Progressive supranuclear palsy Nervous System Diseases Progressive supranuclear ophthalmoplegia (Steele-Richardson-Olszewski), progressive supranuclear palsy
Conditions
Interventions
This trial will use a randomised crossover design to compare the effects of 8 weeks oral solution atomoxetine (40 mg taken as 10 ml of 4 mg/ml oral solution once daily) compared to 8 weeks placebo, wi
Sponsors
Cambridge University Hospitals NHS Foundation Trust
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: People with Progressive Supranuclear Palsy (PSP): 1. Have the mental capacity to give informed consent for participation in the study 2. Have a diagnosis of probable or possible Richardson's Syndrome (PSP-RS), PSP with predominant frontal presentation (PSP-F), PSP with predominant speech/language disorder (PSP-SL), or PSP with corticobasal syndrome (PSP-CBS) variant under the International Parkinson and Movement Disorder Society (MDS) criteria. Patients with an initial diagnosis of progressive gait freezing (PGF) but currently presenting as PSP may also be included. 3. Aged between 50 and 85 years 4. Have a ‘research partner’, such as a relative, unpaid or paid carer, or a care home manager, who has a minimum of once-a-week telephone or face-to-face contact and is able, and consents, to provide information on proxy measures 5. Receiving stable psycho-active medications (such as L-DOPA, dopaminergic agonist, anti-cholinergic, amantadine, other anti-parkinsonian medication, anti-depressants, or any other psychoactive medication) for at least 28 days from visit 1 with no ramping up or weaning off medications 6. Able to take part in this study 7. Not pregnant, surgically sterile, or postmenopausal. Premenopausal patients can be included but will undergo pregnancy tests (at screening and at visits 2 to 5) to confirm that they are not pregnant. Surgically sterile is defined as having had a hysterectomy, bilateral salpingectomy, or bilateral oophorectomy at least 6 weeks prior to enrolment. A postmenopausal state is defined as no menses for 12 months without alternative medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a postmenopausal state in women not using hormonal contraception or hormone replacement therapy. However, in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient. Research partner: 1. A minimum of once-a-month face-to-face or telephone contact with the main study participant 2. Able to provide information on proxy measures 3. Aged =16 years
Exclusion criteria
Exclusion criteria: People with Progressive Supranuclear Palsy (PSP): 1. Use of monoamine oxidase inhibitor, SNRI, or other drugs that alter monoamine concentrations (including tricyclic antidepressants with the exception of low dose amitriptyline = 30mg), systemic pressor agents, and any other medication that in the view of the PI would contraindicate participation within 2 weeks of visit 1 2. Use of high dose (>10 mg) systemic steroids (such as prednisolone). Topical steroid and low dose systemic steroid use are acceptable even if taken long term. 3. Presence of significant cardiovascular disease such as ischaemic heart disease, cardiac rhythm abnormalities, or other clinically significant non-ischemic cardio-vascular disease. If at risk, including those with a family history of ischemic heart disease (parent with heart failure at 30 to 50 years) will undergo an electrocardiogram (ECG) at baseline to confirm eligibility. 4. Narrow (acute) angle glaucoma 5. History of, or current, pheocromocytoma 6. Known hepatic or renal failure (ALT or AST over three times reference range and total birulin >2 times the reference range; eGFR 168 mol/l). 7. Presence or history of a medical condition that the PI feels may interfere with the participant’s ability to comply with study instructions, would place the participant at increased risk, or might confound the interpretation of the study results 8. History of cancer within 3 years of visit 1 with the exception of fully excised non-melanoma skin cancers or non-metastatic prostate cancer 9. Presence of significant neurological (other than PSP) or psychiatric disorders including any psychotic disorder, clinically significant depression, suicidal thoughts or behaviour that are believed by the PI to represent a current safety risk (including a seizure within 3 years of visit 1 or history of recurrent seizures) 10. Known presence of a disease-associated mutation in genes known as C9ORF72, GRN, CHMP2B, TBK1, TARBP, or VCP or other frontotemporal lobar degeneration (FTLD) causative genes which are not associated with underlying tau pathology (individuals with MAPT mutations may participate if they meet all other eligibility criteria) 11. Any major surgery within 28 days of visit 1 12. Evidence of organ dysfunction or any clinically significant deviation from normal function in physical examination, vital signs, ECG, or clinical laboratory determinations beyond what is consistent with the target population 13. Recent (in the last month) or current systemic infections (recent vaccination is not an exclusion criteria) 14. Current participation in any other clinical trial of an investigational medicinal product 15. Likely inability to give blood (such as fear of needles, etc.) 16. Insufficient proficiency in English to provide informed consent and to understand task instructions, as assessed by the clinical or study team 17. Body weight outside of the range 40 kg to 120 kg 18. Contraindications for MRI (only applicable for those consenting to MRI) 19. Breastfeeding 20. Any other contraindication to atomoxetine treatment as detailed in atomoxetine SmPC including, but not limited to, hypersensitivity to the active substance or to any of the excipients Research partner: 1. Does not meet inclusion criteria
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| 1. Efficacy measured using the Cambridge Behavioural Inventory Revised Apathy-Impulsivity Composite Score (CBI-R-I) at 0, 8, 10, and 18 weeks 2. Safety assessed using the numbers and percentages of deaths and unique participants with adverse events (AEs) and serious adverse events (SAEs) leading to discontinuation between 0 and 22 weeks 3. Tolerability assessed using the numbers of adverse events (AEs) and adverse reactions (ARs), including serious AEs and ARs between 0 and 22 weeks | — |
Secondary
| Measure | Time frame |
|---|---|
| 1. Global clinical improvement measured using the Clinical Global Impression of Change (CGI-C) at 8 and 18 weeks and the Clinical Global Impression of severity (CGI-S) at 0 and 10 weeks 2. Behaviour and cognition measured using the Cambridge Behavioural Inventory Revised (CBI-R) total score, and Cambridge Questionnaire for Apathy and Impulsivity Traits (CamQUAIT) apathy score completed by the research partner at 0, 8, 10, 18, and 22 weeks 3. Cognitive and behavioural functioning measured using the Connor’s Adult ADHD Rating Scale (CAARS) Short-Form sub scores completed by both the patient and research partner at 0, 8, 10, 18, and 22 weeks 4. Anxiety and depression measured using the patient-rated Hospital Anxiety and Depression Scale (HADS) at 0, 8, 10, 18, and 22 weeks 5. Patient and carer (research partner) quality of life measured using the Progressive Supranuclear Palsy Quality of Life scale (PSP-QoL) at 0, 8, 10, 18, and 22 weeks 6. General measures of cognitive functioning measured using the clinician-rated Repeatable Battery for the Assessment of Neuropsychological Disease Severity (RBANS) which includes verbal fluency) at 0, 8, 10, and 18 weeks Exploratory outcome measures: 1. Cognition measured using the clinician-rated Montreal Cognitive Assessment (MoCA) at 0, 8, 10, and 18 weeks 2. Severity of PSP and disease progression measured using the clinician-rated Progressive Supranuclear Palsy Rating Scale (PSP_RS) at baseline, 0, 8, 10, and 18 weeks 3. Influence of baseline clinical deficit on response to atomoxetine measured using the clinician-rated the Progressive Supranuclear Palsy Clinical Deficits Scale (PSP_CDS) at baseline 4. Executive function is measured using the clinician-rated the Frontal Assessment Battery (FAB) at 0, 8, 10, and 18 weeks 5. Response inhibition is measured using the clinician-rated stop-signal task (SST) at 0, 8, 10, and 18 weeks 6. Influence of genetic variations on response to atomoxetine, including but not limited to, differe | — |
Countries
England, Scotland, United Kingdom
Outcome results
None listed