Objective: The NORAPS Phase II clinical trial seeks to demonstrate safety, tolerability and efficacy of atomoxetine in Progressive Supranuclear Palsy (PSP).

Background: PSP is a degenerative neurological condition with a limited evidence-base for effective treatment. Neuropsychiatric symptoms are common, including apathy and impulsivity. Post mortem data indicates early and severe loss of noradrenergic cells in the locus coeruleus. Noradrenergic deficits are associated with apathy and impulsivity in several diseases, including PSP, and noradrenergic treatments can be effective in Alzheimer’s-associated apathy. Atomoxetine, a noradrenaline reuptake inhibitor, is efficacious against several markers of apathy and impulsivity in experimental medicine studies of PSP and Parkinson’s disease.

Method: Patients with probable or possible PSP, Richardson’s syndrome or cortical variants, are screened for safety before a double-blinded randomised crossover study (minimum 2 week washout between phases), with two 8-weeks periods with 40mg atomoxetine (in liquid form) or matched liquid placebo. Exclusion criteria include cardiac arrhythmias, ischaemic heart disease and co-prescription of other noradrenergic treatments. Participants are invited to baseline MRI scan, with MT-weighted imaging for locus coeruleus integrity at 3T or 7T. Co-primary outcomes are safety and efficacy on a challenging-behaviours subscale of the Cambridge Behavioural Inventory. Secondary and exploratory outcome measures include the PSP rating scale (full and modified forms), response-inhibition paradigm, CGI, HADS, CAARS, CBI-R, RBANS, MOCA, FAB, PSP-QoL and the effects of baseline locus coeruleus variance on drug response.

Results: At the time of submission, 40 patients have been recruited, with two sites open. Four further sites are expected to open within 3 months. Target enrolment is 84 participants, to achieve 80% power for primary endpoints with 10% attrition.

Conclusion: NORAPS tests the hypothesis that atomoxetine is safe and well tolerated in PSP, with benefits on apathy and impulsivity. A secondary hypothesis to be tested is that behavioural and cognitive outcomes are dependent on baseline integrity of the locus coeruleus noradrenergic system. Given locus coeruleus involvement in many neurodegenerative disorders, findings from NORAPS may have broad transdiagnostic validity.

References: Similar abstract submitted to Tau24 (March 2024), and DPUK Translation 2024 (April 2024).

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MDS Abstracts - https://www.mdsabstracts.org/abstract/noradrenaline-treatment-of-apathy-and-impulsivity-in-participants-with-progressive-supranuclear-palsy-syndromes-noraps-a-phase-ii-clinical-trial-isrctn99462035/