Intraocular Pressure Outcomes After Lampalizumab Injections in Patients With Geographic Atrophy

This post hoc analysis of a randomized clinical trial investigates intraocular pressure outcomes after 1 year of repeated 0.1-mL intravitreous injections by analyzing data from 2 randomized clinical trials that investigated the safety of lampalizumab.

Key Points

Question

What are the intraocular pressure (IOP)–related outcomes associated with repeated 0.1-mL intravitreous injections for 1 year?

Findings

This post hoc analysis of data from 2 randomized clinical trials found low rates of clinically relevant IOP-related events after 1 year of intravitreous injections of lampalizumab, 0.1 mL.

Meaning

These results suggest that repeated 0.1-mL intravitreous injections can be administered with a low risk of IOP-related adverse events, which is valuable in designing future therapeutic trials of intravitreous agents that use volumes of 0.07 to 0.1 mL.

Abstract

Importance

Intraocular pressure (IOP) elevations of clinical relevance have been observed after the commonly used 0.05-mL volume for intravitreous injections. However, more recently approved intravitreous agents involve volumes from 0.07 to 0.1 mL. It is not well established whether repeated 0.1-mL intravitreous injections may result in IOP-related complications.

Objective

To investigate the effect of 1 year of repeated 0.1-mL intravitreous injections on IOP outcomes.

Design, Setting, and Participants

This study was a post hoc analysis of 2 clinical trials investigating the IOP safety of intravitreous lampalizumab on geographic atrophy secondary to age-related macular degeneration. Both trials were conducted between 2014 and 2018 and recruited participants who were 50 years or older and had bilateral geographic atrophy. This post hoc analysis was performed between 2018 and 2022.

Interventions

Intravitreous lampalizumab, 0.1 mL, every 4 weeks; lampalizumab, 0.1 mL, every 6 weeks; or sham procedure every 4 weeks or 6 weeks for 48 weeks.

Main Outcomes and Measures

IOP changes in the 4-week-frequency study arms and ocular adverse events to week 48 in all arms. The hypothesis for this analysis was formulated after data collection.

Results

Among a total of 1851 participants, there was no change in mean pre-injection IOP values through 48 weeks in either arm. The adverse events glaucoma and ocular hypertension were reported for 1.8% of participants treated with lampalizumab and 1.6% of those in the sham arm.

Conclusions and Relevance

Over 1 year, IOP increases were rare and did not affect treated participants more frequently than sham arm participants. These findings support the low risk of persistent IOP increases, on average, of intravitreous 0.1-mL injection volumes administered for 1 year in a manner similar to that performed in these clinical trials. These results may be valuable in the design of future therapeutic trials considering this volume for injections particularly as more recently approved agents use volumes of 0.07 to 0.1 mL.

Trial Registration

ClinicalTrials.gov Identifiers: NCT02247479 and NCT02247531

Introduction

Age-related macular degeneration (AMD) is a leading cause of blindness in the US.¹ The first line of clinical practice management for symptomatic neovascular AMD is frequent intravitreous injections of anti–vascular endothelial growth factor (anti-VEGF).^2,3 Although anti-VEGF agents are approved by the US Food and Drug Administration approved and associated with low incidence of serious adverse events (AEs),⁴ acute increases in intraocular pressure (IOP) were reported in patients receiving 0.05-mL intravitreous anti-VEGF injections.⁵ Typically, IOP returns to baseline at 30 minutes or less postinjection⁵; however, chronic increases in IOP have been reported in a small proportion of patients.^6,7 Recently approved intravitreous agents have involved greater monthly or every other month volumes of 0.07 to 0.1 mL.^8,9,10

Lampalizumab is an antigen-binding fragment of a humanized monoclonal antibody that inhibits complement factor D.^11,12 It was evaluated in participants with geographic atrophy, an advanced stage of AMD, in 2 identical phase 3 clinical trials, CHROMA and SPECTRI.¹² Trial participants received repeated doses of intravitreous lampalizumab, 0.1 mL, twice the volume used for anti-VEGF intravitreous injections in clinical practice, allowing study of the effects of repeated intravitreous injections larger than 0.05 mL. The current study investigated IOP outcomes at 1 year, including glaucoma and ocular hypertension, after 1 year of repeated injections of 0.1-mL volume.

Methods

Trial Design and Participants

The CHROMA (NCT02247479) and SPECTRI (NCT02247531) studies were identical global, randomized, double-masked, sham injection–controlled, phase 3 trials in geographic atrophy.¹² Participants were randomized in a 2:1:2:1 ratio to receive intravitreous lampalizumab, 10 mg/0.1 mL, every 4 weeks; sham procedure every 4 weeks; lampalizumab, 10 mg/0.1 mL, every 6 weeks; or sham procedure every 6 weeks, respectively.¹²

Current analyses address the data for the 4-week-frequency arms, assuming that monthly treatments potentially carry higher risk for IOP-related AEs. IOP data analyses from 6-week-frequency arms are reported in the eAppendix in Supplement 1, along with additional details on inclusion and exclusion criteria and the lampalizumab injection procedure. Note that the current study did not require ethical review because it reports post hoc analyses of data from 2 clinical trials and is not the primary publication from either trial.

IOP Measurement

IOP was measured at screening, at baseline, and before treatment administration at every study visit in both the study and fellow eyes. The measurement method was chosen by the site investigator and remained consistent for each participant throughout the study. For approximately 100 of 1881 enrolled participants, optional aqueous humor sampling occurred on day 1 and at weeks 24 and 44 before the start of ocular assessments or study treatment. A finger counting test was conducted 15 minutes or sooner after treatment administration, followed by IOP measurement only in the study eye at 30 and 50 minutes after study treatment administration. If IOP increased 10 mm Hg or more, it was measured again 60 to 80 minutes posttreatment. Data points both before and after the injection were not censored for participants who had aqueous humor collection performed because of a small participant population.

Definitions for IOP Elevation and AEs

Increased IOP was defined by several established criteria (eTable 1 in Supplement 1).^6,13,14 AEs indicative of persistent IOP changes were assessed, including incident and worsening of ocular hypertension and glaucoma, as diagnosed by the investigator. The eAppendix in Supplement 1 provides details on the management of IOP-related ocular AEs.

Results

Treatment Overview

Baseline ocular characteristics for the every-4-weeks groups are summarized in the Table. The mean (SD) numbers of injections per participant in lampalizumab (n = 627) and sham procedure (n = 311) arms were 11.6 (2.7) and 11.7 (2.7), respectively.

Table. Ocular Characteristics at Baseline for Participants in the Study Arms Receiving Injections Every 4 Weeks.

	Study eye, No. (%)		Fellow eye, No. (%)
	Lampalizumab, 10 mg, every 4 wk (n = 628)	Sham every 4 wk (n = 314)	Lampalizumab, 10 mg, every 4 wk (n = 628)	Sham every 4 wk (n = 314)
Lens status
Phakic	241 (38.4)	121 (38.5)	237 (37.7)	121 (38.5)
Pseudophakic	385 (61.3)	192 (61.1)	389 (61.9)	192 (61.1)
Other	2 (0.3)	1 (0.3)	2 (0.3)	1 (0.3)
Medical history
Overalla	56 (8.9)	19 (6.1)	65 (10.4)	22 (7.0)
Glaucoma	42 (6.7)	15 (4.8)	49 (7.8)	18 (5.7)
Glaucoma (suspect)	10 (1.6)	3 (1.0)	9 (1.4)	3 (1.0)
Ocular hypertension	5 (0.8)	1 (0.3)	7 (1.1)	1 (0.3)

^a Overall refers to a history of glaucoma, glaucoma (suspect), or ocular hypertension.

IOP Changes

There was no change in mean pre-injection IOP values through 48 weeks in both 4-week-frequency arms (eFigure 1 in Supplement 1. Most study eyes (lampalizumab every 4 weeks, 85.7%; sham every 4 weeks, 91.6%) had maximum postbaseline preprocedural IOPs of 21 mm Hg or less (eFigure 2 in Supplement 1). The every-6-weeks arm results did not appear to be different from the 4-week-frequency arms and are reported in eFigures 3 and 4 in Supplement 1.

Three established criteria for defining sustained IOP elevation were applied in the current analysis (eTable 1 in Supplement 1). Applying DRCR.net criteria¹³ showed that the majority of changes from baseline preprocedural IOP were less than 6 mm Hg (Figure 1). Applying criteria by Bakri et al⁶ showed that a higher proportion of study eyes in the 4-week-frequency lampalizumab arm compared with those in the sham arm had maximum preprocedural IOP measurements of at least 21, 25, or 30 mm Hg with changes of at least 6, 8, or 10 mm Hg from baseline preprocedural IOP (Figure 2A and B). These trends were also seen in fellow eye results. IOP changes per criteria by Morshedi et al¹⁴ showed a slight sustained increase in IOP of at least 21 mm Hg in the sham arm (1.8%) greater than the 4-week-frequency treatment arm (1.3%) (eFigure 5 in Supplement 1).

Figure 1. Application of DCRC.net Criteria for Intraocular Pressure (IOP) Elevation¹³.

^aA ≥6 mm Hg increase from baseline and occurring on ≥2 consecutive visits at least 1 month apart.

Figure 2. Application of Intraocular Pressure (IOP) Elevation Criteria Defined by Bakri et al⁶.

^aAbsolute preprocedural IOP refers to a discrete measurement of preprocedural IOP during the 48 weeks that differed from the IOP at baseline.

Overview of IOP AEs

The AEs of glaucoma and ocular hypertension as well as other serious ocular AEs related to IOP are summarized in eTables 3 and 4 in Supplement 1, respectively. Events requiring IOP-lowering medication were reported more in the lampalizumab arm than the sham arm (65/ 628 participants [10.4%] vs 5/314 [1.6%]) (eTable 2 in Supplement 1). However, most participants who required IOP-lowering medications or procedures to treat these AEs only required these interventions for a single day (lampalizumab: 41/65 [63.1%]; sham procedure arm: 3/5 [60.0%]) (eTable 2 in Supplement 1).

Discussion

Most participants in the lampalizumab and sham arms experienced mild posttreatment IOP increases of less than 10 mm Hg. One-time elevations of at least 6 or 8 mm Hg occurred slightly more frequently in the lampalizumab-treated group in participants with an absolute or discrete preprocedural IOP measurement of 21 mm Hg or greater as compared with their baseline value (Figure 2). IOP increases based on Bakri et al⁶ criteria occurred slightly more often in participants treated with lampalizumab compared with sham in both study and fellow eyes. Glaucoma and ocular hypertension events were low in both arms. In addition, most participants did not require IOP-lowering medications, and most interventions lasted a single day.

Strengths and Limitations

The study strengths include using clinical trial data, a sham procedure–controlled arm, and a large sample size. Data analysis was based on previously established criteria for IOP increase,^6,13,14 facilitating future potential comparisons.

This analysis has several limitations. Method of measuring IOP were not protocol-specified. Ocular axial length was not measured, and scleral rigidity was not evaluated, which may have affected clinical interpretation of IOP changes. No placebo injection was used, which might have allowed for evaluation of any IOP effect related to lampalizumab independent of the volume of vehicle injected. While unlikely, pressure from the sham treatment might have had an effect on IOP compared with no treatment. Glaucoma rates were based on site investigator diagnoses and reported AEs but not confirmed by a glaucoma specialist. Participants with advanced glaucoma were excluded from the trials; therefore, extrapolation of these analysis results should not be extended to such participants. Investigators may have been less likely to enroll participants with a less severe degree of glaucoma because of a perceived potential effect on IOP. In addition, approximately 100 of 1881 enrolled participants had aqueous humor samples taken (~100 μL) before the study procedure. These participants may have had lower IOP measurements prior to study treatment administration, which could disguise IOP elevations after treatment administration. Findings stem from a post hoc analysis, which provides hypotheses for future investigations but cannot determine or rule out a definitive causal relationship between these injections and IOP changes. However, from this analysis, over the 48-week follow-up period, no persistent increase in mean preinjection IOP was observed.

Conclusions

Findings suggest that a volume of 0.1 mL, at least within the formulation of lampalizumab, can be administered by intravitreous injection monthly over 1 year with low risk of persistent ocular IOP alterations. This information could help inform future clinical trial design as well as support safety evaluations of more recently approved intravitreous injections that use volumes of 0.07 to 0.1 mL.

Supplement 1.

eAppendix. Lampalizumab Injection and Sham Arm Procedures, Inclusion and Exclusion criteria, Ocular Characteristics at Baseline, and Management of Intraocular Pressure–Related Ocular Adverse Events

eReferences

eTable 1. Established criteria for the definition of sustained IOP used in the current study.

eTable 2. New Initiation/Augmentation of IOP-Lowering Treatments or Use of Procedure During the First 48 Weeks (Q4W arms)

eTable 3. AEs of Glaucoma and Ocular Hypertension During the First 48 Weeks of Treatment (Q4W)

eTable 4. Serious Ocular AEs of Special Interest per 1000 Injections/Sham Procedures in the Study Eye During the First 48 Weeks (Q4W; Safety Evaluable Populationb)

eFigure 1. Mean (SD) Preprocedural IOP in the Q4W Study Arms

eFigure 2. Distribution of Maximum Preprocedural IOP in the Q4W Study Arms

eFigure 3. Mean (SD) Preprocedural IOP in the Q6W Study Arms

eFigure 4. Distribution of Maximum Preprocedural IOP in the Q6W Study Arms

eFigure 5. Application of Criteria for Persistent IOP Elevation, Defined by Morshedi et al

Supplement 2.

Data sharing statement