NORAPS Phase 2 Trial to Test Noradrenaline Reuptake Inhibitor Atomoxetine in PSP Apathy and Impulsivity

Robert Durcan, PhD

The phase 2 NORAPS trial, a double-blinded, randomized crossover study, represents a unique study, evaluating the safety and efficacy of atomoxetine, a noradrenaline reuptake inhibitor, in patients with progressive supranuclear palsy (PSP) with apathy and impulsivity concerns. With 40 patients recruited thus far across 2 trial sites, the study will also test the hypothesis that behavioral and cognitive outcomes are dependent of baseline integrity of the locus coeruleus noradrenergic system.¹

The outline was presented as a poster at the 2024 International Congress of Parkinson’s Disease and Movement Disorders, held September 27 to October 1, in Philadelphia, Pennsylvania. The study, which evaluates 40 mg atomoxetine (in liquid form) against matched liquid placebo, has a target enrolment of 84 participants to achieve 80% power for primary end points with 10% attrition. Co-primary outcomes are safety and efficacy on a challenging-behaviors subscale of the Cambridge Behavioral Inventory.

Led by Robert Durcan, PhD, a clinical research fellow at the University of Cambridge, the study includes a preliminary staging process, followed by an 8-week treatment period. After this, patients undergo a 2-week washout period, followed by a switch to the crossover drug. The trial excludes those with cardiac arrhythmias, ischemic heart disease, or currently taking a prescription of other noradrenergic treatments.

The idea behind testing a noradrenaline inhibitor has been floated in the movement disorder field for a few years. In 2020, research by several notable physicians showed significantly higher levels of noradrenaline in patients with PSP, similar to controls, in comparison with patients with Parkinson diseas (PD). In contrast, the study also showed that cerebrospinal fluid (CSF) samples in PD were significantly reduced in CSF noradrenaline and its major metabolite, which confirmed that PD is a multi-system disease involving several endogenous pathways.²

In that study, the noradrenaline axis impairments were prominent in PSP featuring worse Neuropsychiatric Inventory (NPI) scores. Investigators concluded that it might represent a counterpart to the early and peculiar psycho-pathological profiles that are observed in tauopathies like PSP. Furthermore, they concluded that early alterations in endogenous noradrenaline machinery in atypical parkinsonism may represent a specific risk train in forms characterized by a worse prognosis.

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The same year, in 2020, research found that degenerarion and tau pathology in the locus coeruleus are related to clinical heterogenetiy of PSP. Published in Acta Neuropathologica Communications, investigators used immunohistochemistry in post mortem tissues from 31 patients with a clinical diagnosis of PSP (22 with Richardson’s syndrome) and 6 control cases. In total, there was an average 49% reduction of pigmented neurons in patients with PSP relative to controls. The loss of pigmented neurons correlated with disease severity, even after adjusting for disease duration and the interval between clinical assessment and death.³

The trial also quantified the presence of hyperphosphorylated tau, the number of pigmented cells indicative of noradrenergic neurons, and the percentage of pigmented neurons with tau-positive inclusions. All told, the degree of neuronal loss was negatively associated with tau-positive inclusions, with an average of 44% of pigmented neurons displaying tau-inclusions. In the study, the average 49% loss of pigmented neurons was highly consistent with the 53% and 51% reduction of medium-to-large neurons in the locus coeruleus reported in 2 previous studies.

"The use of the neuromelanin pigment to identify post mortem the noradrenergic cells in the LC also supports the development of non-invasive in vivo neuroimaging markers that exploit the MRI signal linked to the presence of neuromelanin," senior author James B. Rowe, director of the Cambridge Center for Frontotemporal Dementia and Related Disorders, wrote.³ "The degeneration of the locus coeruleus may be relevant to the development of better stratification procedures in clinical trials. Our study also highlights the importance of considering noradrenergic restoration as a potential treatment for PSP."

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REFERENCES
1. Noradrenaline treatment of apathy and impulsivity in participants with Progressive Supranuclear Palsy syndromes (NORAPS). A Phase II clinical trial – ISRCTN99462035. Presented at: 2024 MDS Congress; September 27-October 1; Philadelphia, PA. ABSTRACT 640.
2. Cerroni R, Liguori C, Stefani A, et al. Increased Noradrenaline as an Additional Cerebrospinal Fluid Biomarker in PSP-Like Parkinsonism. Front Aging Neurosci. 2020;12:126. doi:10.3389/fnagi.2020.00126.
3. Kaalund SS, Passamonti L, Allinson KSJ, et al. Locus coeruleus pathology in progressive supranuclear palsy, and its relation to disease severity. Acta Neuropathol Commun. 2020;8:11. doi:10.1186/s40478-020-0886-0