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Retinal Physician

Article

Clinical Trials in Pediatric Retinal Disease

The number of potential therapies is growing.

By: Brittni A. Scruggs, MD, PhD, J. Peter Campbell, MD, MPH
Retinal Physician March 1, 2021 Vol 18, Issue March 2021 Page(s): 27, 30, 31

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In the past decade, there have been a number of therapeutic advances that have added complexity to the treatment of pediatric retinal diseases such as retinopathy of prematurity (ROP) and that have opened new therapeutic options where none existed for diseases such as Leber congenital amaurosis (LCA). This review highlights the landmark studies that should guide counseling and decision making for treating ROP and other pediatric retinal diseases.

CLINICAL TRIALS IN PEDIATRIC RETINA

Design and Implementation

There are numerous challenges to designing and implementing clinical trials in pediatric retina, and, for many rare conditions, trials are not likely to be feasible. When possible, it is imperative to use natural history studies to guide clinical design.1,2 Obtaining major funding to study diseases with low prevalence can also be difficult, especially without market incentives attracting industry investment.1 Recruiting pediatric patients is more difficult than recruiting adults, and there are associated increased costs and liabilities;3 further, low participation may lead to inconclusive results and an inability to assess adverse events or treatment effect.2

Ethical Considerations and Challenges

Recruitment of children in clinical trials requires the ability to facilitate the decision-making process without coercion.2 Patients and their families should be adequately informed of all trial options to avoid biases toward specific trials. The Monaciano Symposium reviews pediatric action plans for clinical trials with emphasis on developing pediatric patient registries, engaging networks of pediatric retina experts, and establishing genetic counseling guidelines.1 Many institutions require a safety monitoring board with pediatric experts for overseeing trials.2 Finally, the majority of children globally live in low- or middle-income countries, where community engagement for recruiting is essential to implement ethical trials that address health care needs of this vulnerable population.4,5

Enrolling children with good visual acuity in preventative trials, such as gene replacement studies, requires excellent counseling with the family, validated outcome measures for long-term monitoring, and safe therapeutics that minimize procedural complications.1 Families must also understand that trial participation may preclude participants from enrollment in future trials.

Complicating pediatric retina research is that at least 270 different causative genes for inherited retinal diseases (IRD) have been characterized;6 thus, researchers must be creative in developing treatments that are versatile without increasing costs.1 Conversely, obtaining a pediatric retina genetic diagnosis may not be possible in up to 40% of cases;7 this, of course, prevents enrollment in most interventional clinical trials. The limited number of pediatric retina specialists and participating institutions may limit access to certain trials, while approved therapies may be cost prohibitive for some families.1

CLINICAL TRIALS FOR RETINOPATHY OF PREMATURITY

ROP is a leading cause of childhood blindness worldwide, although the epidemiology differs between high-income and low-income countries.8 The following sections highlight a selection of clinical trials and large population-based studies that should guide screening, diagnosis, and treatment for ROP.

Epidemiology

An epidemiologic modeling study and meta-analysis estimated that of the approximately 185,000 preterm babies with ROP worldwide born each year, between 20,000 and 50,000 babies become blind or visually impaired.9 The Global Burden of Disease study estimated that 257,000 years lived with disability worldwide in 2010 were associated with ROP-related visual impairment.10 Improved infant survival rates at younger gestational ages (GA) will further increase ROP incidence.

The cryotherapy for ROP (CRYO-ROP) natural history study found that every additional gestational week led to a 19% decrease in developing severe ROP requiring treatment (ie, threshold ROP), whereas each 100 g increase in birth weight (BW) was associated with a 27% decrease in threshold ROP.11 Ten years later, the Multicenter Study of Early Treatment for Retinopathy of Prematurity (ET-ROP) found that 68% of infants born <1,251 g developed mild ROP or worse.12,13

ROP Classification

ROP is classified based on the location, extent, and severity of disease (stage and vascular changes), according to the International Classification of Retinopathy of Prematurity (ICROP) guidelines.14-16 “Threshold ROP” is ROP requiring treatment, defined by the CRYO-ROP study as 5 or more contiguous or 8 total clock-hours of stage 3 ROP in zone I or II in the presence of plus disease.17 Plus disease is defined as venous dilation and arteriolar tortuosity in 2 or more quadrants within the posterior pole.18 The ET-ROP trial further classified ROP into type 1 and type 2 prethreshold disease to guide the treatment of high-risk infants with early laser before the development of threshold ROP.12

ROP Screening

In the CRYO-ROP study,17 more than 4,000 infants with <1,251 g BW had serial eye examinations.19 ROP was observed in 1 or both eyes of 65.8% of infants, with ROP observed in 90% of those with <750 g BW, in 78% of those with 750 g to 999 g BW, and in 47% of those with 1,000 g to 1,250 g BW.17 Mean onset of stage 1 occurred at 34.3 weeks GA in the CRYO-ROP trial and at 34.1 weeks GA in the ET-ROP study.12,17 Based on these pivotal studies, ROP screening guidelines have been jointly published and updated by the American Academy of Pediatrics, the American Association for Pediatric Ophthalmology and Strabismus, and the American Academy of Ophthalmology.20,21 All infants ≤1,500 g BW or ≤30 weeks GA should be screened at 31 weeks GA or 4 weeks chronological age, whichever is later.

Clinical Trials Related to Supplemental Oxygen in Premature Babies

The Surfactant, Positive Airway Pressure, Pulse Oximetry Randomized Trial (SUPPORT) and Benefits of Oxygen Saturation Targeting Study II (BOOST-II) reported lower oxygen levels reduce the incidence of ROP blindness but at the expense of reduced survival and higher morbidity.30 Conversely, the Canadian Oxygen Trial (COT) was a large multicenter, double-blind randomized trial that showed 85% to 89% oxygen saturation (SpO2) targets for extremely premature babies had no effect on ROP, mortality, or morbidity compared to higher oxygen levels.31 The Supplemental Therapeutic Oxygen for Prethreshold Retinopathy of Prematurity (STOP-ROP) trial found no difference in ROP incidence in infants receiving 89% to 94% SpO2 compared to 96% to 99% SpO2.32

A meta-analysis concluded that high supplemental oxygen given at or after 32 weeks post-menstrual age was associated with reduced incidence of severe ROP.33 In a recent study, biphasic oxygen targets (eg, 85% to 92% at <34 weeks and >95% at >34 weeks) have shown a decrease in ROP incidence and severity without increasing mortality.34

ROP Telemedicine Studies

Telemedicine programs are successfully providing efficient screening methods for at-risk babies where screening ophthalmologists may be limited.22-26 In the 2014 Stanford University Network for Diagnosis of Retinopathy of Prematurity (SUNDROP) trial, RetCam digital images were captured for 1,755 infants over 6,995 examinations with high reported sensitivity and specificity for detection of type 1 ROP.27 The e-ROP Cooperative Group more formally evaluated the role of nonphysician graders and reported a sensitivity and specificity for detecting referral-warranted ROP as 90.0% and 87.0%, respectively,23,28 albeit with wide variation between graders.28,29

Pivotal Studies of ROP Ablative Treatment

In the CRYO-ROP study, 291 infants across 23 US centers were randomized to cryotherapy or observation.17,19 Cryotherapy reduced unfavorable structural outcomes of threshold ROP by 49.3% at 3 months and by 45.8% at 12 months.17 At the 1-year visit, there was significantly better grating acuity in the treated eyes.35 However, at 15 years, only 23% of treated and control eyes had visual acuity of 20/40 or better.35 It was the less-than-ideal response following cryotherapy that generated the ET-ROP multicenter randomized study of safety and efficacy of earlier or conventionally timed ablation of the peripheral retina in 7,000 infants.13 The ET-ROP study defined high-risk prethreshold ROP as type 1 ROP: zone I stage 3 ROP without plus disease; any stage ROP in zone I with plus disease; or zone II stage 2 or 3 ROP with plus disease.12,13 The ET-ROP study demonstrated that early laser treatment of severe ROP significantly reduced poor outcomes; based on these results, type 1 ROP remains the currently accepted treatment cutoff for ROP.12

VEGF Inhibitors as ROP Treatment

Around 32 weeks post-menstrual age, the vascular endothelial growth factor (VEGF) drive increases proportionally to the amount of avascular retina present and the degree of hypoxia. Increased VEGF levels can lead to arteriovenous shunts, retinal neovascularization, vitreoretinal traction, retinal detachments (RDs), and blindness. Although a mainstay treatment, dense laser to the avascular peripheral retina is associated with strabismus and high myopia,36 and incomplete or delayed treatment can lead to ROP progression and RD.

The Bevacizumab Eliminates the Angiogenic Threat of Retinopathy of Prematurity (BEAT-ROP) and Ranibizumab Compared with Laser Therapy for the Treatment of Infants Born Prematurely With Retinopathy of Prematurity (RAINBOW) trials demonstrated the utility of using VEGF inhibitors instead of laser in certain cases, such as zone I stage 3 ROP with plus disease.37,38

The Comparing Alternative Ranibizumab Dosages for Safety and Efficacy in Retinopathy of Prematurity (CARE-ROP) multicenter randomized clinical trial demonstrated that ranibizumab doses of 0.12 mg and 0.2 mg both controlled acute ROP without affecting systemic VEGF levels; the lower dose had improved peripheral vascularization.39 Similarly, the Pediatric Eye Disease Investigator Group (PEDIG) performed a multicenter, phase 1 dose de-escalation study and found that low doses of bevacizumab, including doses as low as 0.031 mg, were effective for treating type 1 ROP.40

Despite encouraging results suggesting fewer unfavorable ocular outcomes, less refractive error, and less acute morbidity from anesthesia, intravitreal therapy for ROP introduces new challenges, including the need for increased monitoring, potentially for years, to assess for reactivation,41 and the theoretical concerns about effects on neurodevelopment.42

Ongoing and Future ROP Studies

The ROP model of the Children’s Hospital of Philadelphia (CHOP-ROP) uses BW, GA, and daily weight gain to determine if type 1 ROP is likely to develop.43,44 In a cohort of 524 at-risk infants in a level III neonatal intensive care unit, this model accurately predicted, well in advance, all infants who developed type 1 ROP, and it would have reduced the number of examinations required by almost 50% had it been implemented clinically.44 However, larger validation studies need to be conducted in various clinical settings to determine the utility of this approach.43,45

Optical coherence tomography (OCT) and OCT angiography (OCTA) are being studied as tools to identify the structural signs (eg, vitreoretinal traction) preceding ROP progression.46-48 A fully automated deep-learning-based system for automated diagnosis of plus disease exists; this deep convolutional neural network, called the i-ROP DL system, was trained and validated on more than 5,000 images.49 DeepROP is a different automated ROP detection system that also achieved high sensitivity and specificity for ROP identification; however, neither have been tested in prospective clinical trials.50 Further research is needed prior to clinical implementation of these systems and algorithms to improve generalizability and to overcome regulatory issues.51

CLINICAL TRIALS FOR INHERITED RETINAL DYSTROPHIES

Retinal regeneration research is growing, with the greatest potential to treat diseases affecting the photoreceptors and retinal pigment epithelium (RPE), such as IRDs. Subretinal and intravitreal injections of novel therapeutics (eg, gene augmentation, oligonucleotide therapy, stem-cell–derived therapy) are being tested for treatment of retinal degenerative diseases, such as retinitis pigmentosa (RP), and the number of IRD clinical trials is expected to accelerate. A recent publication reviewed the 50 interventional IRD studies currently listed in the US National Clinical Trials Database;1 this review provides detailed recommendations for advancing IRD clinical trials.1

Photoreceptor Diseases

Subretinal gene replacement using the adeno-associated virus (AAV) AAV2-RPE65 improved functional vision in RPE65-associated LCA patients in a phase 3 randomized clinical trial.52 These promising results led to US Food and Drug Administration (FDA) approval for the first prescription gene therapy, voretigene neparvovec-rzyl (Luxturna; Spark Therapeutics), which is available for adult and pediatric patients with biallelic RPE65 mutations.

Editas Medicine recently received FDA authorization to conduct a phase 1/2 dose-escalation clinical trial using clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 therapy, which has the potential to silence deleterious alleles, for LCA patients with CEP290 gene mutations.53 For the first time in any human clinical trial, this genome editing therapy was used in 2020 for a patient with CEP290-associated LCA. A separate clinical trial sponsored by ProQR Therapeutics is actively testing the splice-modulating oligonucleotide QR-110 for CEP290-associated LCA.54 Numerous study sponsors are investigating gene therapies for RP.1 Similarly, multiple achromatopsia and choroideremia gene therapy trials are under way.

Macular Diseases

Autosomal recessive Stargardt disease associated with ABCA4 mutations remains the most common inherited macular disease, often affecting children and adolescents. Multiple active clinical trials are testing therapeutics for Stargardt disease; these include randomized studies of modified vitamin A supplements,55 complement factor inhibitors,56 and visual cycle modulators.1,57 Two-year results of a trial studying the safety of embryonic stem-cell–derived RPE in Stargardt disease demonstrated long-term safety and graft survival.58

X-linked retinoschisis is the most common juvenile macular dystrophy that occurs due to the loss of the retinoschisin protein (RS1). A phase 1/2a trial has been performed to test human gene therapy for XLRS.59 This 3-dose-escalation safety study over 18 months demonstrated overall tolerability to a single intravitreal injection of AAV2/8-RS1 vector, yet vector concentration directly correlated with increased intraocular inflammation, including vitritis and 1 case of vasculitis.59

Vitreoretinopathies

High myopia, frequent RDs, and systemic features (eg, facial dysgenesis, debilitating arthritis) cause increased morbidity in patients with Stickler syndrome, which is the most common hereditary vitreoretinopathy secondary to a procollagen mutation. An active randomized controlled trial60 is investigating the effects of scleral buckling for retinal detachment prevention in fellow eyes after recent RDs. RP

Brittni A. Scruggs, MD, PhD, and J. Peter Campbell, MD, MPH, are with the Casey Eye Institute, Department of Ophthalmology, Oregon Health & Science University in Portland, Oregon. This article was supported by grants R01EY19474, R01 EY031331, P30 EY10572 from the National Institutes of Health (Bethesda, Maryland), and by unrestricted departmental funding and a Career Development Award (JPC) from Research to Prevent Blindness (New York, New York). Reach Dr. Campbell at campbelp@ohsu.edu. Editor’s note: Listen to discussion of this article on the Retina Podcast at www.retinapodcast.com.

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