Clinical Trials of Neuro-Ophthalmic Interest (abstract)

2016 was a good year for clinical trials of interest to neuroophthalmologists. In this syllabus, I will discuss final or preliminary results from five treatment trials dealing with four disorders: primary pseudotumor cerebri syndrome (n=1), leber hereditary optic neuropathy (n=2), giant cell (temporal) arteritis (n=1), and optic pathway gliomas (n=1). It also is possible that preliminary or final results from one other trial for patients with leber hereditary optic neuropathy and one other trial for patients with giant cell arteritis will be published before the NANOS meeting, in which case these will be discussed in addition to what is presented in this syllabus.

CLINICAL TRIALS OF NEURO-OPHTHALMIC INTEREST Neil R. Miller, MD Johns Hopkins University School of Medicine Baltimore, MD LEARNING OBJECTIVES 1. Describe the results of a randomized clinical trial of treatment for mild/moderate primary pseudotumor cerebri syndrome 2. Recognize the potential for an adjunctive treatment for patients with giant cell arteritis 3. Explain the status of two gene therapy trials for patients with Leber hereditary optic neuropathy 4. Tell about a new treatment for children with optic pathway gliomas CME QUESTIONS 1. Patients with primary pseudotumor cerebri syndrome can often tolerate up to what daily dose of acetazolamide? a. b. c. d. 1 gram 2 grams 4 grams 6 grams 2. A new add-on drug for patients with giant cell arteritis is: a. b. c d. Rituximab Tocilizumab Infliximab Methotrexate 3. A new potential treatment for children with an optic pathway glioma is: a. Murine nerve growth factor b. Adalimumab c. Human growth hormone d. Bone marrow transplant KEYWORDS 1. Pseudotumor Cerebri Syndrome 2. Leber Hereditary Optic Neuropathy 3. Optic Pathway Glioma 4. Giant Cell Arteritis 5. Tocilizumab INTRODUCTION 2016 was a good year for clinical trials of interest to neuroophthalmologists. In this syllabus, I will discuss final or preliminary results from five treatment trials dealing with four disorders: primary pseudotumor cerebri syndrome (n=1), leber hereditary optic neuropathy (n=2), giant cell (temporal) arteritis (n=1), and optic pathway gliomas (n=1). It also is possible that preliminary or final results from one other trial for patients with leber hereditary optic neuropathy and one other trial for patients with giant cell arteritis will be published before the NANOS meeting, in which case these will be discussed in addition to what is presented in this syllabus. PRIMARY PSEUDOTUMOR CEREBRI SYNDROME (AKA, IDIOPATHIC INTRACRANIAL HYPERTENSION) The idiopathic intracranial hypertension treatment trial (IIHTT) run by NORDIC and funded by the NEI (NCT01003639) continues to generate important information. This treatment trial was designed to determine if weight loss alone was as effective as weight loss combined with acetazolamide for subjects with mild/ moderate primary pseudotumor cerebri characterized by papilledema and mean deviation on automated perimetry of -2 to -5 dB in the worse eye. Participants were randomized into one of two groups: a weight loss program + acetazolamide beginning at 500 mg bid or a weight loss program + placebo. The weight loss part of the trial was run by the New York Obesity Research Center (NYORC). Weight loss was monitored by counselors who interacted with the participants by telephone. The primary outcome measure was visual status at 6 months. The results of the study, published in 20141 were: 1) average weight loss of the participants who completed the study was about 6%, 2) participants in the weight loss + acetazolamide group had a better visual outcome than participants treated with weight loss alone, and 3) the effects of acetazolamide are not due solely to its effect on weight. Several papers subsequently were published in 2015, dealing with photographic methods and baseline results,2 quality of life,3 retinal and choroidal folds in the participants,4 and risk factors for poor outcome in the trial.5 In 2016, five further papers were published in peer-reviewed journals. Wall et al.6 reported the results of an in-depth assessment of the visual field findings in the two groups of participants enrolled in the IIHTT. They found using pointwise linear regression that the average study eye had 36 of 52 test 2017 Annual Meeting Syllabus | 213 locations with improving sensitivity and that differences between the acetazolamide and placebo groups were not significant. Pointwise results mostly improved in both treatment groups, with the magnitude of the mean change within groups greatest and statistically significant around the blind spot and the nasal area, especially in the acetazolamide group. The consensus classification of visual field change from baseline to 6 months in the study eye yielded percentages (acetazolamide, placebo) of 7.2% and 17.5% worse, 35.1% and 31.7% with no change, and 56.1% and 50.8% improved; group differences were not statistically significant. Thus, the only real difference between the groups was a reduction in blind spot size related to improvement in papilledema. Cello et al.7 reported the prevalence of visual field treatment failures (TFs) and performance failures (PFs), and discussed the factors associated with PFs in the IIHTT. The IIHTT Visual Field Reading Center evaluated 2950 fields from the participants in the study. They diagnosed a TF when the participant's mean deviation (MD) worsened ≥2-3 dB from the average baseline MD (with a second retest confirming the deterioration). They considered a PF to have occurred when the participant's: 1) visual field results met TF criteria but were not confirmed on retest, 2) deterioration was confirmed on retest but the IIHTT Adjudication Committee concluded a TF was clinically unlikely. Using these criteria, the authors identified a TF in 7/165 (4%) of the participants and a PF in 35/165 (21%) of the participants on at least one examination. Four of the 35 PFs were adjudicated for a TF; however, based on clinical review by the Adjudication Committee and a third retest, these were judged instead to be PFs. Thus, of the 2,950 total IIHTT field examinations, 2.7% met the criteria for a PF. Thus, a PF was identified in 21% of participants and in 2.7% of the total number of VF examinations and was reversible on repeat testing. The bottom line was that in this cohort of participants, when perimetric worsening appears to have occurred in someone with papilledema who otherwise is clinically stable or improving, retesting is likely to reveal that the apparent worsening is due to poor performance rather than true worsening of the condition. This phenomenon applies to other settings as well, particularly subjects with glaucoma and ocular hypertension. The protocol for the IIHTT allowed participants to have their oral treatment (acetazolamide or placebo) increased to a dose of (in the case of acetazolamide) 4 gm per day if, in the opinion of the investigator, the participants were failing therapy. Ten Hove et al.8 reported that during the course of the trial, 38 of 86 participants randomized to the acetazolamide group (44.1%) tolerated the maximum allowed dosage of 4 g/d. The percentages of participants reporting at least one adverse event in the nervous, gastrointestinal, metabolic, and renal organ systems were significantly higher in the acetazolamide group (P < 0.05). The odds of paresthesia (OR 9.82; 95% CI 3.87-27.82), dysgeusia (OR ∞; 95% CI 3.99-∞), vomiting and diarrhea 214 | North American Neuro-Ophthalmology Society (OR 4.11; 95% CI 1.04-23.41), nausea (OR 2.99; 95% CI 1.26-7.49) and fatigue (OR 16.48; 95% CI 2.39-702.40) also were higher in the acetazolamide group than in the placebo group. Nevertheless, the authors concluded that acetazolamide is likely to be tolerated and appears to have an acceptable safety profile at dosages up to 4 g/d in the treatment of subjects with primary pseudotumor cerebri. As noted above, all participants in the IIHTT were enrolled in a weight loss program that was run by the NYORC and monitored via telephone by counselors. Weil et al.9 compared the results in both the acetazolamide and placebo groups and concluded that a telephonebased weight loss program achieves results similar to those of a personal-interaction program in subjects who presumably do not have primary pseudotumor cerebri. This presumption is reasonable if one considers that Krispel et al.10 performed a photographic assessment of the fundi in 606 subjects with an average body mass index of 47 kg/m2 who attended the UC Davis Bariatric Surgery Clinic over a 3-year period. These investigators found that 17 of these individuals (2.8%) had photographic optic disc findings or symptoms suspicious for papilledema; however, of the 11 who subsequently were evaluated clinically, seven did not have disc swelling. Of the four subjects in whom disc swelling was confirmed on clinical examination, all had "subtle" swelling only. These four subjects all had normal neuroimaging and the three who subsequently underwent lumbar puncture had only borderline high opening pressure. Thus, even if one assumes that the six subjects who had photographic findings suggesting optic disc swelling, 10/600 subjects (1.7%) may have had increased intracranial pressure (ICP). Thus, if one accepts the findings of these investigators that fewer than 2% of neurologically asymptomatic individuals who are morbidly obese are likely to have increased ICP, the findings in the IIHTT regarding weight loss indicate that there is no reason that with the proper regimen, subjects with primary pseudotumor cerebri should be able to lose weight to the same degree (ie, about 6% over 6 months) as individuals who do not have primary pseudotumor cerebri. Finally, Bruce et al.11 assessed the quality of life (QOL) in participants in the IIHTT using three measures: the NEI-VFQ-25, the 10-item NEI-VFQ-25 Neuro-Ophthalmic Supplement, and the 36-item Short form Health Survey. These authors found marked reductions in baseline QOL that were improved in the subjects treated with acetazolamide. Their findings would appear to support the use of acetazolamide in addition to dietary intervention in this group of patients. LEBER HEREDITARY OPTIC NEUROPATHY The quest for a method of preventing vision loss and restoring vision once it has been lost in patients with Leber hereditary optic neuropathy (LHON) continues following the failure of idebenone,12 brimonidine,13 and other agents14. In recent years, gene therapy using an adeno-associated viral (AAV) vector carrying ND4 genetic material has emerged as the next great hope. This has led to three prospective clinical trials, one in China, one in Europe (with sites in the US as well), and one in the United States. To date, only the Japanese trial has published final results, whereas the US trial has published some preliminary data. The trial in France (and the US) has yet to publish anything in the peerreviewed literature; however, there are some data that are discussed below. Investigators in China15, 16 performed a prospective, openlabel trial (NCT01267422) involving nine subjects with LHON associated with the G11778A mitochondrial mutation at Tongji Hospital, Wuhan, China, from August 2011 to December 2015. All nine subjects, whose symptoms and signs had begun between 1 and 17 years previously, received a single intravitreal injection of rAAV2-ND4. Systemic examinations and visual function tests were performed during the 36-month follow-up period to determine the safety and efficacy of this gene therapy. Based on successful experiments in an animal model of LHON, 1 subject also received a rAAV2-ND4 injection in the second eye 12 months after gene therapy was administered in the first eye. The primary outcome of this trial was recovery of visual acuity. Secondary endpoints were changes in the visual field, visual evoked potential (VEP), optical coherence tomography (OCT) findings, liver and kidney function, and antibodies against AAV2. Eight subjects received unilateral gene therapy, following which improvement in visual function was observed in both treated (Subjects 4, 6, 7, and 8) and untreated eyes (Subjects 2, 3, 4, 6 and 8). Visual regression fluctuations, defined as changes in visual acuity greater than or equal to 0.3 logMAR, were observed in two subjects. Age at disease onset, disease duration, and the amount of remaining optic nerve fibers by OCT did not have a significant effect on the visual function improvement. The visual field improved in all subjects, with both eyes improving in five, two of whom subsequently had worsening. There was a statistically significant decrease in the P100 latency on the patternreversal VEP in these subjects, and the P100 amplitude also increased although the increase was not significant. The one subject (Subject 1) who received gene therapy in both eyes had improved visual acuity in the injected eye after the first treatment; however, visual acuity in this eye decreased 3 months after he received gene therapy in the second eye. No serious adverse events occurred during the 3-year follow-up in any of the nine participants. Feuer et al.17 reported preliminary results of a phase 1 prospective open-label trial (NCT02161380) of intravitreal gene therapy for LHON associated with the G11778A mutation being conducted at the Bascom Palmer Eye Institute in Miami, Florida. There are three groups of subjects in this trial. Group I: Patients with ≥12 months since onset in one eye and at least 6 months onset in the more recently affected eye. Both eyes must have acuity reduced to ≤ 35 letters. If both eyes have ≥12 months since onset, the eye with worse visual acuity is injected. If both eyes have the same acuity, the eye with longest onset is injected. If one eye has <12 months and >6 months since onset and the difference in acuity between the eyes is ≤10 letters, the eye with ≥12 months is injected. If eyes have an acuity difference >10 letters, the eye with worse acuity is injected. Group II: Acute and bilateral loss of visual acuity to < 35 ETDRS letters (Snellen = 20/200) in both eyes for less than 12 months. Group III. Unilateral loss of acuity to < 35 ETDRS letters in one eye, but with mildly impaired but good acuity ≥ 70 letters (Snellen = 20/40) in the contralateral eye. For each group, administration of study drug follows an adaptive plan to identify the maximum tolerated dose. If none of three subjects at a given dose level develops a Safety Endpoint, the next cohort of patients receives the next higher dose. The investigators wait a minimum of 6 weeks between patient injections of the same dose and 3 months before moving to the next higher dose. They test the low dose first in 3 patients of group I, before moving on to testing this low dose in group 2, then last in group 3. Even in the absence of Safety Endpoints in groups I and II, there will be a delay of 12 months before the first injection in group III. In this trial, the study drug is selfcomplementary AAV-P1ND4v2. The preliminary results reported by the investigators indicate that they injected the drug unilaterally into the eyes of five participants with G11778A LHON. Four participants with bilateral visual loss for more than 12 months (Group I) were treated. The fifth participant had bilateral visual loss for less than 12 months (Group II). The first 3 participants (Group I) were treated with the low dose of vector (5 × 10(9) vg), the fourth participant (also in Group I) was treated with the medium dose (2.46 × 10(10) vg). The fifth participant with visual loss for less than 12 months (Group II) received the low dose. Treated participants were followed for 90 to 180 days and underwent ocular and systemic safety assessments along with visual structure and function examinations. Among these five participants, no one lost vision, and no serious adverse events were observed. Minor adverse events included a transient increase of intraocular pressure, exposure keratitis, subconjunctival hemorrhage, a sore throat, and a transient increase in neutralizing antibodies (NAbs) against AAV2 in 1 participant. All blood samples were negative for vector DNA. Visual acuity as measured by the Early Treatment Diabetic Retinopathy Study (ETDRS) eye chart remained unchanged from baseline to 3 months in the first three participants. For two participants with 90-day follow-up, acuity increased from hand movements to seven letters in 1 and by 15 letters in 1, representing an improvement equivalent to 3 lines. Additional study followup of these and additional participants is planned for the next 4 years. The European trial (NCT02064569) was sponsored by Gensight. Each subject (G11778A mutation) in this phase 1/2 trial had one eye randomly selected to receive a single injection of GS010, a recombinant AAV vector serotype 2 2017 Annual Meeting Syllabus | 215 (rAAV2/2) containing the wild-type ND4 gene (rAAV2/2-ND4); the other eye received a sham injection. Although the investigators have not published the results of this trial in a peer-reviewed journal at the time this syllabus was written, they gave a press release recently that indicated that they had treated 15 subjects who were divided into groups of three in a dose-escalation fashion similar to that in the trial reported by Feuer et al. described above. At 48 weeks after treatment, there were no significant adverse effects. In addition, LHON patients who had lost vision within 2 years of treatment showed a gain of 30 letters in the treated eye and a gain of 13 letters in the untreated eye. No significant change in visual acuity, however, was reported in those with disease onset of more than 2 years (on average, trial participants had been symptomatic for 6 years). The company also reported that the vision in those subjects whose vision improved remained stable beyond 48 weeks. These results were sufficient for the company to begin two new phase 3 trials, one (NCT02652767) assessing treatment effects of GS010 in subjects with vision loss that began less than 6 months earlier (PI: Nancy Newman) and the other (NCT02652780) assessing treatment effects in subjects with visual loss between 7 and 12 months earlier (PI: Patrick YuWai Man). GIANT CELL (TEMPORAL) ARTERITIS At this time, the only accepted treatment for patients with giant cell arteritis (GCA) is systemic steroids. Unfortunately, steroids produce significant side effects that increase in frequency and severity the longer they are used. Thus, investigators have attempted to identify other drugs that either might be used instead of systemic steroids or might reduce the length of time that steroids are required. Until recently, the only randomized prospective clinical treatment trials were those in which the efficacy of methotrexate as an adjunctive agent was assessed.18, 19 These studies showed no efficacy. Recently, however, the results of a single-center, randomized, placebo-controlled, phase 2 trial in Switzerland using tocilizumab (TCZ) as addon therapy, were published.20 Tocilizumab is a humanized monoclonal anti-IL-6 receptor antibody that binds both soluble and membrane-bound IL-6 receptors and, thus, inhibits Il-6 signal transduction. It has been approved for treatment of patients with rheumatoid and juvenile rheumatoid arthritis and is administered as a monthly infusion of 4 or 8 mg/kg. In this trial, participants satisfying 1990 ACR criteria were randomly assigned in a 2:1 ratio to receive either prednisone + TCZ (8 mg/kg IV of body weight) or prednisone + intravenous placebo. The dose of prednisone was started at 1mg/kg/d and tapered by 0.1mg/kg/d weekly until week 8, then by 0.05mg/kg/d weekly until week 12 (0.1mg/kg/d). Thereafter, the dosage was decreased by 1mg/d monthly to 0mg. The dosage of TCZ was 8mg/kg of body weight, with infusions given every 4 weeks. The primary outcome was the number of subjects in complete remission at week 12 (steroid dose of 0.1mg/ 216 | North American Neuro-Ophthalmology Society kg/d). The secondary outcome was the number of subjects who remained relapse-free at week 52 while the steroids were being tapered. After 12 weeks, 17 participants (85%) in the TCZ group versus four (40%) in the placebo group were in complete remission (P = 0.030). At end of trial, 17 subjects (85%) in the TCZ group versus two (20%) in the placebo group had experienced no relapse (P = 0.008) (Figure below). In terms of safety, 75% of subjects in the TCZ group had side effects vs 70% in the placebo group. Most of the side effects were gastrointestinal and minor; however, nine of the subjects in the TCZ group developed neutropenia. The conclusion of this study was that TCZ is efficacious for induction and maintenance therapy in patients with newly diagnosed or relapsed GCA in the context of rapidly tapered corticosteroids. However, both the investigators and the writer of an accompanying editorial21 emphasized that the long-term efficacy of TCZ remains unknown as does whether or not the drug should be used instead of steroids as first-line therapy for GCA. A second trial, the GiACTA Trial, designed to assess the efficacy of TCZ as an add-on drug for GCA finished recruiting in April of 2016. This was a multicenter, placebo-controlled trial in which, like the previous study, patients were randomized to receive either systemic corticosteroids + TCZ or corticosteroids + placebo. The primary outcome was sustained remission at 52 weeks.22 As of the writing of this syllabus, the results of this study have not been reported; however, the "word on the street" is that the results were similar to those of the Swiss trial (see a NANOS 2017 poster by S Mollan). OPTIC PATHWAY GLIOMAS Most optic pathway gliomas occur in children, are extremely slow growing, and do not damage vision sufficiently to require treatment. Nevertheless, treatment may be appropriate in some patients with gliomas confined to one optic nerve as well as patients with chiasmal gliomas. Falsini et al.23 treated five children with optic nerve gliomas and severe optic disc pallor with a 10-day course of topical murine nerve growth factor. After treatment, all five showed an increase in VEP amplitudes that persisted for 90 days. The amplitudes declined by 180 days but remained above baseline. During this period, MR imaging showed no change in tumor size. Falsini et al.24 also performed a randomized, double-masked, phase 2 clinical trial in 17 patients with optic pathway gliomas who had stable visual function and imaging. Patients were treated with either a 10day course of 0.5 mg of murine nerve growth factor (n=10) or placebo (n=8). All were evaluated at baseline and at 15, 30, 90 and 180 days. The evaluation included assessment of visual acuity and visual field as well as VEP amplitudes, OCT of the peripapillary retinal nerve fiber layer, and MR imaging. These investigators noted no adverse effects from treatment and statistically significant improvement in all parameters in subjects receiving nerve growth factor. Visual field worsening occurred only in subjects who had received placebo. These trials suggest that the use of murine nerve growth factor may be a safe and effective way to stabilize or restore vision in eyes with reduced function in the setting of optic pathway gliomas. CME ANSWERS 1. c 2. b 7. Cello KE, Keltner JL, Johnson CA, Wall M, for the NORDIC Idiopathic Intracranial Hypertension Study Group. Factors affecting visual field outcomes in the Idiopathic Intracranial Hypertension Treatment Trial. J Neuro-Ophthalmol. 2016; 36:6-12. 8. ten Hove MW, Friedman DI, Patel AD, Irrcher I, Wall M, McDermott MP, for the NORDIC Idiopathic Intracranial Hypertension Group. Safety and tolerability of acetazolamide in the Idiopathic Intracranial Hypertension Treatment Trial. J Neuro-Ophthalmol. 2016; 36:13-19. 9. Weil R, Kovacs B, Miller N, McDermott MP, Wall M, Kupersmith M, Pi-Sunyer FX, and NORDIC Idiopathic Intracranial Hypertension Study Group. 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