The following article is part of conference coverage from the 2019 American Academy of Neurology Annual Meeting (AAN 2019) in Philadelphia, PA. Neurology Advisor’s staff will be reporting breaking news associated with research conducted by leading experts in neurology. Check back for the latest news from AAN 2019.
PHILADELPHIA – A plenary session at the 2019 American Academy of Neurology Annual Meeting, held May 4 to 10, 2019, in Philadelphia, Pennsylvania, featured important clinical trials from other society meetings that impact patient care in the field of neurology. Holly E Hinson, MD, MCR FAAN and Deborah Hall, MD, PhD, FAAN moderated the session, during which researchers discussed findings from recently published and ongoing trials.
Jeff Williamson, MD, presented results from the SPRINT MIND Trial (ClinicalTrials.gov Identifier: NCT01206062). Investigators in this trial sought to determine whether intensive blood pressure control would be beneficial in reducing dementia and improving cognitive impairment. Although there was a difference in the composite outcome of mild cognitive impairment in favor of the intensive treatment group (hazard ratio, 0.85; 95% CI, 0.74-0.97), there was no significant risk reduction for probable dementia in patients with hypertension, with a treatment goal of systolic blood pressure <120 mm Hg vs <140 mm Hg.2 Dr Williamson also reviewed unpublished brain magnetic resonance imaging (MRI) results, showing that white matter lesion volume and total brain volume decreased in the intensive group from baseline to 4-year follow-up.
Bruce A. C. Cree, MD, PhD, MCR, FAAN, presented data from the randomized controlled trial of inebilizumab in neuromyelitis optica spectrum disorder (NMOSD) (ClinicalTrials.gov Identifier: NCT02200770).3 Investigators sought to determine the safety and efficacy of inebilizumab on relapse prevention in patients with NMOSD in a phase 3, double-masked, randomized, placebo-controlled trial. Inebilizumab is an anti-CD19, B-cell depleting monoclonal antibody. Participants were randomly assigned 3:1 to receive either inebilizumab (n = 174) or placebo (n = 56). The primary outcome was the time to first adjudicated NMOSD attack. A 3-member committee adjudicated all reported attacks.3
Inebilizumab resulted in risk reduction of 77.3% for attacks in NMOSD compared with placebo in patients who were AQP4-IgG seropositive. Of these patients, 11.2% presented with attacks compared with 42.3% of patients in the placebo group. The number needed to treat at day 197 was 3.23 (95% CI, 2.72-4.54). In the overall population, inebilizumab resulted in a risk reduction of 72.8% for attacks in NMOSD compared with placebo. Of these patients, 12.1% presented with attacks compared with 39.3% of patients in the placebo group. The number needed to treat at day 197 was 3.73 (95% CI, 3.06-5.66).
Overall, inebilizumab significantly reduced the risk for adjudicated NMOSD attack in both study populations. In addition, there were reductions in disability worsening, MRI lesion activity, and hospitalizations in AQP4-IgG seropositive group and overall intent-to-treat population after treatment with inebilizumab. There were 2 deaths in the open-label period, 1 related a severe NMOSD attack and 1 resulting from a brain event of unclear etiology without definitive diagnosis.
Josep Gamez, MD, PhD, presented data from a randomized, controlled, double-blind trial investigating use of intravenous (IV) immunoglobulin after surgery.4 Researchers sought to determine whether preoperative IV immunoglobulin is effective for preventing myasthetic crisis in patients scheduled for surgery under general anesthesia, including thymectomy. Participants in the treatment group (n = 25) were given 0.4 mg/kg/d IV immunoglobulin for 5 days. The placebo group received saline solution (n = 22).
The investigators concluded that in patients with a quantitative myasthenia gravis score <8 and preoperative vital capacity (forced vital capacity >70%), no myasthenic crisis should be expected. In addition, for patients with good preoperative functional status undergoing surgery in the presence of a multidisciplinary group with experience working with patients with myasthenia gravis, IV immunoglobulin is not needed before surgical procedures.
Mark L. Moster, MD, FAAN, presented results from the REVERSE phase 3 clinical trial investigating rAAV2/2-ND4 (GS010) for the treatment of leber hereditary optic neuropathy (LHON) (ClinicalTrials.gov Identifier: NCT03406104).1 In the study, 37 participants with LHON were enrolled; all had vision loss duration of 6 to 12 months, confirmed G11778A mutation, and baseline visual acuity to at least count fingers. The study’s primary outcome was the mean difference in visual acuity of eyes being treated with GS010 vs eyes receiving sham injections at week 48. The most common adverse events were ocular inflammation and intermediate uveitis (89.2% in the treatment group and 8.1% in the sham injection group) and intraocular pressure elevation (27.0% in the treatment group and 2.7% in the sham injection group). No adverse event lead to study discontinuation.
Visual acuity and improvement from nadir increased in both the treatment group and sham injection group after 72 weeks of treatment. Investigators found that eyes treated with GS010 were significantly more likely to be above the legal threshold for blindness than sham injection eyes (odds ratio, 4.07; P =.0012). Low-level contrast and sensitivity improved in both eyes, but much more in the treatment group. The treatment group had a significant sparing of the ganglion cell layer compared with the sham injection group. There were also improvements in the papillo-macular bundle thickness. Composite score for quality of life was improved by approximately 25% at week 72 from baseline.
Given the improvements in both the treatment and sham eyes, Dr Moster raised a question: “Is there a bilateral effect of unilateral treatment or is this placebo, or is the natural history [of improvement in LHON] better than we believe?”
He added that the results from the RESCUE trial will be released soon and mentioned 2 ongoing trials for patients with LHON: REALITY (ClinicalTrials.gov Identifier: NCT03295071) and REFLECT (ClinicalTrials.gov Identifier: NCT03293524).
David W. Dodick, MD, FAAN, presented data from a placebo-controlled study of galcanezumab in patients with episodic cluster headache (ClinicalTrials.gov Identifier: NCT02397473).5 Dr Dodick provided context for the research, noting that, “there is a severe unmet medical need in patients with cluster headache, there is under recognition of the disorder, there is a high misdiagnosis rate…, and on average it takes a patient with cluster headache about 5 to 7 years to receive a diagnosis of cluster headache. There is an underutilization of effective acute treatments for patients with cluster headaches…, and there are no approved medications for cluster headache prevention.”
Dr Dodick and colleagues sought to determine the safety and efficacy of galcanezumab in patients with episodic cluster headache. Investigators determined that subcutaneous galcanezumab 300 mg significantly reduced weekly cluster headaches from week 1 to week 3. Compared with placebo, galcanezumab resulted in more patients achieving a ≥50% reduction in weekly headache attacks by week 3.5 Overall, 21/49 participants in the treatment group experienced treatment-emergent adverse events compared with 19/57 in the placebo group. The most common treatment-emergent adverse events were injection site pain and nasopharyngitis.
Susan Rowell, MD, MCR, FACS, presented data from the Use of Tranexamic Acid in Patients with Traumatic Brain Injury: Results from the North American Multi-Center Prehospital TXA for TBI trial (ClinicalTrials.gov Identifier: NCT01990768).1 Investigators sought to determine whether prehospital tranexamic acid (TXA) administration in patients with moderate or severe traumatic brain injury would produce increased favorable long-term neurologic outcomes. The Extended Glasgow Outcome Scale was utilized to determine functional neurologic outcome 6 months after injury. Investigators discovered no difference in 6-month neurologic outcome between patients who received TXA and those who received placebo (odds ratio, 0.87; 95% CI, 0.65-1.17; P =.18). In addition, prehospital TXA did not decrease intracerebral hemorrhage progression, but a 2-g prehospital bolus improved 28-day survival.
Vinai Gondi, MD, discussed radiotherapy as “one of the most effective treatments for patients with primary metastatic central nervous system tumors.” He outlined translational research in radiation oncology during his presentation titled From Bench to Beside to Beam: Hippocampal-sparing during Brain Irradiation.6,7 He discussed the effect of radiotherapy on cognitive toxicity from brain irradiation, preclinical observations demonstrating memory-specific radiosensitivity of hippocampal neurogenesis, and the ability to spare the hippocampus during brain irradiation to prevent cognitive toxicity.
Dr Gondi discussed 2 clinical trials that showed hippocampal sparing effects during radiotherapy. One was a phase 2 trial, RTOG 0933 (ClinicalTrials.gov Identifier: NCT01227954), in which investigators observed sparing of memory function compared with controls during whole-brain radiotherapy with conformal avoidance of the hippocampus. The second was a phase 3 trial that lead to the conclusion that memantine may have neuroprotective effects on the hippocampus and prevent cognitive toxicity, which “established memantine as standard of care during whole brain radiotherapy.”
The combination of these 2 trials lead to a phase 3 trial, NRG-CC001 (ClinicalTrials.gov Identifier: NCT02360215), where memantine was included with whole-brain radiotherapy, with or without hippocampal avoidance for brain metastases. In conclusion, the trial showed that “hippocampal sparing during whole brain radiotherapy plus memantine for patients with brain metastasis preserves cognitive function and patient reported quality of life.”
Dr Gondi added that a trial investigating proton therapy, a more advanced form of radiotherapy that allows for the sparing of more healthy brain tissue, showed favorable outcomes for intelligence and processing speed in pediatric patients with brain tumors.8 He noted that there are additional ongoing trials of proton therapy in both pediatric and adult cohorts.
Tanya Simuni, MD, presented data from a phase 3 study of isradipine in patients with early Parkinson disease (ClinicalTrials.gov Identifier: NCT02168842).9 The objective of this study was to determine the efficacy of isradipine, a potential disease-modifying agent, to slow progression of Parkinson disease disability as an early intervention. Investigators found that daily isradipine 10 mg failed to slow the progression of Parkinson disease disability. Dr Simunai discussed several reasons as to why the 10-mg dose failed to meet the primary endpoint. Some of the reasons discussed included a potential “lack of human read out on target engagement” or even an insufficient dose of medication, given that the dosage was selected based on tolerability.
Several speakers disclosed affiliations with the pharmaceutical industry. Please refer to original references or clinical trial registries for disclosure information.
For more coverage of AAN 2019, click here.
1. Plenary Session: Clinical Trials. Presented at: 2019 American Academy of Neurology Annual Meeting; May 4-10, 2019; Philadelphia, PA.
2. Williamson JD, Pajewski NM, Auchus AP, et al. Effect of intensive vs standard blood pressure control on probable dementia: a randomized clinical trial. JAMA. 2019;321(6):553-561.
3. Cree B, Bennett J, Kim HJ, et al. A double-masked, placebo-controlled study with open-label period to evaluate the efficacy and safety of inebilizumab in adult subjects with neuromyelitis optica spectrum disorders–top line efficacy and safety results. Neurology. 2019;92(15 Supplement):Plen02.001.
4. Gamez J, Salvado M, Carmona F, et al. Intravenous immunoglobulin to prevent myasthenic crisis after thymectomy and other surgical procedures can be omitted: a randomized, controlled, double-blind trial. Neurology. 2019;92(15 Supplement):Plen02.003.
5. Bardos JN, Goadsby PJ, Dodick D, et al. A placebo-controlled study of galcanezumab in patients with episodic cluster headache: results from the 8-week double-blind treatment phase. Neurology. 2019;92(15 Supplement):Plen02.004.
6. Gondi V. From bench to bedside to beam: hippocampal-sparing during cranial irradiation. Presented at: 2019 American Academy of Neurology Annual Meeting; May 4-10, 2019; Philadelphia, PA.
7. Gondi V. From bench to bedside to beam: Hippocampal-sparing during cranial irradiation. J Thorac Oncol. 2016;11(2):S6.
8. Gross JP, Powell S, Zelko F, et al. Improved neuropsychological outcomes following proton therapy relative to x-ray therapy for pediatric brain tumor patients [published online April 17, 2019]. Neuro-Oncology. doi:10.1093/neuonc/noz070
9. Simuni T, Lowell J, Oakes D, et al. An update on STEADY-PD III: a phase 3 study of isradipine as a disease modifying agent in patients with early Parkinson’s disease. Presented at: 2019 American Academy of Neurology Annual Meeting, May 4-10, Philadelphia, PA. P2.341.