Atomoxetine to reduce freezing of gait in Parkinson's disease by targeting the brain's noradrenaline system

Pharmacologically Modulating the Noradrenergic Arousal System to Reduce Freezing of Gait in Parkinson's Disease: a Multi-centre and Multi-modal Approach

This trial will test whether the medication atomoxetine can reduce how often or how severely people with Parkinson's disease experience freezing of gait.

Quick facts

• Phase: Phase 3
• Study type: Interventional
• Enrollment: 60 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: Radboud University Medical Center (Academic / other)
• Locations: 1 site (Nijmegen, Gelderland)
• Trial ID: NCT07316296 on ClinicalTrials.gov

What this trial studies

This Phase 3, randomized comparison gives people with Parkinson's disease and daily freezing of gait either atomoxetine or a matching placebo and tracks changes in walking and symptoms over time. Participants visit the study site for clinical measurements, standardized walking assessments, MRI scanning, and questionnaires about anxiety, stress, and quality of life. Participants must be on stable dopaminergic treatment and able to walk 10 meters unaided in the ON state, and study procedures include multi-modal motor and imaging measures to probe noradrenergic involvement. The trial aims to link clinical changes in freezing with brain noradrenaline markers to determine whether modulating that system improves gait.

Who should consider this trial

Good fit: Adults with idiopathic Parkinson's disease who experience daily freezing of gait, are on stable dopaminergic therapy, can walk 10 meters unaided in the ON state, and can undergo MRI and study procedures are ideal candidates.

Not a fit: People with severe cognitive impairment, major comorbidities that limit walking, implanted devices or other contraindications to MRI, or those who do not have daily freezing of gait are unlikely to benefit from participating.

Why it matters

Potential benefit: If successful, atomoxetine could reduce the frequency or severity of freezing episodes and improve mobility and quality of life for people with Parkinson's disease.

How similar studies have performed: Small prior and pilot studies targeting the noradrenergic system with drugs like atomoxetine have shown mixed signals of benefit for gait and attention in Parkinson's disease, but large confirmatory Phase 3 evidence is currently lacking.

Eligibility criteria

Inclusion Criteria:

* Aged 18 years or older;
* Diagnosis of idiopathic PD according to MDS Diagnostic Criteria;
* Stabilised on optimal dopaminergic PD treatment for a minimum of four weeks prior to the baseline visit (Visit 1) and for the duration of the trial;
* Presence of FOG symptoms on a daily basis;
* Ability to walk for 10-meters unaided in the dopaminergic ON-state;
* Ability to provide written informed consent in accordance with ICH-GCP and local regulations;
* Willing and able to undergo all clinical trial assessments.

Exclusion Criteria:

* Current and/or previous (within 3 months) participation in a clinical trial;
* Any contra-indications for undergoing MRI-scanning (e.g. claustrophobia or metal parts within the body such as DBS, an infusion pump or a pacemaker);
* Co-morbidity that significantly impacts ambulation (e.g. orthopaedic or rheumatological ailments);
* Severe cognitive impairment hampering the ability to comply with the study protocol;
* Active psychosis that would impact the ability to comply with the study protocol;
* Severe cardiovascular disorders: severe hypertension (Sustained (Sitting) hypertension of ≥180 mmHg systolic or ≥110 mmHg diastolic, defined by the average of three observations, each at least 3 minutes apart, with the participant having assumed the required position for at least 3 minutes), heart failure, arterial occlusive disease, angina, haemodynamically significant congenital heart disease, cardiomyopathies, myocardial infarction, potentially life-threatening arrhythmias, long QT interval syndrome (QTc \> 500ms Bazett-formula) and channelopathies that in the opinion of the study PI would significantly compromise participant safety;
* Severe cerebrovascular disorders: cerebral aneurysm or recent/significant stroke;
* Hepatic or renal insufficiency that in the opinion of the Principal Investigator would impact on the ability of the participant to safely participate;
* Narrow angle glaucoma;
* (History of) pheochromocytoma;
* Use of noradrenergic agents;
* Use of CYP2D6 inhibitors (SSRIs, quinidine, terbinafine);
* Use of high dose salbutamol (or other beta2 agonists) that in the opinion of the Principal Investigator would impact on the ability of the participant to safely participate;
* Pregnancy and/or breastfeeding;
* Known hypersensitivity to atomoxetine.

Where this trial is running

Nijmegen, Gelderland

• Radboudumc — Nijmegen, Gelderland, Netherlands (Recruiting)

Conditions Parkinson's Disease; Freezing of Gait; Freezing of Gait Symptoms in Parkinson Disease