterior uveitis is 400mcg into an approximately 5mL eye. Dosing regimens for these two diseases are typically two injections per week for 1 month, 1 injection per week for 2 months and 1 injection per month for 9 additional months. Extensive off-label clinical experience by our group with methotrexate for PVR prevention in high-risk scenarios (going back to 2006) has led our group to believe that this very aggressive dosing regimen is not needed for a substantial anti PVR effect. Furthermore, the well documented side effect of corneal toxicity is much less frequent at a less aggressive dosing regimen and to that end we have adapted the following dosing strategy. During vitrectomy surgery for retinal detachment repair, 40mg of methotrexate is placed into a 500mL bottle of BSS intraocular irrigation solution yielding and identical final intraocular concentration of methotrexate that is equal to a 400mcg injection into a 5 mL eyeball. Methotrexate is a small and readily soluble molecule so an equilibrium of therapeutic tissue concentrations is achieved quickly. Following the aqueous phase of retinal detachment surgery, the (methotrexate containing) BSS infusion is turned off, all intraocular BSS is removed and replaced with a vitreous fill of either air, gas, or silicon oil. The resulting dramatically altered distribution volume of any water-soluble drug makes intraoperative injection dosing at the end of the surgical case very problematic. The intraoperative infusion methodology eliminates these concerns and doses the eye at the time when surgical manipulation and injury (which are felt to be causative factors in PVR formation) occur. We selected the intraoperative intraocular infusion strategy because of the direct and controlled ocular drug delivery, the ease of this dosing strategy, the simplicity of masking both the surgeon and patient (with an opaquer plastic bag covering the infusion bottle), and the elimination of systemic side effect concerns. Our postoperative injection regimen of 400mcg intravitreal injections - one, three, six, and ten weeks postoperatively - was developed to: 1) provide greatest antiproliferative and anti-inflammatory effects closer to the period of surgical injury, 2) maintain persistent effects through the typical PVR formation window of 4 - 8 weeks after surgery, and 3) minimize the corneal toxicity of accumulating methotrexate exposure. Our group has published and presented convincing evidence that both intraoperative infusion and postoperative injection dosing have clinical efficacy. It remains to be elucidated whether the infusion approach, the injection approach or a combination of both are needed for optimal effect. This is the underlying rationale for the 1:1:1:1 randomization strategy into four groups.

Detailed Study Visit Description

The Study will consist of 11 visits spread out over about 12 months. These are summarized in the table attached below. In order: