
==== Front
Retina
Retina
retina
Retina (Philadelphia, Pa.)
0275-004X
1539-2864
Retina

RETINA-223-1086
10.1097/IAE.0000000000004167
00008
3
Original Study
PROSPECTIVE TRIAL OF HOME OPTICAL COHERENCE TOMOGRAPHY–GUIDED MANAGEMENT OF TREATMENT EXPERIENCED NEOVASCULAR AGE-RELATED MACULAR DEGENERATION PATIENTS
https://orcid.org/0000-0001-7850-8515
Holekamp Nancy M. MD *
de Beus Anthony M. MD, PhD *anthony.debeus@gmail.com

Clark W. Lloyd MD †lclark@palmettoretina.com

Heier Jeffrey S. MD ‡jsheier@eyeboston.com

* Pepose Vision Institute, Saint Louis, Missouri;
† Palmetto Retina Center, Columbia, South Carolina; and
‡ Ophthalmic Consultants of Boston, Boston, Massachusetts.
Reprint requests: Nancy M. Holekamp, MD, Basel Merian Hotel, Apartment 602, Rheingasse 2, 4058 Basel, Switzerland; e-mail: nholekamp@gmail.com
10 2024
12 9 2024
44 10 17141731
Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Opthalmic Communications Society, Inc.
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

All previous home optical coherence tomography studies were observational only, and no patient care activity was undertaken based on remote images. This is the first time that home optical coherence tomography data drove patient management decisions. The results substantiate the expectation that the home optical coherence tomography will personalize neovascular age-related macular degeneration care and reduce the treatment burden.

Purpose:

To evaluate the impact of home optical coherence tomography (OCT)–guided patient management on treatment burden and visual outcomes.

Methods:

An interventional trial was conducted to compare frequency of treatment and visual acuity for the neovascular age-related macular degeneration patients before and during use of home optical coherence tomography over a period of 6 months. Patient adherence to regular scanning was measured by the number of scans performed per week. The characteristics of episodes of fluid recurrence and classification of typical fluid volume trajectories were performed.

Results:

Twenty-seven eyes (21 with diagnosis of neovascular age-related macular degeneration and one converted during the study), of 15 patients were monitored for 6 months, scanning at 6.2 times/week per eye and yielding 4,435 scans of which 91.2% were eligible for artificial intelligence–based fluid volume quantification. Total number of monitoring weeks before and during the study were 1,555 and 509. The mean (SD) number of weeks per injection before and during home OCT management were 8.0 (4.7) and 15.3 (8.5) (P = 0.004), respectively. The mean (SD) visual acuity change before and during home OCT-based management was 3.5 (12.0) letters and 0.0 (9.5) letters (P = 0.45), respectively, showing no significant impact on visual acuity.

Conclusion:

For the first time, remote patient monitoring with a home OCT allowed personalized management of neovascular age-related macular degeneration. This study showed significant reduction in treatment burden while maintaining stable visual acuity.

Key words:

age-related macular degeneration
home optical coherence tomography
remote monitoring
retina
personalized medicine
artificial intelligence
anti-VEGF therapies
neovascular AMD
home monitoring
telemedicine
Notal VisionNot ApplicableOPEN-ACCESSTRUE
==== Body
pmcAge-related macular degeneration (AMD) is the leading cause of legal blindness in the United States.1 With the use of anti–vascular endothelial growth factor (VEGF) agents coupled with optical coherence tomography (OCT) imaging, neovascular AMD (nAMD) is now treatable, with a potential prognosis of maintained or improved vision.2–5

Currently, therapies for nAMD cost the US health care system approximately four billion USD per year.6 Despite the high cost, several studies performed over the past 10 years have found that visual outcomes for patients in the real world are significantly below those reported in the clinical trials.7,8 Undertreatment is considered a significant factor in such outcomes. With an aging population, the societal burden of AMD is likely to increase. The question arises whether a new disruptive approach to patient and disease management is needed. Ideally, patients would receive the minimum number of anti-VEGF treatments necessary to control disease activity while not sacrificing clinical outcomes. Efforts in this direction might include the development of longer-acting drugs and drug delivery solutions5,9–11 and personalized treatment algorithms.

Personalized treatment algorithms have the potential to reduce the burden on patients, their caregivers, retinal clinics, and health care systems. Personalized health care in nAMD would require a treatment regimen based on each individual's unique disease pattern per eye, treatment response per eye, and medication durability per eye. Currently, OCT is only available at each clinic visit, with clinicians making treatment decisions based on sparse data points weeks to months apart. Such information is used in treat-and-extend (TAE) protocols, currently the most widely practiced treatment regimen in the United States, as clinicians try to balance injection efficacy, treatment burden, and health care costs.

Recently, studies of a patient-operated spectral-domain OCT system, the Notal Vision Home OCT System (NVHO, Notal Vision Inc, Manassas, VA), demonstrated excellent feasibility and performance of daily self-imaging at home.12–14 AK15 With support from a monitoring center, patients self-acquire OCT images; scans are automatically uploaded to a centralized database and analyzed by a validated artificial intelligence–based software that automatically detects and quantifies the volume of intraretinal and subretinal fluid.16,17 The scans are also available for ad hoc viewing through a cloud-based dashboard. Fluid quantification on daily-acquired OCT scans allows for the presentation of fluid volume trajectories to inform clinical decision making. Importantly, those studies used the home OCT in parallel with the current standard of care for nAMD, and the remotely acquired images were not used for treatment decisions.

The purpose of this study was to investigate the impact of home OCT data to guide retina specialists in the management of nAMD. We compared the results from home OCT-guided management of nAMD with findings from the same eyes managed with standard of care treatment regimens during a preceding reference period based solely on in-clinic OCT scans. In addition, the study also investigates a future treatment landscape that includes the practical implementation of personalized management of nAMD with remote monitoring using the home OCT. Key issues such as patient scheduling and practice workflow as well as roles, responsibilities, and liabilities of the treating physician and remote monitoring service in a shared care model are explored.

Methods

The Home OCT Guided Management Study of Subjects Diagnosed with nAMD is an interventional study conducted from December 2022 to September 2023. It was approved by the IntegReview Institutional Review Board and conducted in accordance with the Tenets of the Declaration of Helsinki. Written informed consent for the study was obtained from all study participants. The clinical trial registration information is publicly available at https://clinicaltrials.gov (NCT05650047).

Study Population

Study participants were recruited from three retina clinics: the Ophthalmic Consultants of Boston (Boston, MA), Pepose Vision Institute (Chesterfield, MO), and Palmetto Retina Center (Columbia, SC). Eligible participants needed to have at least one eye with active nAMD undergoing active anti-VEGF treatments, the ability to give informed consent, Snellen visual acuity (VA) of 20/320 or better in the study eye, and the ability to undergo OCT imaging. Patients with constricted pupils, ptosis, and/or significant media opacity that interfered with OCT imaging were excluded.

Procedures

Patient demographics, baseline clinical characteristics, including best-corrected visual acuity (BCVA), biomicroscopy findings, and history of VA, and prior anti-VEGF treatments were obtained at the initial study visit. Baseline macular SD-OCT images were also obtained using the Spectralis OCT device (Heidelberg Engineering, Heidelberg, Germany). After the initial study visit, an NVHO device and a printed User Manual were delivered to each participant's home through a courier service. Each study participant was required to set up the device, review an on-device tutorial video on how to operate the device, and perform initial calibrations. Clinically, trained staff at a remote monitoring center were available for assistance throughout the study should participants encounter any device-related issues. The participants were asked to perform self-imaging in each eligible eye on a daily basis for a period of 6 months. Participants who did not attempt to self-image on two consecutive days received a reminder call by the monitoring center. The preplanned visits of the study included a visit at 3 months, which could be delayed if an unplanned visit took place and an exit visit at 6 months. During these visits, the participants' BCVA, biomicroscopy findings, treatment decisions, and SD-OCT scans were acquired.

Notal Vision Home Optical Coherence Tomography Device and the Notal Optical Coherence Tomography Analyzer

Details of the NVHO system have been described previously.12–14 Briefly, it is an SD-OCT device compactly designed for patient self-operation at home. It uses a fixed pattern of 88 B-scans over a 3 × 3 mm area or 10° × 10° field of view, with a scanning speed of 10,000 A-scans per second and 500 A-scans per B-scan. Patient head positioning and fixation are guided by a proprietary automatic visual feedback system. During a patient's first use, the device performs an automatic calibration to adjust for each eye's refractive error and axial length. The NVHO device also calculates a manufacturer signal quality index (MSI) that provides an objective and quantifiable representation of image quality. An MSI ≥ 2 is the recommended level for acceptable image quality. The captured scans are automatically uploaded to the Notal Health Cloud through a built-in cellular modem. Once volume scans are reconstructed, they are analyzed by the Notal OCT Analyzer (NOA) and are available for physician review. Details of NOA and its performance have been described elsewhere.12,17 Briefly, NOA employs deep learning techniques to automatically segment B-scans, detect and quantify fluid volume in nanoliters (nL) in various compartments of the retina, including intraretinal fluid (IRF) and subretinal fluid (SRF), as well as total retinal fluid volume (TRF), which is the sum of IRF and SRF volumes. The output of the NOA includes the segmentation mask of the fluid over each B-scan by type, the fluid volume, and a fluid thickness map of each volume scan and a trajectory of the fluid volume over time.

Management of neovascular age-related macular degeneration with the Notal Vision home optical coherence tomography during the study

The reconstructed volume scans and the NOA analysis results were available for remote review by a physician through a password-protected end-to-end encrypted web viewer. The investigators' review of the scans and NOA analysis was driven by two types of notification mechanisms: a time-based notification at intervals of 7 days and a fluid volume notification based on physician set thresholds. The fluid volume notification was generated when the fluid volume was measured to be greater than the set threshold by 10 nL in a single scan or was measured to be greater than the set threshold in three consecutive scans. The objective of the review was to inform a decision whether an office visit is required before the next prescheduled visit. The threshold was set by the investigator by fluid type individually for each eye and was adjusted by the investigator according to the eye's fluid dynamics over time. The recommended physician review procedure and decision-making process included four steps: 1) observe the fluid volume trajectory and place the vertical review indicator on a date of interest; 2) use the associated fluid thickness maps to navigate to the B-scans with most fluid or use the automated ranking function to review B-scans in order of fluid area; 3) observe the B-scans and/or scroll through additional B-scans and decide whether a prompt office visit is required; or 4) using the notification panel, set parameters for the next review, including time interval and fluid volume threshold. A sample report and these steps are illustrated in Figure 1. The investigator had sole discretion regarding treatment, drug choice, and the use of additional diagnostics to complement NVHO data for decision making.

Fig. 1. Portal for data review. 1) Fluid volume trajectories showing intraretinal, subretinal and total retinal fluid. 2) Fluid thickness maps with projection of fluid on 3 × 3 mm grid, 3) OCT volume scans, and 4) Notification settings pane for investigators to enter.

Performance of home optical coherence tomography self-imaging and characteristics of retinal fluid volume distribution

The performances of NVHO self-imaging at home were evaluated. Weekly scan frequency, self-imaging duration, MSI, and the proportion of scans that were eligible for fluid quantification were obtained and compared over the duration of the study. The longitudinal fluid volume data for all the study eyes was extracted from a database for analysis. The quantitative characteristics of the fluid trajectories were reported with discrete comparable parameters, including the mean (SD) of the maximum, minimum, and mean total fluid volume reached per study eye and the area under the fluid volume curve reported in nL × days (nanoliters times days).

Impact of management by Notal Vision home optical coherence tomography in neovascular age-related macular degeneration

The impact of management by NVHO was evaluated by measuring differences in treatment burden and changes in VA during the reference period before management with NVHO and during the study period using management with NVHO. The reference period was defined as shorter of 2 years before the study started or period from diagnosis of nAMD to the time of study start. The treatment burden was evaluated by the ratio of total time to the number of treatments in the two comparison periods. This measure was chosen in contrast to retreatment interval because the compared periods were not defined by an event of treatment but rather a period of follow-up and data collection. The impact on VA was evaluated by measuring the mean (SD) and median (IQR) difference between the VA at the start and end of the two periods. The analysis includes a contingency test comparing the sum of monitoring weeks divided by the sum of treatments between the two periods (Fisher exact test), giving more weight to longer periods and a paired test of means of the two groups of duration per treatment (t test) representing within-eye findings. The analysis included a brief case description and classification of fluid volume trajectories.

Fluid volume dynamics during episodes of recurrence

For each of the episodes of fluid recurrence–treatment–resolution, parameters include the duration of the segments of recurrence defined as fluid volume >3 nL to time of significant fluid volume defined as >10 nL for 3 consecutive scans and to time of treatment, time to resolution defined as fluid volume <3 nL, the fluid type, the maximal fluid volume during the episode, the area under the fluid volume curve, and, when applicable, the interval between repeat fluid recurrences.

Classification of trajectories

The study for the first time allows us to categorize fluid volume trajectories in nAMD under NVHO-based management, in contrast to earlier work that demonstrated such trajectories under in-office–based management.13 The fluid volume trajectories were classified into three main groups and two of them into two additional subgroups: A first group of eyes previously diagnosed with nAMD that reached good fluid control, with a period of absence of fluid. This group was then divided into two subgroups: A subgroup that had at least one episode of recurrence of fluid and a subgroup of eyes that remained dry throughout the study. A second group included eyes with persistent fluid, with a subdivision into eyes with significant fluid volume and fluid dynamics throughout the study and eyes with minimal residual fluid such as degenerative cysts. A third group of eyes had dry AMD and were monitored to allow early detection of conversion to nAMD (Figure 2).

Fig. 2. Proposed classifications of home OCT-based fluid volume trajectories of eyes with AMD.

Results

Study Population

A total of 15 eligible participants were enrolled in the study, 5 from each clinic, with a mean (SD) age of 75.1 (5.7) years (range 64–88 years). Fifty-three percent of the participants were female. At enrollment, all but 3 patients had both eyes eligible for the study, with a total of 27 eyes: 21 eyes (77.8%) had a prior diagnosis of nAMD, 1 eye (3.7%) identified as normal, 5 eyes (18.5%) had a diagnosis of intermediate AMD, and one eye converted to nAMD during the study. The prestudy reference period for which real-world data were collected from the medical records included the duration from the first treatment to the enrollment to the study, limited to 2 years. Thirteen eyes had data for 2 or more years and 14 eyes for shorter periods, with a mean (SD) of 87.0 (32.3) weeks. Mean, median, and range of the BCVA at the beginning of the prestudy reference period were 20/35, 20/30, and 20/200 to 20/20, respectively. Mean, median, and range of BCVA at the time of enrollment were 20/35, 20/30, and 20/200 to 20/20, respectively. Mean, median, and range of BCVA at the end of the study were 20/35, 20/28, and 20/200 to 20/20, respectively.

Performance of Home Optical Coherence Tomography Self-Imaging and Characteristics of Retinal Fluid Volume Distribution

All 15 patients completed the study for the prespecified duration of 6 months ± 2 weeks, with a mean (SD) of 186 (20) days in the study. A mean (SD) of 164 (21) scans were performed per study eye during this time, totaling 4,435 successful scans with a 91.2% (14%) eligible for fluid quantification. This translated to a mean weekly scan frequency of 6.2 (0.6) scans per eye. The mean weekly frequency of scanning during the first month and the last month were similar at 6.16 scans/eye and 6.37 scan/eye (P = 0.226) The mean (SD) MSI among all acquired scans was 4.2 (0.9). The mean (SD) and median (IQR) of the means of imaging durations per scan of all eyes were 47.8 (12.2) and 44 (40–48) seconds with a range of 36 to 80 seconds. Over time, the duration per self-imaging session decreased from a mean (SD) of 56 (20) seconds at the beginning of the study to 46 (15) seconds at the end; the IQR also narrowed throughout the study from 18 to 7 seconds, generally indicating a positive learning curve in the performance of self-imaging.

The fluid characteristics for 22 nAMD eyes were as follows. The mean (SD) of the maximum, minimum, and mean total fluid volume in any time point during the study were 125 (197) nL, 1.9 (7) nL, and 18 (34) nL, respectively. The median (IQR) of the maximum, minimum, and mean total fluid volume in any time point during were 29 (13–193) nL, 0 (0,0) nL, and 4.3 (1.3–23.2) nL, respectively. The mean and median of AUC 3917 (7,559) nL × days and 763 (259–5,153) nL × days, respectively. The mean (SD) and median (IQR) maximal AUC in a moving window of 28 days were 998 (1,574) and 192 (11–1,582) nL × days. Of the 20 eyes with retinal fluid present during the study, 12 (60%) had SRF alone, 7 (35%) had IRF alone, and 1 (5%) had both. Table 1 includes these parameters for each of the study eyes.

Table 1. VA, Self-Imaging, and Fluid Characteristic

No.	Pt ID	Eye	Diagnosis	Monitoring Duration [Weeks]	No. of Days With Test	Mean Tests Days per week	Std Tests Days per Week	Mean MSI (Eligible)	Std MSI (Eligible_	Mean Test Duration (Seconds)	Std Test Duration	Eligible for Fluid Quantification (%)	Fluid Type (SRF/IRF/Both)	Max FV During Study [nL]	Min FV During Study [nL]	Mean FV During the Study [nL]	Std FV During Study [nL]	Total Fluid AUC During the Study [nL*days]	Max FV AUC for Interval of 28 Test Days	
1	801-1001	OD	nAMD	26.0	174	6.7	0.6	5.3	0.7	36	4	100.0	SRF	36.3	0.0	5.5	7.5	992	491	
2	801-1001	OS	nAMD	26.0	174	6.7	0.6	6.0	0.6	37	4	100.0	SRF	148.4	0.0	10.0	23.0	1,822	892	
3	801-1002	OD	iAMD	23.6	143	6.1	1.0	3.3	0.7	47	15	98.8	None	—	—	—	—	—	2	
4	801-1002	OS	nAMD	23.4	143	6.1	1.0	3.7	0.8	47	18	96.3	IRF	32.8	0.0	2.7	6.1	458	232	
5	801-1003	OD	iAMD/nAMD	21.1	139	6.6	1.4	3.4	0.3	43	10	98.6	IRF	16.5	0.2	3.7	2.7	551	131	
6	801-1003	OS	nAMD	21.3	139	6.5	1.2	3.9	0.3	40	8	100.0	IRF	11.1	0.0	1.0	1.9	146	103	
7	801-1004	OD	nAMD	28.0	183	6.5	0.7	4.0	0.9	45	16	96.9	SRF	23.5	0.0	1.4	4.4	276	269	
8	801-1004	OS	nAMD	28.0	166	5.9	1.5	4.2	1.2	60	32	47.7	SRF	215.5	0.0	8.2	27.1	2,701	1,992	
9	801-1005	OD	nAMD	31.4	202	6.4	1.4	4.3	1.0	39	4	95.7	SRF	418.2	0.0	46.6	86.7	9,865	5,520	
10	801-1005	OS	nAMD	31.4	202	6.4	1.4	4.3	0.8	38	4	99.0	SRF	207.6	0.0	27.6	48.7	5,971	2,256	
11	802-2001	OD	nAMD	28.0	180	6.4	1.0	4.4	0.8	40	12	85.6	Both	16.1	0.0	1.7	3.1	294	178	
12	802-2001	OS	nAMD	28.0	183	6.5	1.0	4.2	0.4	39	8	87.7	IRF	150.7	2.8	39.3	31.2	7,797	2,206	
13	802-2002	OS	nAMD	26.6	179	6.7	0.8	4.0	0.5	37	2	98.9	SRF	6.0	0.0	0.4	1.0	82	40	
14	802-2003	OD	nAMD	26.6	159	6.0	0.9	4.0	0.7	40	6	98.8	SRF	107.2	0.0	49.4	26.0	9,276	2,267	
15	802-2003	OS	iAMD	26.6	159	6.0	0.9	2.8	0.5	41	6	69.0	None	—	—	—	—	—	0	
16	802-2004	OD	iAMD	24.1	147	6.1	1.4	4.3	0.5	46	6	100.0	None	—	—	—	—	—	0	
17	802-2004	OS	nAMD	24.1	147	6.1	1.4	5.2	0.6	46	9	100.0	None	0.0	0.0	0.0	0.0	0	0	
18	802-2005	OS	nAMD	25.6	165	6.5	1.1	2.7	0.5	58	18	81.8	IRF	24.4	0.0	2.3	4.2	424	192	
19	803-3002	OS	nAMD	26.0	182	7.0	0.0	3.4	0.4	47	7	100.0	SRF	236.7	0.0	7.4	32.3	1,347	1,171	
20	803-3003	OD	Normal	32.1	192	6.0	2.2	5.4	0.7	49	10	100.0	None	—	—	—	—	—	0	
21	803-3003	OS	nAMD	31.7	164	5.2	2.2	5.6	0.6	76	29	89.9	SRF	855.5	32.2	151.2	111.8	34,155	5,133	
22	803-3004	OD	nAMD	27.0	124	4.6	2.8	4.9	0.6	39	11	100.0	IRF	4.1	0.0	0.5	0.8	89	20	
23	803-3004	OS	nAMD	27.0	123	4.6	2.8	2.8	0.6	44	23	81.7	SRF	12.6	0.0	1.3	2.4	254	53	
24	803-3005*	OD	nAMD	26.9	167	6.2	1.1	3.9	1.0	68	27	51.4	SRF	215.0	6.8	41.6	51.0	8,704	3572	
25	803-3005	OS	iAMD	26.9	172	6.4	1.0	5.4	0.8	44	9	100.0	None	—	—	—	—	—	0	
26	803-3006	OD	nAMD	26.6	164	6.2	1.7	4.2	1.0	80	27	90.5	IRF	13.2	0.0	5.0	3.2	975	212	
27	803-3006	OS	nAMD	26.6	163	6.1	1.6	4.0	1.0	66	25	94.7	None	0.4	0.0	0.0	0.1	4	1	
Mean				26.7	164.3	6.2	1.3	4.2	0.7	47.8	12.9	91.2		125.1	1.9	18.5	21.6	3917	998	
SD				2.8	21.0	0.6	0.6	0.9	0.2	12.2	8.8	14.2		197.0	6.9	34.0	30.0	7,559	1,574	
Median				26.6	165.0	6.2	1.1	4.2	0.7	43.9	9.6	98.6		28.6	0.0	4.3		763	192	
IQR 1				25.8	147.0	6.0	0.9	3.8	0.5	39.5	6.1	88.8		12.8	0.0	1.3		259	11	
IQR 3				28.0	179.5	6.5	1.5	4.6	0.8	48.2	17.8	100.0		193.4	0.0	23.2		5,153	1,582	
Min										36.31										
Max										80.48										
Total					4,435															
Self-imaging and fluid characteristic.

* VA drop because of worsening cataract during the study.

Impact of Management by Notal Vision Home Optical Coherence Tomography in Neovascular Age-Related Macular Degeneration

Table 2 includes the duration of collection of data before and during the study, the number of treatments in each period when applicable, the ratio of duration per treatment, an indication of eyes that should not be included in a statistical analysis, an assessment of the effect that the NVHO data had on the management of nAMD, a brief description of the case, and a classification of the fluid volume trajectory. Of the 27 eyes that participated in the study, 21 eyes were diagnosed with nAMD before the study, and one converted during the study. Eighteen and 19 eyes provided analyzable data from the periods before and during the study, respectively. Exclusion from the analysis was for one eye treated with a Susvimo implant, one eye with VA ranging from 20/250 to CF5 for which the investigator decided not to consider NVHO data, and one eye that received no treatment for 2 years. The total number of monitoring weeks before and during the study were 1,555 and 509, respectively. The total number of treatments were 251 and 44, respectively, a ratio of 6.2 weeks per treatment prestudy versus 11.6 weeks per treatment during the study. The difference between these ratios was statistically significant (P = 0.0002). Comparing the paired means and medians (IQR) of the duration per treatment indicates a mean (SD) of 8.0 (4.7) and 14.9 (8.6) weeks per treatment in the prestudy and study period, respectively (P = 0.004). The median duration per treatments were 7.0 (5.0–8.3) and 10.8 (7.8–25.8), respectively.

Table 2. Treatment of nAMD With Home OCT Before and During the Study

No.	Pt ID	Eye	Diagnosis	Date of Initial Diagnosis of nAMD	Duration With nvAMD Before the Study [Weeks]	No. of Injections Before the Study	Mean No. of Weeks per Injection Before the Study	Duration With nvAMD During the Study [Weeks]	No. of Injections during the Study	Mean No. of Weeks per Injection During the Study	Include in Statistical Analysis (Y/N)	Case Description	Classification of Trajectory	
1	801-1001	OD	nAMD	December 29, 2017	108	6	18.1	26	2	12.9	Y	Eye followed PRN before the study, hence large prestudy intervals. Responded to two episodes of recurrence. First after a longer f/u and second promptly	Episodical, transient fluid	
2	801-1001	OS	nAMD	December 29, 2017	104	6	17.3	26	3	8.6	Y	Eye followed PRN before the study and hence large prestudy intervals. Prompt response to three recurrences	Episodical, transient fluid	
3	801-1002	OD	iAMD	NA	—	—	—	23	—	—	N	—	iAMD	
4	801-1002	OS	nAMD	November 2, 2022	4	1	4.0	23	3	7.8	Y	Initial diagnosis 4 weeks before enrollment. Prompt response to three recurrences	Episodical, transient fluid	
5	801-1003	OD	iAMD/nAMD	May 15, 2023	NA	—	—	21	1	21.0	Y	Observed iAMD, treated promptly after 5 months upon increase in IRF to >10 nL	Episodical, transient fluid	
6	801-1003	OS	nAMD	July 27, 2021	72	6	12.0	21	1	21.1	N	Susvimo implant April 12, 2022. Due to product recall no refill after 6 months, in October 2022, instead, started NVHO December 10, 2022, upon recurrence of IRF, refill March 1, 2023 (after 10.5 months). Since then, 5 months without fluid and no refill, still testing with NVHO	Episodical, transient fluid	
7	801-1004	OD	nAMD	December 27, 2021	50	3	16.7	28	1	27.9	Y	Prompt response to a recurrence	Episodical, transient fluid	
8	801-1004	OS	nAMD	October 19, 2021	60	6	10.0	28	2	13.9	Y	Start without fluid. Degrading image quality because of worsening cataract, resume testing after surgery with 142 nL SRF treated promptly and dropped fast; 11 weeks later, another fast recurrence treated promptly	Episodical, transient fluid	
9	801-1005	OD	nAMD	November 6, 2020	113	21	5.4	31	4	7.8	Y	Prompt response to three recurrences. Symmetry in recurrence OU	Episodical, transient fluid	
10	801-1005	OS	nAMD	December 8, 2021	56	8	7.0	31	4	7.8	Y	Prompt response to three recurrences. Symmetry in recurrence OU	Episodical, transient fluid	
11	802-2001	OD	nAMD	August 6, 2020	104	14	7.4	28	4	7.0	Y	A single response to recurrence followed by 3 injections without evidence of fluid. Continuing past pattern of treatment every 1–2 months. Fellow eye with poor vision	Episodical, transient fluid	
12	802-2001	OS	nAMD	October 2, 2014	104	4	26.0	28	5	5.6	N	Significant persistent central IRF growing and shrinking at the same location under monthly treatment— VA 20/400–20/250 to CF5, per PI, not managed with NVHO data	Persistent IRF	
13	802-2002	OS	nAMD	January 19, 2019	109	27	4.0	26	3	8.8	Y	Rarely minimal SRF < 6 nL, treated twice without meaningful fluid. Continuing prestudy monthly injection pattern	nAMD with very minimal or without any fluid	
14	802-2003	OD	nAMD	October 25, 2021	71	16	4.4	27	1	26.6	Y	Fluid thickness map indicated fluid away from center, allowed to wait and observe. Per PI, VA was stable during visit allowing to extend interval further	Episodical, transient fluid	
15	802-2003	OS	iAMD	NA	—	—	—	27	—	—	N	—	iAMD	
16	802-2004	OD	iAMD	NA	—	—	—	24	—	—	N	—	iAMD	
17	802-2004	OS	nAMD	April 19, 2019	162	19	8.5	24	0	24.0	*Y	Allowed to observe and not treat, changing from long standing q8w TAE	nAMD without any fluid	
18	802-2005	OS	nAMD	January 27, 2022	57	10	5.7	25	2	12.7	Y	Moved from consistent q6wks treatment without fluid (TAE) to observe and responded to a single episode. Dry for 2 months than small fluctuation IRF, upon increase to 20 nL treated promptly	Episodical, transient fluid	
19	803-3002	OS	nAMD	March 19, 2019	102	21	4.9	26	3	8.6	Y	Treat in response to two episodes of recurrence	Episodical, transient fluid	
20	803-3003	OD	Normal	NA	—	—	—	32	—	—	N	—	Normal	
21	803-3003	OS	nAMD	April 16, 2010	102	19	5.4	32	4	7.9	Y	Allowed to watch trends of persistent SRF, respond to changes and safely treat less often	Persistent large volume of SRF	
22	803-3004	OD	nAMD	December 16, 2019	97	2	49	27	0	NA	N	Treated twice in April and July 2021 and not treated since, including during NVHO study. Excluded from comparison. Allowed to observe and not treat	nAMD without any fluid	
23	803-3004	OS	nAMD	May 27, 2015	97	14	6.9	27	1	27.0	Y	Allowed to observe and treat after 3.5 months upon recurrence	Episodical, transient fluid	
24	803-3005	OD	nAMD	August 18, 2010	102	40	2.6	27	4	6.7	Y	Allowed to watch trends of the persistent SRF, respond to changes and safely treat less often	Persistent SRF	
25	803-3005	OS	iAMD	NA	—	—	—	27	—	—	N	—	iAMD	
26	803-3006	OD	nAMD	December 6, 2021	63	8	7.9	26	1	26.4	Y	Allowed to watch the stability of persistent, stable cyst at the same location. FV fluctuating between 3 and13 nL, treat with a single maintenance injection midstudy OU	Persistent IRF	
27	803-3006	OS	nAMD	May 20, 2021	92	12	7.6	26	1	26.4	Y	Allowed to watch absence of fluid, treat with a single maintenance injection midstudy	nAMD without any fluid	
N					18	18	18	19	19	19				
Total					1,555	251	6.2	509	44	11.6				
Mean					86	14	8.0	27	2	15.3				
SD					28.5	9.3	4.7	2.6	1.3	8.5				
* Number of treatment for the duration of the study. The duration was conservatively assumed as time per treatment.

The VA changes during these periods were similar with a mean (SD) and median (IQR) of 3.5 (12.0) and 3 (1.0 to 10) letters prestudy and a mean (SD) and median (IQR) of 0 (13.0) and 0.0 (−5 to 5) letters during the study (P = 0.39).

Fluid Volume Dynamics during Episodes of Recurrence

Twenty-five episodes of fluid recurrence that intermittently completely resolved were identified. Table 3 provides details of all episodes.

Table 3. Analysis of Fluid Recurrence Episodes

No.	Pt ID	Eye	Updated No. of Episodes	First Episode	Time From Recurrence (>3 nL) to Significant Fluid Volume (10 nL ×3)	Second Episode	Third Episode	
Time From Recurrence (>3 nL) to Significant Fluid Volume (10 nL ×3)	Time From Significant Fluid (10 nL ×3) to max Fluid	Time From Recurrence (>3 nL) to Treatment/max FV [Days]	Time From Treatment/max FV to Resolution (<3 nL) [Days]	Max Fluid Volume NVHO [nL]	AUC of Fluid Volume During Episode [nL*Days]	Time From Significant Fluid (10 nL ×3) to max Fluid	Time From Recurrence (>3 nL) to Treatment/max FV [Days]	Time From Treatment/max FV to Resolution (<3 nL) [Days]	Max Fluid Volume NVHO [nL]	AUC of Fluid Volume During Episode [nL*Days]	Time From Recurrence (>3 nL) to Significant Fluid Volume (10 nL ×3)	Time From Significant Fluid (10 nL ×3) to max Fluid	Time From Recurrence (>3 nL) to Treatment/max FV [Days]	Time From Treatment/max FV to Resolution (<3 nL) [Days]	Max Fluid Volume NVHO [nL]	AUC of Fluid Volume During Episode [nL*Days]	Duration Between First and Second Recurrence [Days]	Duration Between Second and Third Recurrence [Days]	
1*	801-1001	OD	2	45	23	68	9	36.3	955	14	0	14	1	11.1	69							117		
2	801-1001	OS	3	5	4	9	11	108.4	606	5	0	5	28	148.4	944	1	0	1	9	40.3	142	66	47	
3	801-1002	OS	3	4	0	4	4	22.6	94			8	3	32.8	139	2	0	2	9	16.4	71	53	55	
4	801-1003	OD	1	22	3	25	8	16.5	235															
5	801-1003	OS	1	5	0	5	8	11.1	85															
6	801-1004	OD	1	6	0	6	10	23.5	235															
7	801-1004	OS	1	4	11	15	10	118.1	1,083															
8	801-1005	OD	3	2	7	9	24	418.2	5,869			17	15	191.8	3027			7	11	82.4	707	57	58	
9	801-1005	OS	3	4	10	14	19	207.6	2,333			11	16	154.7	1725			5	12	107.7	716	59	61	
10	802-2001	OD	1	11	2	13	3	16.1	141															
11	802-2003	OD	1	2	12	14	25	86.5	2,149															
12	802-2005	OS	1	3	0	3	3	21.85	75															
13*	803-3002	OS	3	1	0	1	17	14.2	110			3	7	236.7	1,047			2	4	41.6	136	78	58	
14	803-3004	OS	1	3	5	8	1	12.6	49															
Mean/Total			25			14	11	80	1,001			10	12	129	1,158			3	9	58	354	72	56	
SD						16.8	7.7	113.2	1,595			5.4	10.1	89.1	1,105			2.5	3.1	36.7	327	23.9	5.4	
* Second episode of 801-1001 OD and third episode of 803 to 3003 OS were short, did not meet the criteria of 3 × 10 nL; however, they were promptly treated.

The mean (SD) duration of recurrence, defined as first time point with fluid volume >3 nL to time of maximal fluid, was 10.8 (13.3) days and the mean (SD) duration of recovery, defined as fluid volume returning to less than 3 nL, was similar with 10.7 (7.4) days (P = 0.98). Fourteen eyes had a first episode, six eyes had a second episodes, and five eyes had a third episodes; there were a total of 11 interepisode durations with a mean (SD) of 64.5 (19.1) days. The pairs of duration for the five eyes with 3 episodes (801-1001 OS, 801-1002 OS, 801-1005 OD, 801-1005 OS, and 803-3002 OS) were 66 versus 47, 53 versus 55, 57 versus 58, 59 versus 61, and 78 versus 58 days, respectively.

Fluid Volume Dynamics of Eyes With Persistent Fluid

Four eyes had a persistent fluid throughout the study period, despite repeated injections. One of the eyes (803-3006 OD) had a chronic central cyst, with a mean (SD) IRF volume of 5.0 nL (3.24) during the study. The other three eyes (802-2001 OS, 803-3003 OS, and 803-3005 OD) had large fluid volume, mean (SD) and AUC of 39.26 (31.17) 7,797 nL × days, 151.17 (111.83) 34,155 nL × days, and 41.56 (50.9) 8,704 nL × days, respectively, and were treated periodically.

Cases of Special Interest

One of the study eyes (801-1003 OS) received a Susvimo (Genentech, South San Francisco, CA) implant in a procedure performed on April 12, 2022. In light of a voluntary product recall, a preplanned refill in October 2022 was not performed. Instead, the patient enrolled in the NVHO study on December 12, 2022 with the intent to refill as needed. Intraretinal fluid recurrence was identified and triggered an office visit where a refill was performed on March 1, 2023, 10.5 months after placement of the implant. The fluid volume trajectory shows rapid resolution of the IRF following the refill exchange procedure. With continued follow-up for five additional months and monitoring with the NVHO, there has been no recurrent fluid and no refill.

One eye with persistent SRF (803-3003 OS) developed 25 nL of IRF during the course of the study. This eye had shown no IRF while enrolled in a previous study from January 10, 2021 to April 21, 2021. This observation is possibly related to long-standing disease with observed presence of SRF and over 20 injections in 30 months.

Classification of Fluid Volume Trajectories

The first group included 14 eyes (14/22 = 63.6% of eyes with CNV) with good fluid control, i.e. enrolled or reached a period of absence of fluid, followed by 24 episodes of recurrence. A second group of four eyes (4/22 = 18.2%) remained dry throughout the study. Two of these eyes were observed and not treated, one eye was treated once and one eye was treated twice, with a mean of 26.4 monitoring weeks per treatment for this group. A third group included four eyes (4/22 = 18.2%) with consistently persistent fluid. Three had a significant volume of fluid, and one eye had fluctuating persistent IRF <10 nL that was treated once. Five eyes with dry AMD and one normal eye were monitored to allow early detection of conversion while at home. Examples of fluid volume trajectories from all classes are shown in Figure 3.

Fig. 3. Fluid volume trajectories representing different groups of proposed classification. Syringe indicates date of injection.

Discussion

During this study, for the first time, data received from daily, remote self-imaging with the NVHO was used by the investigators to manage eyes diagnosed with nAMD and make decisions about the need for office visits.

All patients were able to self-install the device at home and to self-image for 6 months. The self-imaging frequency was high at six scans per eye per week and stable throughout the study, with an improving self-imaging duration producing a large number of 4,435 volume scans with acceptable image quality: more than 91% of scans were eligible for artificial intelligence–based fluid quantification by NOA. For general perspective, the mean number of 164 scans in 6 months represents a more than 30-fold increase in the number of OCT scans typically performed with clinic-based imaging. This large number of scans generated fluid volume trajectories with fluid thickness maps, fluid volume results, and fluid segmentation masks that were periodically remotely reviewed online by the treating physicians. Fluid volume parameters allow quantitative characterization of the fluid dynamics, including the area under the fluid volume curve in a moving window of 28 days, representing a recommended review cycle. The fluid volume trajectory results from these 15 patients show a high degree of heterogeneity among eyes with nAMD.

Comparing the frequency of treatments of an individual eye before the study and during the study indicated a clinically and statistically significant longer period between treatments while being monitored with the NVHO. The number of weeks per injection approximately doubled while still maintaining stable vision. Seven of the 18 eyes that are included in the analysis of the reference period had loading doses of three monthly injections. These have a minimal impact on the results and are estimated to contribute only 14 extra injections to the total of 250 injections in the group. Not knowing the potential effect of home OCT on a loading period, remote monitoring could potentially eliminate some of the treatments. The observed treatment interval increased during home OCT management; however, it is unknown what the actual treatment requirements in the reference period were, as patients may have often been treated without fluid, as seen in treat and extend.

This reduction in treatments for patients managed by the NVHO could potentially mean substantial savings for the health care systems. The therapies for nAMD cost more than four billion USD per year in the United States alone.6 The demonstrated reduction of treatment frequency could possibly cut this significant health care expense in half.

It should be noted that there are limitations when comparing outcomes of the same patient with their past data. Unless the patient is stable, it may result in higher number of injections in the earlier part of their management. Similarly, it is well known that patients show significant VA gains in the early part of their management, and this can bias the comparison in favor of period before the use of home OCT. The study did not put a limitation on the period of treatment before enrollment into the study.

The other limitations of this study include the small number of patients and eyes used in this study. The eye was selected nonrandomly, non-ETDRS VA measurements, and the fact that the nonmonitoring period always preceded the NVHO-monitoring period. The study did not enforce a fixed criterion for treatment decision, and investigators were allowed to use their discretion in terms of fluid tolerance. The investigators had the option to choose newer therapies like Faricimab during the home OCT period. However, at the same time, a unique strength of these findings includes the use of the same eyes in a consecutive manner, therefore reducing the variability that can be seen in analyzing parallel cohorts.

This study demonstrated that near daily self-imaging with the NVHO enabled the successful management of eyes with nAMD. AI-generated fluid volume trajectories could be easily reviewed on a remote physician web viewer by treating physicians. Eyes without fluid could be observed. Eyes that initially responded well to treatment with complete fluid resolution could then be treated again in response to a notification of fluid recurrence, resulting in a typical episode of recurrence–treatment–response. The effect of treating eyes with persistent fluid could be monitored closely to inform decisions about the timing of the next office visit and the type of drug to be used. Finally, one of the eyes with minimal persistent fluid could be treated once during the 6-month study, in contrast to treatment every 8 weeks in the prestudy period, while maintaining stable vision.

In this small study, home OCT data pointed out the exact time of recurrence, allowing measurements of the duration of fluid exposure. It also allowed for patterns of fluid recurrences to be classified as episodic or transient. This study demonstrated that the duration of recurrence and resolution were similar. On average, it took less than 2 weeks for fluid to develop to a meaningful volume. Similarly, it took less than 2 weeks for fluid to resolve.

The question of characterizing the recurrence rhythm of fluid in nAMD eyes is often discussed in the context of a treat and extend regimen, which aims to extend the treatment interval but keep the eye without fluid. Data from this study identified two eyes with a variation of 20 days in the reactivation interval, whereas 2 eyes of a single patient and 1 eye of another patient showed remarkable predictable pattern of reactivation interval every 57 to 61 days and 53 to 55 days, respectively. Thus, not every patient demonstrates a recurrence rhythm that is amenable to a typical treat-and-extend paradigm.

Analysis of temporal fluid volume dynamics allows for nAMD disease classification according to distinct trajectory patterns. Such classification is enabled by the high density of data output from the home OCT and provides valuable insight into nAMD disease. It is plausible to envision an evolution of this nAMD understanding and classification because more eyes are managed with home OCT for longer periods. This may lead to more sophisticated management guideline and personalized treatment approaches for this very heterogeneous disease.

AI-based image analysis allows extraction of actionable disease activity and treatment response insights from up-to daily high-density home OCT scans. These insights may prove essential for integration of this new imaging modality in an efficient physician-led clinical decision-making process. Review of remote images and data, setting of notification criteria, and response to time and fluid volume-based notifications demands implementation of new practice workflows and physician reimbursement. Moreover, home OCT-based patient management requires office visits to be scheduled on short notice as well as responsiveness by patients and caregivers to attend. Practice guidelines and patient consent should be established to address potential liability concerns.

In conclusion, a small cohort of nAMD patients successfully self-installed and self-imaged with the NVHO, producing good-quality volume scans for remote visualization by the physician and AI-based NOA fluid quantification.

For the first time, monitoring with the NVHO aided treating physicians in personalized management of nAMD. This study showed a significant reduction in treatment burden by almost 50% while maintaining stable VA. The clinical and health care economic impact of this new nAMD management paradigm should be studied in larger controlled long-term studies.

Study Sponsor: Notal Vision.

Paper presented at Retina Society New York, NY, November 4, 2023; American Academy of Ophthalmology San Fransisco, CA, October 13, 2023.

None of the authors has any conflicting interests to disclose.
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References

1. Fleckenstein M Keenan TDL Guymer RH . Age-related macular degeneration. Nat Rev Dis Primers 2021;7 :31.33958600
2. Rosenfeld PJ Brown DM Heier JS . Ranibizumab for neovascular age-related macular degeneration. N Engl J Med 2006;355 :1419–1431.17021318
3. Heier JS Brown DM Chong V . Intravitreal aflibercept (VEGF trap-eye) in wet age-related macular degeneration. Ophthalmology 2012;119 :2537–2548.23084240
4. Busbee BG Ho AC Brown DM . Twelve-month efficacy and safety of 0.5 mg or 2.0 mg ranibizumab in patients with subfoveal neovascular age-related macular degeneration. Ophthalmology 2013;120 :1046–1056.23352196
5. Heier JS Khanani AM Quezada Ruiz C . Efficacy, durability, and safety of intravitreal faricimab up to every 16 weeks for neovascular age-related macular degeneration (TENAYA and LUCERNE): two randomised, double-masked, phase 3, non-inferiority trials. Lancet 2022;399 :729–740.35085502
6. Patel S Sternberg P . Is there a cost benefit to the ranibizumab port delivery system? JAMA Ophthalmol 2022;140 :723–724.35708666
7. Khanani AM Skelly A Bezlyak V . SIERRA-AMD: a retrospective, real-world evidence study of patients with neovascular age-related macular degeneration in the United States. Ophthalmol Retina 2020;4 :122–133.31812631
8. Ho AC Kleinman DM Lum FC . Baseline visual acuity at wet AMD diagnosis predicts long-term vision outcomes: an analysis of the iris registry. Ophthalmic Surg Lasers Imaging Retina 2020;51 :633–639.33231696
9. Holekamp NM Campochiaro PA Chang MA . Archway randomized phase 3 trial of the port delivery system with ranibizumab for neovascular age-related macular degeneration. Ophthalmology 2022;129 :295–307.34597713
10. Wykoff CC Brown DM Reed K . Effect of high-dose intravitreal aflibercept, 8 mg, in patients with neovascular age-related macular degeneration: the phase 2 CANDELA randomized clinical trial. JAMA Ophthalmol 2023;141 :834–842.37535382
11. Khanani AM Thomas MJ Aziz AA . Review of gene therapies for age-related macular degeneration. Eye 2022;36 :303–311.35017696
12. Keenan TDL Goldstein M Goldenberg D . Prospective, longitudinal pilot study: daily self-imaging with patient-operated home OCT in neovascular age-related macular degeneration. Ophthalmol Sci 2021;1 :100034.36249303
13. Liu Y Holekamp NM Heier JS . Prospective, longitudinal study: daily self-imaging with home OCT for neovascular age-related macular degeneration. Ophthalmol Retina 2022;6 :575–585.35240337
14. Kim JE Tomkins-Netzer O Elman MJ . Evaluation of a self-imaging SD-OCT system designed for remote home monitoring. BMC Ophthalmol 2022;22 :261.35689210
15. Blinder KJ Calhoun C Maguire MG . Home OCT imaging for newly diagnosed neovascular age-related macular degeneration: a feasibility study. Ophthalmol Retina 2024;8 :376–387.
16. Chakravarthy U Goldenberg D Young G . Automated identification of lesion activity in neovascular age-related macular degeneration. Ophthalmology 2016;123 :1731–1736.27206840
17. Keenan TDL Chakravarthy U Loewenstein A . Automated quantitative assessment of retinal fluid volumes as important biomarkers in neovascular age-related macular degeneration. Am J Ophthalmol 2021;224 :267–281.33359681
