Methotrexate for Retinal Detachment

(FIXER Trial)

Overseen By Christopher Riemann, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Cincinnati Eye Institute, Southwest Ohio

Disqualifiers: Pregnancy, Chronic retinal detachment, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 12

860 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine if methotrexate, a medication, can prevent proliferative vitreoretinopathy (PVR) after surgery for a specific type of retinal detachment. Researchers are testing various methods of administration, including infusions and injections, to identify the most effective approach. Individuals scheduled for retinal detachment surgery at the Cincinnati Eye Institute, who have not previously undergone this surgery, may be suitable candidates. As a Phase 2 trial, the research focuses on assessing the treatment's effectiveness in an initial, smaller group of participants.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinator or your doctor.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

A previous study found that methotrexate lowered the risk of proliferative vitreoretinopathy (PVR) by about 50%. This finding is encouraging because PVR can occur after surgery to repair a detached retina. Methotrexate has been used safely in various eye treatments. Some patients experienced mild side effects, such as eye discomfort or blurry vision, but these were not serious. While methotrexate is generally well-tolerated, it is important to note that this study is in phase 2. This phase indicates that earlier trials demonstrated sufficient safety to test the treatment on more people, but researchers continue to monitor for any side effects. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Most treatments for retinal detachment involve surgical procedures to reattach the retina, sometimes complemented by laser therapy or cryotherapy. However, researchers are excited about methotrexate because it offers a new approach by potentially reducing inflammation and preventing scar tissue formation, which are crucial in maintaining retinal attachment post-surgery. Methotrexate is unique in this context as it can be delivered directly into the eye either through an infusion during surgery or via injections after surgery, which might enhance its effectiveness compared to systemic treatments. This targeted delivery could lead to better outcomes and fewer complications, making it an exciting development in the management of retinal detachment.

What evidence suggests that this trial's treatments could be effective for preventing PVR after retinal detachment repair?

Research has shown that methotrexate may help after surgery for a detached retina. In this trial, participants will be assigned to different treatment arms to evaluate its effectiveness. One arm will receive both intraoperative intraocular methotrexate infusion and postoperative methotrexate injections. Another arm will receive standard surgery followed by postoperative methotrexate injections. A third arm will receive surgery with intraoperative methotrexate infusion and postoperative sham injections. A control group will receive no methotrexate. In previous studies, 77.8% of eyes treated with methotrexate stayed attached without needing more surgery. Another study found that using methotrexate after surgery reduced the need for another operation and improved vision. Patients who took methotrexate were less likely to develop a complication called PVR. Overall, the evidence suggests methotrexate can effectively aid recovery after retinal detachment surgery. ^{6 7 8 9 10}

Are You a Good Fit for This Trial?

Adults over 18 undergoing primary retinal detachment surgery at Cincinnati Eye Institute who can consent. Excluded are those under 18, pregnant or not using contraception for 12 weeks post-surgery, with eye infections/trauma, chronic detachment, prior retinal surgeries (except pneumatic retinopexy), Grade C PVR, methotrexate contraindications like allergy or breastfeeding.

Exclusion Criteria

I am under 18 years old.

I have had a detached retina for more than six weeks.

I have had surgery for a detached retina but not pneumatic retinopexy.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

1-2 weeks

1 visit (in-person)

Surgery

Vitrectomy surgery for retinal detachment repair is performed with randomization into one of four study groups

1 day

1 visit (in-person)

Postoperative Treatment

Participants receive either methotrexate or sham injections at weeks 1, 3, 6, and 10 post-surgery

10 weeks

4 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness, including visual acuity and presence of PVR, up to 12 months post-surgery

12 months

6 visits (in-person)

What Are the Treatments Tested in This Trial?

Interventions

• Methotrexate
• Sham Injection

Trial Overview The FIXER trial is testing if methotrexate prevents scarring after retina surgery. Patients are randomly put into four groups: some get methotrexate in an infusion and as injections; others get a placebo injection with/without the methotrexate infusion.

How Is the Trial Designed?

Group I: Injection group Experimental Treatment 1 Intervention

receiving standard surgery without intraoperative methotrexate followed by postoperative 400µg intravitreal methotrexate injections 1, 3, 6, and 10 weeks after surgery.

Group II: Infusion Group Experimental Treatment 1 Intervention

receiving surgery with intraoperative intraocular methotrexate infusion as described above and postoperative sham injections.

Group III: Combined Infusion/Injection group Experimental Treatment 2 Interventions

receiving both intraoperative intraocular methotrexate infusion and postoperative 400µg intravitreal methotrexate injections 1, 3, 6, and 10 weeks after surgery.

Group IV: Control Group Placebo Group 1 Intervention

receiving no methotrexate

Methotrexate is already approved in United States, Canada, European Union for the following indications:

Approved in United States as Trexall for:

• Acute lymphoblastic leukemia
• Non-Hodgkin's lymphoma
• Osteosarcoma
• Breast cancer
• Lung cancer
• Head and neck cancer
• Psoriasis
• Rheumatoid arthritis

Approved in Canada as Mexate for:

• Acute lymphoblastic leukemia
• Non-Hodgkin's lymphoma
• Osteosarcoma
• Breast cancer
• Lung cancer
• Head and neck cancer
• Psoriasis
• Rheumatoid arthritis

Approved in European Union as Methotrexate for:

• Acute lymphoblastic leukemia
• Non-Hodgkin's lymphoma
• Osteosarcoma
• Breast cancer
• Lung cancer
• Head and neck cancer
• Psoriasis
• Rheumatoid arthritis
• Crohn's disease
• Ulcerative colitis

Who Is Running the Clinical Trial?

Cincinnati Eye Institute, Southwest Ohio

Lead Sponsor

Trials

1

Recruited

860+

Published Research Related to This Trial

In a study involving 11 patients with rhegmatogenous retinal detachment and grade C proliferative vitreoretinopathy, repeated intra-silicone oil injections of methotrexate led to successful retinal reattachment in all cases during a follow-up period of 6 to 15 months.

The treatment resulted in a significant improvement in best-corrected visual acuity, with no observed ocular or systemic side effects, suggesting that this method is both effective and safe for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Repeated Injection of Methotrexate into Silicone Oil-Filled Eyes for Grade C Proliferative Vitreoretinopathy: A Pilot Study. Nourinia, R., Borna, F., Rahimi, A., et al.[2019]

In a pilot study involving 30 patients with advanced proliferative vitreoretinopathy (PVR) undergoing vitrectomy, 80% maintained retinal attachment after four months, indicating the efficacy of intravitreal methotrexate (MTX) infusion as an adjunctive therapy.

The study found no methotrexate-related complications, suggesting that this treatment is safe for patients with complicated retinal detachment, although further controlled studies are needed to confirm its benefits.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Use of Intravitreal Methotrexate Infusion in Complicated Retinal Detachment for Prevention of Proliferative Vitreoretinopathy in a Pilot Study. Jahangir, S., Jahangir, T., Ali, MH., et al.[2021]

Intravitreal methotrexate (MTX) significantly improved visual acuity in 85.7% of patients with refractory retinal vasculitis due to Behcet disease, with an average improvement of 3.3 lines over a follow-up period of about 25 weeks.

MTX treatment led to a significant reduction in the levels of inflammatory cytokines IL-6 and IL-8 in the aqueous humor, suggesting its efficacy in addressing the underlying inflammation associated with the condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of intravitreal methotrexate and aqueous humor cytokine levels in refractory retinal vasculitis in Behcet disease. Bae, JH., Lee, SC.[2013]

Methotrexate (MTX) used as an adjunctive treatment for proliferative vitreoretinopathy (PVR) in patients with retinal detachment showed an 80% retinal re-attachment rate and a significant improvement in visual acuity after 10 months, indicating its potential efficacy.

While MTX demonstrated promising results compared to controls, with a slightly lower reattachment rate of 83%, the study highlights the need for further research due to the limited number of studies, potential biases, and variations in treatment protocols.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intravitreal Methotrexate for the Prevention and Treatment of Proliferative Vitreoretinopathy in Rhegmatogenous Retinal Detachment: A Systematic Review. Balas, M., Abdelaal, A., Popovic, MM., et al.[2022]

Methotrexate (MTX) is biocompatible up to a concentration of 266 µg/ml and effectively inhibits the proliferation of retinal pigment epithelial (RPE) cells, making it a potential adjunct treatment during retinal detachment surgery to reduce the risk of proliferative vitreoretinopathy (PVR).

In contrast, fluorouracil (5-FU) shows an antiproliferative effect at low concentrations but causes cell damage and apoptosis in photoreceptor cells at higher concentrations, limiting its use in the posterior segment of the eye.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparative cytotoxic and antiproliferative profile of methotrexate and fluorouracil on different ocular cells. Schulz, A., Rickmann, A., Julich-Haertel, H., et al.[2022]

Intravitreal methotrexate infusion (IMI) was found to be safe for use in patients undergoing surgery for retinal detachment, with no adverse events reported up to 3 months postoperatively.

However, IMI did not significantly improve the rates of retinal attachment or reduce the incidence of proliferative vitreoretinopathy (PVR) compared to the control group, indicating that while it is safe, its efficacy in preventing PVR after surgery is limited.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intravitreal methotrexate infusion for prophylaxis of proliferative vitreoretinopathy after pars plana vitrectomy for rhegmatogenous retinal detachment. Fouad Aziz, JH., Abd Al-Hakim Zaki, M., Abd El-Fattah El-Shazly, A., et al.[2023]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40632995/

Real-World Efficacy of Intravitreal Methotrexate for ... Results: Retinal reattachment was achieved without additional surgery in 21 (77.8%) eyes in group 1 and 10 (71.4%) in group 2 at final follow-up ...

2. journals.healio.com journals.healio.com/doi/10.3928/23258160-20250826-01

Outcomes of Complex PVR Retinal Detachment Repair With ... At 1 year, 78.4% of MTX eyes (29/37) and 78.5% of control eyes (62/79) were attached (risk difference: 0.1%, 95% CI: −14.4% to +17.4%). At final ...

3. medpagetoday.com medpagetoday.com/meetingcoverage/asrs/116811

'Amazing' Results With Methotrexate for Retinal ... A retrospective review of 255 cases of complex RD showed that postoperative methotrexate alone reduced the reoperation rate and improved vision ...

4. ophthalmologyretina.org ophthalmologyretina.org/article/S2468-6530(24)00524-4/fulltext

Association between Systemic Methotrexate Therapy and ... The 6-month incidence of PVR in patients on systemic MTX was 4.2%, compared with 9.2% for those not taking MTX. In the regression analysis, ...

5. journals.sagepub.com journals.sagepub.com/doi/10.1177/24741264251323305

Postoperative Methotrexate to Reduce Reoperation Rate ... In summary, our results suggest that postoperative IVT MTX injections reduce reoperation rates and improve vision for patients with complex ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC2926651/

Ocular side effects of anti-rheumatic medications Methotrexate-related ocular toxicities consist of peri-orbital edema, ocular pain, blurred vision, photophobia, conjunctivitis, blepharitis, decreased reflex ...

7. esmed.org esmed.org/MRA/mra/article/view/6695

Methotrexate as an Adjunctive Therapy for Proliferative ... Notably, some randomized control trials suggest that methotrexate may modulate proliferative vitreoretinopathy severity, significantly reducing ...

8. clinicaltrials.gov clinicaltrials.gov/study/NCT07058337?cond=%22Retinal+Diseases%22

Methotrexate in Retinal Detachment With Proliferative ... A phase of research to describe clinical trials that focus on the safety of a drug. They are usually conducted with healthy volunteers, and the goal is to ...

9. ophthalmologyretina.org ophthalmologyretina.org/article/S2468-6530(24)00477-9/fulltext

A Modified Intravitreal Methotrexate Protocol for the ... The use of IVT MTX injections in eyes with PVR undergoing RD repair was associated with a high rate of primary retinal attachment after SOR.

10. aao.org aao.org/eyenet/article/antimetabolites-to-reduce-pvr-risk

Methotrexate or Azathioprine May Reduce PVR Risk After ... MTX was found to reduce the risk of PVR by approximately 50% (adjusted risk ratio [aRR] 0.58 [95% CI 0.47-0.71]). Similar findings were observed ...