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

Trial Summary

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.

What data supports the effectiveness of the drug Methotrexate for retinal detachment?

Research shows that Methotrexate, when injected into the eye, helped maintain retinal attachment in 80% of patients with complicated retinal detachment and improved vision in some cases. However, more studies are needed to confirm these findings. ^{1 2 3 4 5}

Is methotrexate safe for use in treating retinal detachment?

Studies suggest that methotrexate is generally safe for use in treating retinal detachment, with only a few mild complications reported. However, more research is needed to confirm its safety and effectiveness. ^{1 2 3 4 6}

How is the drug methotrexate unique for treating retinal detachment?

Methotrexate is unique for treating retinal detachment because it is used as an intravitreal (injected into the eye) agent to prevent and treat proliferative vitreoretinopathy (PVR), a complication that can occur after retinal detachment surgery. This approach is different from standard treatments as it directly targets the eye to reduce the risk of PVR, which is not typically addressed by other treatments. ^{1 2 3 4 5}

What is the purpose of this trial?

I. Title Prevention of ProliFerative Vitreoretinopathy with Intravitreal MethotreXate in Primary Retinal DEtachment Repair (FIXER) Trial * Today's Date: September 18, 2023 II. Principal Investigator * Principal Investigator: Christopher D. Riemann, M.D. (Cincinnati Eye Institute) * Email: [e-mail], Phone: [phone] V. Research Summary Purpose: To evaluate methotrexate for the prevention of PVR after primary rhegmatogenous retinal detachment repair. Methods: Inclusion Criteria: • Any adult patient, age ≥18 years-old, undergoing primary rhegmatogenous retinal detachment surgery with pars plana vitrectomy at the Cincinnati Eye Institute in Blue Ash, Ohio who is able to give informed consent. Exclusion Criteria: * Age \<18 years old * Pregnant patients or patients of child bearing potential unwilling to utilize long term contraception for the 12-week period spanning vitrectomy surgery for retinal detachment repair up until the 3 month postoperative visit. * History of endophthalmitis, ruptured globe or significant trauma in the affected eye * Chronic retinal detachment (symptoms greater than or equal to six weeks) * Any previous previous retinal detachment repair with pars plana vitrectomy, or scleral buckling surgery. Patients having undergone previous pneumatic retinopexy will not be excluded. * Presence of Grade C PVR: full thickness retinal folds or subretinal bands * Patients with contraindications to methotrexate, including breastfeeding, pregnancy, attempting to conceive a child or any known hypersensitivity or intolerance to methotrexate * Patients with diminished mental capacity precluding their ability to give informed consent. Study Design and Randomization This prospective double masked trial will randomize patients into four groups in a 1:1:1:1 fashion. All attending surgeons and patients will be masked to group randomization. Randomization into four groups will occur on the day of surgery by the Cincinnati Eye Institute's pharmacist, Deepali Chachare. Group A will consist of ≥ 150 patients receiving intraoperative infusion with balanced salt solution containing methotrexate (40mg/500mL BSS), and methotrexate intravitreal injections (400mcg/0.05mL) at postoperative weeks 1, 3, 6, and 10. Group B will consist of ≥ 150 patients receiving intraoperative balanced salt solution infusion containing methotrexate, and sham intravitreal injections at postoperative weeks 1, 3, 6, and 10. Group C will consist of ≥ 150 patients receiving a balanced salt solution infusion without methotrexate, and methotrexate injections at postoperative weeks 1, 3, 6, and 10. Group D will consist of ≥ 150 patients receiving intraoperative balanced salt solution infusion without methotrexate, and sham intravitreal injections at postoperative weeks 1, 3, 6, and 10.

Eligibility Criteria

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

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)

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

References

1. Switzerland pubmed.ncbi.nlm.nih.gov

Repeated Injection of Methotrexate into Silicone Oil-Filled Eyes for Grade C Proliferative Vitreoretinopathy: A Pilot Study. [2019]

2. United States pubmed.ncbi.nlm.nih.gov

Intravitreal Methotrexate for the Prevention and Treatment of Proliferative Vitreoretinopathy in Rhegmatogenous Retinal Detachment: A Systematic Review. [2022]

3. England pubmed.ncbi.nlm.nih.gov

Comparative cytotoxic and antiproliferative profile of methotrexate and fluorouracil on different ocular cells. [2022]

4. United States pubmed.ncbi.nlm.nih.gov

Use of Intravitreal Methotrexate Infusion in Complicated Retinal Detachment for Prevention of Proliferative Vitreoretinopathy in a Pilot Study. [2021]

5. United States pubmed.ncbi.nlm.nih.gov

Effect of intravitreal methotrexate and aqueous humor cytokine levels in refractory retinal vasculitis in Behcet disease. [2013]

6. United States pubmed.ncbi.nlm.nih.gov

Intravitreal methotrexate infusion for prophylaxis of proliferative vitreoretinopathy after pars plana vitrectomy for rhegmatogenous retinal detachment. [2023]