Bevacizumab for Retinopathy of Prematurity

(ROP4 Trial)

Recruiting at 35 trial locations

Overseen By Brooke P Fimbel

Age: < 18

Sex: Any

Trial Phase: Phase 2

Sponsor: Jaeb Center for Health Research

Disqualifiers: Previous ROP treatment, Stage 4/5 ROP, 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

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Approved in 4 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 1

Duration: Immediate

80 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial information does not specify whether participants need to stop taking their current medications.

What data supports the effectiveness of the drug Bevacizumab (Avastin) for treating retinopathy of prematurity?

Research shows that Bevacizumab (Avastin) is a promising treatment for retinopathy of prematurity, as it is administered directly into the eye and may be more effective with fewer complications compared to other treatments. ^{1 2 3 4 5}

Is bevacizumab safe for use in humans, particularly for retinopathy of prematurity?

Bevacizumab has been used in retinopathy of prematurity with satisfactory results and no systemic complications, but some cases reported increased fibrosis (thickening and scarring of tissue) and tissue contraction as side effects. ^{3 6 7 8 9}

How is the drug Avastin (bevacizumab) unique in treating retinopathy of prematurity?

Avastin (bevacizumab) is unique because it is injected directly into the eye to block a protein called VEGF, which can cause abnormal blood vessel growth in the retina. This method may be more effective and have fewer complications compared to other treatments for retinopathy of prematurity. ^{1 2 3 5 10}

What is the purpose of this trial?

Type 1 retinopathy of prematurity in zone I represents the most severe type of ROP and has the worst prognosis. It is unknown whether low-dose bevacizumab will be successful in these severe cases. Also unknown is the timing and extent of peripheral retinal vascularization after low-dose bevacizumab compared with the standard dose. The current study will evaluate whether doses of 0.063 mg and 0.25mg are effective as treatment for type 1 ROP, with ROP and retinal vessels all in zone I.

Research Team

David K Wallace, MD, MPH

Principal Investigator

Vanderbilt University

Eligibility Criteria

This trial is for premature babies with a birth weight under 1251 grams who have been newly diagnosed with severe type of retinopathy (eye disease) in zone I. Babies can't participate if they have other significant eye problems, previous ROP treatments, active infections around the eye, advanced stages of ROP, or if they cannot receive treatment within two days of diagnosis.

Inclusion Criteria

I was recently diagnosed with a specific eye condition in the past 2 days.

My birth weight was less than 1251 grams.

Exclusion Criteria

I have been treated for retinopathy of prematurity before.

Opacity that precludes an adequate view of the retina

My eye condition is at stage 4 or 5 ROP.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2 days

Treatment

Participants receive a single intravitreal injection of either 0.063 mg or 0.25 mg of bevacizumab in one or both eyes

Immediate

1 visit (in-person)

Initial Follow-up

Study exams to monitor treatment success and safety at 1 day, 4 days, 1, 2, 3, and 4 weeks post-treatment

4 weeks

Multiple visits (in-person)

Extended Follow-up

Additional study exams to assess long-term outcomes at 2 and 4 months post-treatment, and at adjusted age 6 and 12 months

12 months

Multiple visits (in-person)

Treatment Details

Interventions

• Bevacizumab

Trial Overview The study is testing low doses of Bevacizumab (0.063 mg and 0.25mg) to see if it's effective for treating severe retinopathy in very young infants. It will also look at how well the retina's blood vessels develop after treatment compared to standard doses.

Participant Groups

Group I: Bevacizumab- 0.25 mg Experimental Treatment 1 Intervention

Participants will receive a single intravitreal injection of 0.25 mg of bevacizumab in one or both eyes following enrollment into the study. The injection/s should be given as soon as possible but no later than 2 days after the diagnosis of type 1 ROP meeting all of the inclusion criteria and none of the exclusion criteria.

Group II: Bevacizumab- 0.063 mg Experimental Treatment 1 Intervention

Participants will receive a single intravitreal injection of 0.063 mg of bevacizumab in one or both eyes following enrollment into the study. The injection/s should be given as soon as possible but no later than 2 days after the diagnosis of type 1 ROP meeting all of the inclusion criteria and none of the exclusion criteria.

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

Approved in European Union as Avastin for:

• Colorectal cancer
• Breast cancer
• Non-small cell lung cancer
• Renal cell carcinoma
• Ovarian cancer

Approved in United States as Avastin for:

• Colorectal cancer
• Non-small cell lung cancer
• Glioblastoma
• Renal cell carcinoma
• Cervical cancer
• Ovarian cancer

Approved in Japan as Avastin for:

• Colorectal cancer
• Non-small cell lung cancer
• Breast cancer
• Renal cell carcinoma
• Ovarian cancer

Approved in Canada as Avastin for:

• Colorectal cancer
• Non-small cell lung cancer
• Breast cancer
• Renal cell carcinoma
• Ovarian cancer

Who Is Running the Clinical Trial?

Jaeb Center for Health Research

Lead Sponsor

Trials

162

Recruited

36,200+

National Eye Institute (NEI)

Collaborator

Trials

572

Recruited

1,320,000+

Pediatric Eye Disease Investigator Group

Collaborator

Trials

20

Recruited

4,800+

Findings from Research

Intravitreal bevacizumab (Avastin) was used as a salvage treatment for progressive retinopathy of prematurity (ROP) in three patients, showing stabilization of the disease despite previous laser therapy.

The treatment allowed for improved visibility and management of ROP, enabling further laser treatment when necessary, indicating its potential efficacy in difficult cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Off-label use of intravitreal bevacizumab (Avastin) for salvage treatment in progressive threshold retinopathy of prematurity. Lalwani, GA., Berrocal, AM., Murray, TG., et al.[2015]

Avastin (bevacizumab) therapy shows promise as a more effective treatment for retinopathy of prematurity (ROP) with potentially fewer complications, especially in severe cases where traditional LASER therapy has poor outcomes.

Current clinical trials are exploring the use of Avastin alone for acute vision-threatening ROP and in combination with LASER therapy for recurrent cases, indicating a shift towards less destructive treatment methods.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antivascular endothelial growth factor for retinopathy of prematurity. Mintz-Hittner, HA., Best, LM.[2022]

In a study involving 12 eyes of 7 premature infants with type 1 retinopathy of prematurity, a single intravitreal injection of bevacizumab (Avastin) led to complete regression of the disease without the need for further treatment.

The infants treated had a mean weight of 846.57 grams and a mean gestational age of 25.57 weeks, indicating that bevacizumab is a promising therapy for this vulnerable population, although more research is needed to establish its role compared to other treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of type 1 retinopathy of prematurity with intravitreal bevacizumab (Avastin). Dorta, P., Kychenthal, A.[2022]

A premature infant born at 26 weeks was successfully treated for severe retinopathy of prematurity with bevacizumab, leading to complete resolution of the disease.

Bevacizumab is an effective and cost-efficient treatment option for retinopathy of prematurity, which can be administered easily by ophthalmologists without specialized equipment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intravitreal bevacizumab for the treatment of retinopathy of prematurity: a case report. Flavahan, PW., Lavy, TE., Wykes, W.[2015]

In a case series of 11 premature infants with moderate to severe stage 3 retinopathy of prematurity (ROP), treatment with a single intravitreal injection of bevacizumab was safe and effective, with no complications reported.

All 22 eyes treated showed successful outcomes without any retinal detachment or other ocular abnormalities, suggesting that bevacizumab could be a promising alternative to laser therapy for ROP.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intravitreal injection of bevacizumab (avastin) for treatment of stage 3 retinopathy of prematurity in zone I or posterior zone II. Mintz-Hittner, HA., Kuffel, RR.[2022]

In a study involving 24 eyes from 13 infants with severe retinopathy of prematurity (ROP), intraocular bevacizumab treatment led to regression of new blood vessels in all cases, demonstrating its efficacy in managing this condition.

While many eyes experienced vision salvage and no serious neurodevelopmental issues were noted over a mean follow-up of 30.7 months, there were significant adverse events, including retinal detachment and hepatic dysfunction, highlighting the need for careful monitoring when using this treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Serious adverse events and visual outcomes of rescue therapy using adjunct bevacizumab to laser and surgery for retinopathy of prematurity. The Indian Twin Cities Retinopathy of Prematurity Screening database Report number 5. Jalali, S., Balakrishnan, D., Zeynalova, Z., et al.[2016]

Intravitreal injection of bevacizumab is a safe and effective treatment for aggressive posterior retinopathy of prematurity (APROP), as demonstrated in a case involving a premature infant with significant retinal improvements after treatment.

While tissue contraction can occur as a side effect, localized tractional retinal detachment can be effectively managed with lens-sparing vitrectomy, allowing for successful retinal reattachment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adjunctive effect of intravitreal bevacizumab prior to lens-sparing vitrectomy in aggressive posterior retinopathy of prematurity: a case report. Sun, HJ., Choi, KS., Lee, SJ.[2021]

A systematic review of 9 studies involving 77 eyes of 48 infants revealed significant variability in the off-label use of bevacizumab for treating retinopathy of prematurity (ROP), with doses ranging from 0.4 to 1.25 mg, and 0.75 mg being the most common.

The review highlighted the need for further randomized controlled trials to determine the optimal timing, frequency, and dosage of bevacizumab, while also emphasizing the importance of monitoring for potential systemic complications and long-term effects in infants.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A systematic analysis of the off-label use of bevacizumab for severe retinopathy of prematurity. Micieli, JA., Surkont, M., Smith, AF.[2022]

Infants with treatment-warranted retinopathy of prematurity (TW-ROP) who received intravitreal bevacizumab (IVB) injections had significantly fewer diagnoses and readmissions compared to those treated with diode laser photocoagulation (DLP), suggesting better immediate outcomes with IVB.

At an average follow-up of 20 months, there was no significant difference in neurodevelopmental delay between the two treatment groups, indicating that systemic morbidity may be similar for both IVB and DLP treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Outcomes of Intravitreal Bevacizumab and Diode Laser Photocoagulation for Treatment-Warranted Retinopathy of Prematurity. Chen, TA., Schachar, IH., Moshfeghi, DM.[2019]

Intravitreal bevacizumab (Avastin) was found to enter the systemic circulation and cause long-lasting changes in lung matrix metalloproteinases (MMPs) and their inhibitors in neonatal rats, suggesting potential systemic effects beyond its local application.

The treatment with Avastin led to increased levels of MMP-2 and MMP-9 in the lungs of rats exposed to hyperoxia and intermittent hypoxia, which may contribute to impaired lung development and conditions like bronchopulmonary dysplasia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intravitreal bevacizumab alters type IV collagenases and exacerbates arrested alveologenesis in the neonatal rat lungs. Valencia, AM., Cai, CL., Tan, J., et al.[2019]

References

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

Off-label use of intravitreal bevacizumab (Avastin) for salvage treatment in progressive threshold retinopathy of prematurity. [2015]

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

Antivascular endothelial growth factor for retinopathy of prematurity. [2022]

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

Treatment of type 1 retinopathy of prematurity with intravitreal bevacizumab (Avastin). [2022]

4. Scotland pubmed.ncbi.nlm.nih.gov

Intravitreal bevacizumab for the treatment of retinopathy of prematurity: a case report. [2015]

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

Intravitreal injection of bevacizumab (avastin) for treatment of stage 3 retinopathy of prematurity in zone I or posterior zone II. [2022]

6. England pubmed.ncbi.nlm.nih.gov

Serious adverse events and visual outcomes of rescue therapy using adjunct bevacizumab to laser and surgery for retinopathy of prematurity. The Indian Twin Cities Retinopathy of Prematurity Screening database Report number 5. [2016]

7. Japan pubmed.ncbi.nlm.nih.gov

Adjunctive effect of intravitreal bevacizumab prior to lens-sparing vitrectomy in aggressive posterior retinopathy of prematurity: a case report. [2021]

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

A systematic analysis of the off-label use of bevacizumab for severe retinopathy of prematurity. [2022]

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

Outcomes of Intravitreal Bevacizumab and Diode Laser Photocoagulation for Treatment-Warranted Retinopathy of Prematurity. [2019]

10. England pubmed.ncbi.nlm.nih.gov

Intravitreal bevacizumab alters type IV collagenases and exacerbates arrested alveologenesis in the neonatal rat lungs. [2019]