Iopidine to Decrease Intraocular Pressure Rise After Injections

3.1 Primary Objective To compare the acute post-injection IOP response between participants receiving prophylactic Iopidine and control participants receiving no pre-injection study medication.

3.2 Primary Endpoint Change in IOP from the immediately pre-injection measurement to the 1-minute post-injection measurement.

3.3 Secondary Objectives and Endpoints • IOP at 5, 15, and 30 minutes after injection. • Magnitude of peak post-injection IOP elevation. • Proportion of participants with clinically significant IOP elevations, including IOP ≥30 mmHg and IOP ≥40 mmHg.

• Rate and time course of IOP normalization after injection.
• Incidence of transient vision loss after injection.
• Duration of transient vision loss when present.
• Post-injection IOP area under the curve.
• Association between the magnitude/duration of IOP elevation and transient vision loss.
• Exploratory comparison of treatment effect between Eylea HD and Syfovre. 4. Study Design This is a prospective, randomized, controlled, open-label, single-site investigator-initiated clinical trial. A total of 120 participants will be randomized in a 1:1 ratio either to receive one drop of apraclonidine 1% ophthalmic solution (Iopidine) approximately 20-30 minutes before a clinically indicated intravitreal injection of Eylea HD or Syfovre, or to a control group that will receive no pre-injection study medication.

The intravitreal injection is part of the participant's routine clinical care. The research-specific intervention for participants assigned to the Iopidine group is administration of Iopidine. Participants assigned to the control group will receive no pre-injection study medication. Both groups will undergo the additional standardized post-injection IOP assessments and transient-vision-loss assessments.

5. Study Population 5.1 Inclusion Criteria

• Adult patient able to provide informed consent.
• Scheduled to receive a clinically indicated intravitreal injection with Eylea HD or Syfovre.
• Reports a prior history of transient vision loss following intravitreal injection.
• Willing and able to undergo study-specific IOP measurements and complete study assessments.

5.2 Exclusion Criteria • Known hypersensitivity or prior clinically significant allergic reaction to apraclonidine, clonidine, or any component of Iopidine 1% ophthalmic solution.

• Current treatment with a monoamine oxidase inhibitor (MAOI) or use of an MAOI within a clinically relevant washout period before enrollment.

• Age younger than 18 years.
• Pregnancy or breastfeeding, if applicable, unless the investigator determines participation is appropriate based on available safety information and applicable regulatory requirements.
• Severe or unstable cardiovascular disease that, in the judgment of the investigator, could increase the risk associated with apraclonidine, including unstable coronary artery disease, recent myocardial infarction, clinically significant bradycardia, symptomatic hypotension, uncontrolled hypertension, or clinically significant cerebrovascular disease.
• History of clinically significant vasovagal episodes, syncope, or symptomatic hypotension that, in the investigator's judgment, would increase the risk of apraclonidine administration.
• Severe renal or hepatic impairment when, in the investigator's judgment, systemic exposure to apraclonidine could pose increased risk.
• Baseline IOP sufficiently low that additional pharmacologic IOP reduction could pose a clinical risk, as determined by the investigator.
• Active ocular infection or significant ocular inflammation in the study eye at the time of the planned intravitreal injection.
• Any ocular condition that would prevent reliable IOP measurement or substantially confound assessment of the post-injection IOP response.
• Prior glaucoma surgery or other ocular surgery that, in the investigator's judgment, would substantially alter the expected acute IOP response to intravitreal injection, if such patients are not intended to be included in the study population.
• Use of apraclonidine or another short-acting IOP-lowering medication immediately before the study injection when such treatment could materially confound the study endpoint.
• Requirement for prophylactic IOP-lowering treatment before intravitreal injection as part of the patient's usual clinical care, such that assignment to the control group without prophylactic IOP-lowering medication would not be clinically appropriate.
• Inability to complete the required IOP measurements at 1, 5, 15, and 30 minutes after injection.
• Inability or unwillingness to provide informed consent or comply with study procedures.
• Participation in another interventional clinical trial that, in the investigator's judgment, could interfere with the safety assessments or interpretation of study outcomes.

• Any medical, ocular, psychiatric, or other condition that, in the opinion of the investigator, would place the participant at unacceptable risk, interfere with study procedures, or compromise interpretation of the study results.

  6. Recruitment and Informed Consent Potential participants will be identified from patients presenting to Retina Consultants of Delmarva for clinically indicated Eylea HD or Syfovre injections who report prior transient vision loss after intravitreal injection. Participation will be voluntary.

Written informed consent will be obtained before any study-specific intervention or procedure. Participants will be given adequate opportunity to review the consent form, ask questions, and decide whether to participate. Refusal to participate or withdrawal from the study will not affect the participant's routine ophthalmic care.

7. Randomization and Masking 7.1 Randomization

Eligible participants who provide informed consent will be randomized in a 1:1 allocation to one of two study groups:

• Iopidine Group (n=60): Participants will receive one drop of apraclonidine 1% ophthalmic solution (Iopidine) approximately 20-30 minutes prior to the clinically indicated intravitreal injection.
• Control Group (n=60): Participants will not receive Iopidine prior to the intravitreal injection and will otherwise undergo the same study-specific IOP measurements and assessments.

Randomization will be performed using a computer-generated block randomization schedule to maintain balanced allocation between the two study groups throughout enrollment and ensure that, upon completion of enrollment, approximately 60 participants are assigned to each group.

The randomization assignment will be determined after eligibility has been confirmed and informed consent has been obtained. The participant's treatment assignment will be documented in the study records.

7.2 Administration of Study Intervention For participants randomized to the Iopidine group, one drop of Iopidine 1% will be administered by a trained clinical technician approximately 20-30 minutes before the intravitreal injection.

Participants assigned to the control group will receive no study-specific pre-injection medication.

All participants will otherwise receive their clinically indicated intravitreal injection and undergo the same protocol-specified IOP assessments.

7.3 Masking This will be a fully unmasked (open label) study. Participants, the Principal Investigator, treating physicians, clinical technicians, personnel performing IOP measurements, and study personnel responsible for data collection and analysis will be aware of treatment assignment.

Participants randomized to the control group will receive no study-specific pre-injection medication, and no procedures will be undertaken for allocation concealment or masking after randomization.

To minimize potential measurement bias associated with the unmasked design, IOP will be obtained at prespecified standardized time points immediately before injection and at 1, 5, 15, and 30 minutes after injection, using the same standardized IOP measurement technique for both treatment groups. Treatment assignment will not alter the timing or method of IOP measurement.

8. Study Procedures 8.1 Pre-Injection

1. Confirm eligibility and obtain written informed consent.
2. Record relevant study data and the intravitreal agent to be administered.
3. For participants randomized to the Iopidine group, administer one drop of Iopidine 1% approximately 20-30 minutes before the intravitreal injection. Participants randomized to the control group will receive no study-specific pre-injection medication.

4. Measure IOP immediately prior to intravitreal injection. 8.2 Intravitreal Injection The participant will receive the clinically indicated Eylea HD or Syfovre injection according to the site's standard clinical procedure. The protocol does not alter the indication for, selection of, or routine administration of the intravitreal therapeutic agent.

   8.3 Post-Injection Assessments

   • IOP at 1 minute after injection.
   • IOP at 5 minutes after injection.
   • IOP at 15 minutes after injection.
   • IOP at 30 minutes after injection.
   • Assessment for transient vision loss, including occurrence and duration when present.

   The 1-minute measurement is intended to capture the acute IOP spike. Later measurements characterize the magnitude and duration of IOP elevation and subsequent normalization.

   8.4 IOP Measurement Method The sponsor proposal specifies the measurement time points but does not identify the tonometer, measurement technique, number of readings, or handling of implausible measurements. These details should be added before submission to ensure standardized data collection.

9. Study Duration and Participant Completion Each participant's active study participation is expected to occur around a single intravitreal injection visit through completion of the 30-minute post-injection assessment and assessment of transient vision loss. The source proposal does not specify overall recruitment duration, study start/end dates, or whether later safety follow-up will occur; these items should be finalized before submission.

10. Risks and Safety Monitoring Research-related risks include adverse effects associated with apraclonidine 1% and discomfort associated with the additional IOP measurements. Potential ocular adverse effects of apraclonidine include conjunctival blanching, eyelid retraction, mydriasis, ocular irritation or discomfort, dry eye, and allergic or hypersensitivity reactions. Systemic effects may include dry mouth, altered taste, headache, fatigue or drowsiness, dizziness, nausea, and cardiovascular effects such as changes in blood pressure or heart rate. Tonometry may cause brief ocular discomfort or irritation and, rarely, a superficial corneal epithelial injury. Participants in the control group will receive no study-specific pre-injection medication and therefore will not be exposed to apraclonidine-related research risk. All participants will undergo clinically indicated intravitreal injection as part of routine care; the study does not alter the selected intravitreal medication or standard injection procedure. Study information will be handled in accordance with the privacy and confidentiality protections described in Section 14.

Participants will continue to receive standard clinical monitoring associated with intravitreal injection. The investigator will evaluate clinically significant post-injection IOP elevations and other adverse findings and provide treatment according to clinical judgment and standard of care.

10.1 Adverse Events Adverse events will be documented and assessed by the investigator for severity, seriousness, expectedness, and relationship to the study intervention or study procedures, as applicable. Serious or otherwise reportable events will be reported in accordance with WCG IRB requirements, applicable regulations, and any sponsor requirements.

10.2 Stopping/Withdrawal Criteria A participant may withdraw consent at any time. The investigator may discontinue study participation when continued participation is considered medically inappropriate, when a clinically significant adverse event warrants discontinuation, or when protocol requirements cannot be completed. The study may be temporarily suspended or permanently terminated by the Principal Investigator if an unexpected pattern of serious or clinically significant adverse events occurs that is considered possibly, probably, or definitely related to the study intervention; if new information becomes available indicating that continued administration of Iopidine may pose an unacceptable risk to participants; or if the Principal Investigator, IRB, sponsor, or applicable regulatory authority determines that continuation of the study is no longer appropriate. Any suspension or termination will be reported to the IRB and sponsor in accordance with applicable reporting requirements.

11. Potential Benefits Participants may or may not receive direct benefit. Iopidine may reduce the magnitude or duration of the post-injection IOP spike and may reduce transient vision loss, but these benefits are not established. Knowledge gained may help determine whether prophylactic IOP-lowering therapy is useful for patients receiving higher-volume intravitreal injections.

12. Alternatives to Participation The alternative is not to participate in the research and to receive the clinically indicated intravitreal injection and routine ophthalmic care without the study-specific Iopidine and additional research assessments.

13. Statistical Analysis The primary analysis will compare change in IOP from immediately pre-injection to 1 minute post-injection between the Iopidine and control groups.

Longitudinal analysis of IOP measurements at 1, 5, 15, and 30 minutes will characterize the overall post-injection IOP response and recovery between groups. Additional analyses may evaluate peak IOP, the proportions with IOP ≥30 mmHg and ≥40 mmHg, time to return toward pre-injection IOP, post-injection IOP area under the curve, the association between IOP elevation and transient vision loss, and exploratory treatment effects by Eylea HD versus Syfovre.

13.1 Sample Size The planned sample size is 120 participants (60 per group). The sponsor proposal does not provide a formal power or sample-size justification. A statistical power calculation should be added before final IRB submission if available, including the assumed treatment effect, variability, alpha, power, and allowance for non-evaluable participants.

14. Data Collection, Privacy, and Confidentiality Participant privacy and confidentiality will be maintained throughout the study. Information collected specifically for research purposes will be used only for the purposes of this study and will be reported in a de-identified manner. No participant will be identified by name or other direct personal identifier in study analyses, presentations, reports, or publications.

The participant's existing clinical information and routine care will continue to be documented in the practice's electronic medical record in the usual manner. No changes will be made to the practice's existing EMR recordkeeping procedures as a result of participation in this study.

Study-specific data will be maintained separately from the routine clinical record. Each participant will be assigned a unique numerical study identification number. Paper study records containing study-specific results, including protocol-specified IOP measurements and other study outcome data, will identify the participant by this numerical study identifier rather than by name.

Paper research records will be maintained in a secure location within the study site. Access to these records will be restricted to the Principal Investigator and Research Coordinator. Study data will not be used for purposes unrelated to this research.

When study results are analyzed or disseminated, data will be presented in aggregate or otherwise de-identified form so that individual participants cannot reasonably be identified.